CIR ANNUAL REPORT 2014

Transcription

Centre for
Immune Regulation
CIR
ANNUAL
REPORT
2014
RESEARCH GROUPS
PUBLICATIONS
DISSEMINATION
ACTIVITIES
ABOUT
VISION STATEMENT
This centre identifies and
investigates novel mechanisms
of immune dysregulation to
advance the development of
therapeutics.
2
2014
T-B collaboration. Importantly,
dendritic cells are not needed for
such collaboration.
n We described and characterized
Id-driven T B collaboration as a
drive for anti-dsDNA B cells in the
systemic autoimmune disease
Lupus, demonstrating clonal
expansion in lupus-prone mice –
both in terms of BCR sequences
and by demonstrating anti-dsDNA
B cells in functional assays and
flow cytometry.
n Monoclonal antibodies were
cloned from single gluten-specific
plasma cells isolated from coeliac
lesions (Nat Comm 2014). Glutenspecific IgA were found to have
restricted VH/VL usage and limited
numbers of mutations.
n Published an Ig double knock-in
mouse with an anti-Id BCR. Used
this mouse to show that Id-specific
T and B cells can recognize Id+Ig
via conventional mechanisms for
|
ANNUAL REPORT 2014
|
CENTRE FOR IMMUNE REGULATION (CIR)
|
n Increased our understanding
ANNUAL REPORT 2014
of the interaction between the
serum half-life regulating receptor,
FcRn, and albumin. Designed
|
and characterized novel albumin
variants with increased binding to
FcRn that will be used as carriers
of biopharmaceuticals to increase
their serum half-life.
n Defined a role for CCL28-CCR3 in
T-cell homing to the human upper
airway mucosa.
n Showed that a specific Rab,
important in dendritic cells,
interacts with the cytoskeleton and
regulates both actin organization
and cellular migration.
3
DIRECTOR’S
COMMENTS
4
Ludvig M. Sollid
Centre Director
2014 has been an active year for CIR. Perhaps
the most memorable event was when its
members gathered at the end of August for
a retreat at Soria Moria. The three Scientific
Advisory Board members Sirpa Jalkanen,
Søren Buus and Rikard Holmdahl took part in
the meeting. They discussed science with CIR
scientists and they met with group leaders
to advice on scientific matters and priorities
to be made within the Centre. Rudolf Valenta
from Austria gave a keynote lecture, as did
Rikard Holmdahl. The retreat was organised
by an organising committee together with
Anders Sandvik. They did an excellent job
and I thank them for their effort.
There have been a number of scientists who
have visited CIR during the year to give guest
lectures. These include Jacques Neefjes,
Kunchithapadam Swaminathan, Matthew
Collin, Patrick Holt, Ralf Küppers, Yueh-Hsieu
Chien, Ana-Maria Lennon-Dumenil, Gur Yaari
and Gabriel Victora. Most of the speakers
were invited to take part in a seminar series
organised by a postdoctoral committee. I take
the opportunity to thank this committee for
conducting this task which is of immense
importance to CIR.
In my comments from last year I described
the effort we have made to recruit new faculty to CIR. Due to space constraints at the
premises of CIR, the Board of CIR decided that
rather than advertising a full professorship
position, an associate professorship for a junior faculty member should be advertised.
|
ANNUAL REPORT 2014
|
This was done in the autumn of 2014, and 10
applicants had submitted their application by
the deadline. On writing these comments, I
have just learned that the selection board has
submitted their recommendation for the rank
order of the best-qualified applicants. Interviews will be made shortly and a candidate
will be offered the position before the summer. This person then will have the opportunity to work two and half year at CIR before
our Centre is history.
In 2014, CIR scientist authored or co-authored
47 papers in international peer reviewed journals. Two PhD students defended their thesis
in 2014; Synne Jenum and Astrid Tutturen. I
congratulate the candidates and their supervisors. I also thank the opponents for their effort in evaluating the work of our candidates.
CONTENTS
The Research Council of Norway has announced that the forth call in the Centre of
Excellence (SFF-IV) scheme. Applicants will
qualify in a two step application procedure.
The deadline for the first step application
will be in November 2015. My hope is that
the members of CIR will not be too distracted
by this fact and that the inner life of CIR can
continue undisturbed. I know there are many
interesting project running that deserve to
receive our full attention. I hope 2015 will be
an interesting and rewarding year for all the
scientists at CIR.
3
3
4
6
8
12
RESEARCH GROUPS
Bakke group
Bogen group
Jahnsen group
Munthe group
Sandlie group
Sollid group
16
18
20
22
24
26
ABOUT CIR
Facts and figures
30
Funding and expenditures
31
Staff and students
32
Collaboration34
Education and career development
36
Our Visiting Professor programme had visits
from Mark Davis (Stanford) and Susan K.
Pierce (NIAID, NIH) in 2014. In 2015 we expect
revisits from Mark Davis (Stanford) and Bana
Jabri (University of Chicago) as well as a visit
by Bernhard Malissen (Centre d'Immunologie
de Marseille-Luminy, France) who will be a
new Visiting Professor at CIR.
Anders Sandvik left his position as administrative coordinator of CIR. He got an exciting
job offer from industry. I wish Anders the
best of luck in his new job, and thank him
wholeheartedly for the excellent job he did
for us. We have been very fortunate what
regards Anders’ successor – Lise Kveberg. Lise
was working as an experienced postdoc in
a neighbouring group at the Department of
Immunology. Knowing her qualifications we
successfully managed to convince her that
the position as administrative coordinator of
CIR would be a perfect next job station. The
transition has been seamless.
Vision statement
Key accomplishments 2014
Director’s comments
Scientific currency
Innovation and industrialisation
Core competency
ACTIVITIES
Visiting Professor program
40
Minisymposium40
Work package (WP) symposia
41
Guest lectures
42
Internal activities
43
PUBLICATIONS
Papers in scientific journals
46
Other papers
48
Books and book chapters
48
Patents49
DISSEMINATION
Invited lectures
Oral presentations
Poster presentations
Other presentations
Presentations to a targeted audience
and the public
Media coverage
|
ANNUAL REPORT 2014
|
52
53
54
55
55
56
5
Impact factor
distribution – CIR
publications 2014
9%
6%
28%
57%
6
<5
5–10
>10
No IF available
CIR publications
with collaborating
institutions 2014
PAPERS
CIR scientist authored or co-authored 47
papers in international peer-reviewed journals in 2014. The total number of publications per year remains stable. Of the papers
published in 2014, four publications reached
journals with an impact factor above 10.0
and more than one third of the publications
reached journals with an impact factor
above 5.0. In general the quality and visibility of publications from the centre is high.
CIR scientists have extensive collaborations
with national and international research
groups. Close to 6 of 10 papers published in
2014 with one or more CIR authors are the
result of collaborations with international
institutions.
Impact factor distribution and publications
based on collaborations is illustrated in the
figures below. CIR publications in 2014 are
presented on page 4 of this report. National
and international collaborators are listed on
page 4.
19%
53%
19%
9%
International
International and national
PATENTS
Researchers at CIR have a strong interest in,
and record of, innovation and securing of
intellectual property rights from research.
The accumulated number of patents granted
or patent applications filed by CIR scientists
since CIR commenced operations is 28. Read
more in the innovation and industrialisation
section on page 4.
DISSEMINATION OF RESEARCH RESULTS
CIR members gave 32 talks as invited speakers at international scientific meetings in
2014. In addition 12 oral presentations and
20 posters were presented by CIR scientists
at international conferences. Furthermore,
CIR staff gave 25 lectures and articles aimed
at a targeted audience and the general public. These include postgraduate lectures, research seminars, training courses at universities and hospitals, as well as presentations
to patient organisations and professional
organisations. Talks, posters and dissemination activities aimed at a targeted audience
and the public, as well as media coverage,
are listed in the back of this report.
PRIZES AND AWARDS
CIR scientist Inger Sandlie received the
Inven2 honorary award. In 2011, Inger Sandlie was the first to receive UiOs innovation
prize, and now she received an honorary
award for the registration of a total of 100
innovational ideas to Inven2. The prize was
presented at the Cutting Edge/Oslo Innovation Week at Forskningparken in October.
The Oslo University Hospital’s Excellent
Researcher Award 2014 was awarded to CIR
Director Ludvig M. Sollid for his outstanding research on the pathogenesis of celiac
disease. The prize was presented at a staff
meeting in August at Oslo University Hospital, Rikshospitalet.
CONTRIBUTION TO LOCAL RESEARCH
ENVIRONMENT
CIR supports the Norwegian Society for
Immunology (NSI) and has the ambition
to contribute to the whole immunological
research environment in Oslo. CIR members
are collectively members of the NSI and the
centre co-host lectures with the society. Importantly, guest lectures and minisymposia
hosted by CIR are open to anyone interested
and we actively invite the broader immunology community to attend these events.
Furthermore, we also invite researchers
from outside the centre as speakers at these
open events.
Annual Report
2010
Centre staff is involved in the education and
supervision of basic scientists and clinicians
at all levels. CIR scientists have organised or
lectured at graduate courses in molecular
cell biology and immunology including Basic
immunology and immunological techniques
and Advanced immunology offered by the
University of Oslo.
Centre for
Immune Regulation (CIR)
CIR staff manages and operates advanced
technology and share their technical
expertise with the surrounding research
environment. CIR group leader Oddmund
Bakke heads an advanced imaging platform
specialising in subcellular studies of live and
fixed cells. In 2013, the NorMIC-UiO imaging platform opened as a national facility.
CIR group leader Frode Jahnsen is head of
the Confocal microscopy Core facility at the
Department of Pathology, offering services
within confocal laser scanning microscopy.
CIR scientist Gustavo De Souza heads the
Proteomics Core facility at Department of
Immunology. The facility offers advanced
analysis of proteins and peptides by mass
spectrometry.
FOCIS-COE
CIR is a Federation of Clinical Immunology
Societies (FOCIS) Centre of Excellence (FCE)
(www.focisnet.org). The FCEs represents
an exclusive community of institutions of
outstanding clinical and scientific quality.
There are 70 FCE’s worldwide, with approximately 45 centres in North-America and
20 in Europe. The FCE status represents an
international recognition of the quality and
impact of CIR and provides an opportunity
for CIR to strengthen our translational immunology activities.
Above: Oslo 14.10.2014,
Oslo Innovation Week.
Cutting Edge: Inger Sandlie,
winner of Inven2 Ærespris
2014. Photo: Gorm K. Gaare.
Top: Edward Leithe, Institutt
for kreftforskning (Early
Career Award 2014)
Ludvig M. Sollid, Avdeling for
immunologi og transfusjonsmedisin (Excellent Researcher Award 2014)
Kyrre Eeg Emblem, Intervensjonssenteret (Early
Career Award 2014)
Photo: Ram Gupta/OUS
Professor emeritus Per Brandtzæg was
awarded the Nordic Fernström prize 2014
for his major contribution throughout his
career to the understanding of the role and
function of the immune system in the intestinal mucosa.
National
CIR-only
ANNUAL REPORT 2014
|
|
ANNUAL REPORT 2014
|
IR
n tr
e fo
Ce
|
7
lat
r Immune Regu
i
SCIENTIFIC
CURRENCY
Cinzia Progida was awarded the Research
prize from Lab Norge 2014 for her work
on molecular mechanisms for intracellular
transport. This prize is given to stimulate
young scientists below 35 years.
INNOVATION AND
INDUSTRIALISATION
8
VACCIBODY AS
Two of the CIR groups (Bogen and Sandlie)
have developed novel vaccine molecules,
known as Vaccibodies, which induce superior immune responses in a variety of
animals. A spin-out company, Vaccibody AS,
was founded in 2007 based on the patented
technology. Vaccibodies target antigen presenting cells for efficient delivery of antigen
and induction of immune responses. The
vaccines are delivered as DNA plasmids
administered intramuscularly or intradermally. The muscle or skin cells produce
and secrete Vaccibody proteins that target
antigen presenting cells and load them with
antigen for presentation to lymphocytes.
The patent portfolio is continuously
strengthened with clinical use and novel
targeting units for a variety of applications.
In 2014 the European Patent Office granted
European patent No. 1599504 and the U.S.
Patent Office issued patent No. US 8,932,603
B2, covering the Vaccibody format. The patent protects Vaccibody’s platform technology on which the company has based its lead
human drug candidate VBV1016, as well as
a license agreement with the Phibro Animal
Health Corporation, covering vaccines for
poultry. The company has made significant
progress with VBV1016, a therapeutic vaccine against cervical pre-cancerous lesions,
and plans to initiate its first clinical trial in
2015. Vaccines for other indications within
cancer and infectious diseases for human
and veterinary use are also developed with
academic and industrial partners. In July
2014, Vaccibody issued new shares for 35
million NOK. An investment by the Norwegian Cancer Society was instrumental in the
process.
|
ANNUAL REPORT 2014
|
NEXTERA AS
Phage display is the dominating technology for discovery and refinement of novel
protein-based diagnostics and therapeutics.
A significantly improved version termed SSIp
display has been developed by the Sandlie
group at CIR, and commercialized by a spinout company, Nextera AS. Nextera was established by key inventor CIR scientist Geir Åge
Løset and Biomedical Innovation AS, and Geir
Åge Løset has been the Chief Scientific Officer
since the company was established in 2009.
Additional jointly developed IPR was aquired
from Affitech AS in 2012 and Nextera has
furthermore inlicensed innovations related
to MHC class II through Inven2. These were
jointly developed by the Sandlie and Bogen
groups at CIR. Through 2013, Nextera were
granted patent rights to W02009/024591,
WO2010/097411, WO2010/097589,
WO2011/036555 and WO2011/101681. The
technology platform is continually strengthened and national IPR was granted in several
major countries in 2014.
The core activity of the company is presently focused on phage display of T cell receptors and MHC class II molecules, socalled
Phagemers.
Nextera AS is performing joint research
with the Sollid and Sandlie groups at CIR
partially funded by a major NRC BIA grant
using Phagemers with the aim of developing
novel therapeutics for Crohns disease. In
2013 Nextera raised 550 000€ in private
equity which secures continuous funding of
research activities, as well as strengthening
the Board of Directors, management and
R&D team.
9
EXTENDING IN VIVO HALF-LIFE
OF SMALL DRUGS
The efficacy of chemical drugs, peptides,
small proteins and engineered antibody
fragments are hampered by short serum
half-life, ranging from minutes to a few
hours. Therefore, strategies to tailor their
serum persistence and biodistribution
are needed. Inger Sandlie and Jan Terje
|
ANNUAL REPORT 2014
Andersen have developed a unique technology that may extend the in vivo half-life of
potentially all chemical and protein drugs.
This will ultimately result in drugs with stabilized serum levels, which means less side
effects and less frequent dosing. Together
with Inven2, they have signed agreements
with Novozymes Biopharma, and together
with Novozymes, established a very success
|
Human FcRn
His 161
His 166
ful research program. So far, six patent families have been filed by Novozymes based on
the results of the collaborative research.
10
As a result of this collaboration, Novozymes
has launched new products initially named
Albufuse Flex and Recombumin Flex, and
recently the Veltis® technology. In short,
the new products are based on a list of new
albumin variants. All have one or more amino acids that differ from normal albumin.
They bind the neonatal Fc receptor with a
range of different affinities, and when tested
in rats and rhesus monkeys show greatly
altered half-life. The best binders have
increased and the poorest binder decreased
half-life. Now, either genetic fusion (peptide
or protein) or chemical conjugation of small
drugs to either of these albumin variants
will greatly alter the serum half-life of the
drug. In 2013 and 2014, new albumin variants have been designed with increased
half-life beyond that of earlier versions.
Novozymes presents the technolgy as
follows:
• Veltis® – engineered albumins for optimized drug dosing
• Veltis® enables you to control dose
frequency, drug tolerability and dose
quantity. So, now you can optimize your
therapeutic window easily, and naturally.
Novozymes Veltis® is a half-life extension
platform based on engineered albumins
designed to provide once-weekly, once twoweekly or once-monthly peptide or protein
dosing and stricter patient adherence (compliance) for improved therapeutic impact.
In addition to being developed by
world-leading science the technology is also
backed up by the deep technical and regu-
|
ANNUAL REPORT 2014
|
latory support available from Novozymes.
Furthermore, based on Novozymes'
decades-long experience of recombinant
albumin GMP manufacturing, the access
to large-scale yeast expression and protein
production ensures a secure route to commercial exploitation of the system.
The unique advantages provided by Veltis®
include:
• proven clinical performance with significant half-life extension improvement over
native albumin and other technologies
• flexible and scalable manufacturing by fusion or conjugation for commercial supply
• long life IPRs
• patient-friendly dosing and low risk of
adverse effects
• provided by a technology developer with
a strong heritage and track record in commercial albumin supply
Copenhagen, Denmark – 13 March 2014 –
Novozymes Biopharma, part of Novozymes
A/S, a world leader in bioinnovation, has
today announced a collaboration with Janssen Research & Development, LLC (Janssen).
The agreement will enable Janssen to evaluate Novozymes Biopharma’s engineered
albumin-based VELTIS™ technology for
potential drug candidates.
Novozymes Biopharma has entered a new
collaborative research agreement with one
of the world’s top vaccine companies. The
partnership will enable the company to
evaluate Novozymes Biopharma's modified recombinant human albumin VELTIS
technology to assess the dosing and performance of a novel subunit antigen vaccine
candidate.
Copenhagen, Denmark – 31 March 2014
– Novozymes Biopharma DK A/S, a subsidiary of Novozymes A/S, a world leader
in bioinnovation, has announced that its
albumin-based VELTIS half-life extension
technology is being used by GlaxoSmithKline in the recently authorized Eperzan®
(albiglutide) for the treatment of type 2
diabetes in Europe.
Trp 51
Trp 59
Trp 61
Val 52
Trp 53
The US Food and Drug Administration
(FDA) has granted marketing approval to
GlaxoSmithKline's new type 2 diabetes drug,
branded Tanzeum in the US and Eperzan
in Europe, which uses Novozymes' Veltis
technology to achieve an extended half-life
that means patients are only required to
inject their medication once a week. The
FDA approval follows GlaxoSmithKline's
announcement in March that albiglutide
received marketing authorization in Europe.
Rat FcRn
Glu 163
PATENTS
Patents and filed patent applications by CIR
scientists are listed on page 6.
His 168
Trp 51
Trp 59
Trp 61
FcRn regulates serum half-life of albumin and IgG.
Comparison of human and rat FcRn crystal structures.
The residues shown are involved in albumin binding.
The tryptophan residues shown in red make hydrophobic
contacts with albumin. Histidine 166 in human and histidine
168 in rat FcRn regulate the pH dependence of the
interaction. Illustration: Kine M.K. Sand.
Modified by Millimeterpress with permission.
|
ANNUAL REPORT 2014
Ile 52
Trp 53
|
11
CORE
COMPETENCY
AT CIR
12
• A wide variety of cellular and humoral
immune assays.
• Advanced methods in molecular biology,
proteomics and cellular imaging.
• Disease models in humans and animals.
The models are used to understand the
molecular mechanisms of immune regulation and autoimmunity.
• Transgenic mouse models.
• Functional characterisation of immune
cells in human tissue.
• Study of immune molecules and their
intracellular functions in antigen presenting cells.
• Molecular engineering for the development of new therapeutic agents and
research reagents.
ANNUAL REPORT 2014
SANDLIE GROUP
• Structure and ligand
binding properties of
antibodies and T-cell receptors
• Phage display
• Recombinant molecule
expression and purification
• Interaction studies
JAHNSEN GROUP
• Human model of
airway allergy in vitro
and in vivo
• Mucosal antibody system
• Dendritic cells
• Immunohistochemistry
• Flow cytometry
13
CIR
SOLLID GROUP
• Human cellular
immunology
• In vitro study of CD4+ T cells
• Recombinant soluble
HLA molecules
• Mass spectrometry and
proteomics
• Characterisation of
lymphocyte antigen
receptors
MUNTHE GROUP
• Cellular assays
• Mouse experiments
including xenograft
• Cell culture,
functional biology
• Flow cytometry
|
BAKKE GROUP
• Live cell Imaging
• Confocal microscopy
• Characterisation of intracellular
trafficking pathways
• Transfection of cells and
the study of binding kinetics
of cytosolic molecules
|
BOGEN GROUP
• Cellular immunology
• Experimental studies
in mice
• Transgenic mice
The centre consists of research groups with
complementary scientific expertise. Two groups,
headed by Inger Sandlie and Oddmund Bakke,
are affiliated with the Department of Biosciences
at the Faculty of Mathematics and Natural
Sciences. Three research groups, headed by
Bjarne Bogen, Ludvig A. Munthe and Ludvig
|
ANNUAL REPORT 2014
Sollid are affiliated with the Department of
Immunology at the Faculty of Medicine. One
group, headed by Frode L. Jahnsen, is a member
of the Laboratory for Immunohistochemistry and
Immunopathology, Department of Pathology, at
the Faculty of Medicine.
|
14
RESEARCH
GROUPS
|
ANNUAL REPORT 2014
|
15
|
ANNUAL REPORT 2014
|
BAKKE
GROUP
16
Our group has since
the early nineties
aimed to understand
the endocytic pathway
and how peptide
loading of the MHC
class II complexes
(MHC II) is regulated.
A special focus for the
group is to elucidate
the contribution of the
invariant chain (Ii) to
the biogenesis of an
antigen presenting
cell (APC) specific
endocytic pathway
(Landsverk et al., 2009,
2011, 2012).
OVERVIEW OF RESEARCH IN THE GROUP
Invariant chain (Ii) plays a vital role in MHC
II assembly and intracellular transport, but
has been attributed an increasing number of
additional functions in both antigen presentation, cell signalling and as a vehicle for
loading antigens in immunisation protocols.
An evolutionary conserved property of Ii
is to induce the convergence, or fusion of
early endocytic vesicles, and this property
may serve vital functions in antigen presentation, cell signalling and beyond. Furthermore we study the influence of other
regulatory molecules essential for the antigen loading compartment such as the small
GTP-ases (Berg-Larsen et al., 2013, Borg et
al., 2014). The group consist of 2 researchers, 2 postdocs, 2 PhD students, 4 master
students and 2 technicians. The Bakke
group also runs the NFR- INFRASTUCTURE
supported Norwegian Molecular Imaging
Consortium, NorMIC-Oslo. NorMIC-Oslo
opened as a national imaging facility in 2013
and was in 2014 recommended to become
an Eurobioimaging node in a pan European
network of imaging nodes.
KEY PROJECT SUMMARIES
• The group is focusing on the properties of
the endosomal pathway in cells in general
and the adaptations to this pathway in
immune cells. The projects can be divided
into five sub themes:
• Sorting and trafficking of immune molecules in model cell lines and in dendritic
cells.
• Regulation of vesicular transport between
the Golgi network and the endosomal and
auophagosomal pathway searching for
new players.
|
ANNUAL REPORT 2014
|
Oddmund Bakke
• Study of endosomal maturation and how
the antigen loading compartment, the
immunoendosome, is formed.
• Regulation of receptor signalling by
endocytic sorting and endosomal effector
kinetics in the endosomal pathway.
• Investigation of the mechanisms by which
activated macrophages kill cancer cells in
mice and humans.
Our work is primarily focused on understanding the process of antigen uptake,
processing and presentation. These events
are instrumental to the initiation and propagation of adaptive immune responses. The
endocytic pathway common to all cells is
uniquely adapted by specific immune cells
to achieve this purpose. In order to achieve
our ultimate goals with regard to discovering the specifics of immune cell functions,
we have invested a large body of research
on how the endocytic pathway functions in
general in model cell systems. We have contributed to the current understanding of cell
biological processes in the endocytic pathway in general and our current goal is to
use this foundation to elucidate the unique
adaptations to this system in antigen-presenting cells. This will provide the basis to
better understand vaccination regimes and
protocols for immune therapy of cancers,
autoimmune-, and infectious diseases.
Our main strategy employs a wide array
of advanced live cell imaging technologies,
supplemented by biochemistry, immunological assays and DNA/RNA techniques. The
group collaborates in studies within CIR,
where we provide the cell biological outlook
and essential microscopy expertise. These
include:
• Uptake and sorting of targeted antigen
(Bogen).
• B lymphoma cells with complementary
BCRs delete each other in vitro (Jacobsen/
Bogen)
• Intracellular trafficking of the FcRn receptor (Andersen/ Sandlie)
CENTRAL PUBLICATIONS IN 2014
Borg M, Bakke O, Progida C (2014) A novel
interaction between Rab7b and actomyosin
reveals a dual role in intracellular transport
and cell migration. J Cell Sci.;127:4927-39
Knudsen Sand KM, Landsverk OJ, BergLarsen A, Bakke O, Gregers TF. (2014) The
human-specific invariant chain isoform
Iip35 modulates Iip33 trafficking and function. Immunol Cell Biol. 2014 92:791-798.
Wälchli S, Kumari S, Fallang LE, Sand KM,
Yang W, Landsverk OJ, Bakke O, Olweus
J, Gregers TF (2014) Invariant chain as a
vehicle to load antigenic peptides on human
MHC class I for cytotoxic T-cell activation.
Eur J Immunol. 44, 774-84.
|
ANNUAL REPORT 2014
ACHIEVEMENTS IN 2014
• Showed that a specific Rab, important
in dendritic cells, interacts with the
cytoskeleton and regulates both actin
organization and cellular migration (J Cell
Science, 2014).
• Described how the human specific form
of invariant chain may influence the trafficking of other forms of the molecule and
thereby trafficking of MHC II (Immunol
and Cell Biol, 2014).
• Developed a patented and invariant chain
based vector for immune therapy against
cancer (Patent submitted).
AMBITIONS FOR 2015
• Dissect elements of the molecular mechanisms for sorting to the intracellular antigen loading compartment based on high
throughput antigen loading screens.
• Using an autophagosomal interaction
partner of Rab7B we will elucidate how
autophagy is connected to transport from
the trans Golgi network.
• Characterise endosomal maturation in
dendritic cells and the Meljuso model antigen presenting cells. Define a pathway
to the MHC II antigen loading compartment.
|
17
BOGEN
GROUP
18
The Bogen group
runs projects with
three areas,
1) Idiotype-driven
T-B collaboration
and its role in health
and disease,
2) The mechanism by
which CD4+ T cells
can reject cancer cells,
3) Novel vaccine
molecules for cancer
and infectious
diseases (organized in
K.G. Jebsen Centre for
Research on Influenza
Vaccines).
INTRO
Immunoglobins (Ig, antibodies) are extremely diverse, the heterogeneity being
localized to their variable (V) regions. Bogen
and co-workers showed more than 25 years
ago that Ig is partially broken down inside
cells and that proteolytic fragments of the
V-regions [Idiotypic (Id)-fragments] are presented on Major Histocompatibility Complex
(MHC) class II molecules to Id-specific CD4+
T cells. This phenomenon forms the foundation for the CIR-related projects of the
research group, outlined below.
The basis for Id-driven T-B collaboration
is that B cells spontaneously degrade their
Ig-receptor for antigen (BCR), and display
Id-peptides bound to MHC class II molecules
on their cell surface. Such Id/MHCII complexes can be recognized by Id-specific CD4+
T cells. Now, if a B cell happens to recognize
a self-antigen with its BCR, and at the same
time receives help from an Id-specific CD4+
T cell, the B cell receiving these two distinct
signals will be activated, proliferate and
differentiate. This may result in immune
dysregulation, autoimmunity and B lymphoma development. To study Id-driven T-B
collaboration in even more detail, we have
generated novel BCR knock-in mice. In one
of these strains, a mutated Id-sequence (3
amino acids) have been successfully inserted
in a germ-line V gene segment. The latter
mouse should represent a close to physiological model for Id-driven T-B collaboration. A project on elucidation of the ternary
Id-specific TCR/Id-peptide/MHC class II (I-Ed)
molecule is in progress (with Inger Sandlie).
Id-driven T-B collaboration is now being
|
ANNUAL REPORT 2014
|
Bjarne Bogen
extended to human autoimmune disease
and lymphoma development in collaboration
with Ludvig Munthe (see his report)
The basis for the tumor immunological
experiments of the group is that Ig secreted
by multiple myeloma cells (malignant
plasma cells) is processed and presented on
MHC class II molecules of tumor-infiltrating
macrophages. An interplay between Id-specific CD4+ T cells and macrophages results
in activation of macrophages that in turn
kill the tumor cells. In 2014 we have reported that the above described mechanism
does not confer bystander killing of antigennegative tumor cells. Moreover, we have
detected a mechanism by which tumor cells
can escape killing by CD4+ T cells. Ongoing
experiments focus on the molecular mechanisms by which activated macrophages kill
tumor cells. A bone-marrow model for
multiple myeloma (the MOPC315.BM
model), published by our group in 2012,
has now been distributed to a large number
(>20) collaborators world-wide. Our group
is doing work in this model, and we have
demonstrated that CD4+ T cells can kill
tumor cells residing in the bone marrow.
Internationally, it is now increasingly recognized that CD4+ T cells play an important
role in rejection of tumors, also in humans.
Jacobsen J, Haabeth OA, Tveita AA, Schjetne
KW, Munthe LA, Bogen B.Naive idiotope-specific B and T cells collaborate efficiently in
the absence of dendritic cells. J Immunol.
2014 ,192(9):4174-83. PMID: 24706724
Tveita AT, Schjesvold FM, Sundnes O,
Haabeth OAW, Haraldsen G, Bogen B. Indirect CD4+ T cell-mediated elimination of
MHC IINEG tumor cells is spatially restricted
and fails to prevent escape of antigen-negative cells. Eur. J. Immunol, Sep; 44(9): 262537. PMID: 24846412
Ruffini PA, Os A, Dolcetti R, Tjonnfjord GE,
Munthe LA, Bogen B. Targeted DNA vaccines eliciting crossreactive anti-idiotypic
antibody responses against human B cell
malignancies in mice. Journal of Translational Medicine. Jul 25;12:207, 2014, PMID:
25059102
Fossum E, Grødeland G, Terhorst D, Tveita
AA, Vikse E, Mjaaland S, Henri S, Malissen
B, Bogen B. Vaccine molecules targeting Xcr1
on cross-presenting DCs induce protective
CD8+ T-cell responses against influenza
virus. Eur J Immunol Nov 20 doi:10.1002/
eji.201445080 [Epub ahead of print] PMID:
25410055
• Published an Ig double knock-in mouse
with an anti-Id BCR. Used this mouse to
show that Id-specific T and B cells can
recognize Id+Ig via conventional mechanisms for T-B collaboration. Importantly,
dendritic cells are not needed for such
collaboration.
|
ANNUAL REPORT 2014
• Established an Ig VH knock-in mouse
that, when bred with 2315-transgenic
mice, establishes a model for an Id+ BCR.
• Established a knock in mouse where 3
mutated amino acids have replaced 3
germline-encoded residues in a V gene
segment. This is the first time such a
knock-in has been generated. The mouse
should be an important tool for studies on
Id-driven T-B collaboration.
• Published that the CD4+ T cell/macrophage mechanism for tumor cell killing
does not confer elimination of antigennegative tumor cells.
• Detected a molecular mechanism by
which tumor cells can escape elimination
by CD4+ T cells/macrophages.
AMBITIONS FOR 2015
• To investigate the importance of BCR-ligation by self-antigen in Idiotype-driven T-B
collaboration, using the new BCR knockin mice described above.
• To study interaction of B cells with complementary BCRs by use of the knock-in
mice generated in 2014.
• To explore the molecular mechanism by
which CD4+ T cells reject tumour cells.
• To study CD4+/macrophage-mediated
elimination of tumor cells in the bone
marrow.
|
19
JAHNSEN
GROUP
We study the
mucosal immune
system in the human
gut and airways both
under homeostatic
conditions and
during inflammation.
20
The turn-over rate of immune cells in the
human body is an important characteristic
of their function. However, surprising little
is known about the turn-over and longevity of human immune cells. In collaboration with surgeons at the hospital we have
established several new methods to study
the longevity of immune cells in various
human tissues, both during homeostasis
and inflammation.
By isolating cells from surgical specimens
(cancer surgery and transplanted patients)
we have been able to perform detailed characterization of immune-cell subsets (B cells,
macrophages and dendritic cells) in the
human small intestine and determined their
phenotypic characteristics, their differentiation, longevity and replacement kinetics.
Such studies have never before been performed in humans. We show that proinflammatory monocytes are constantly recruited
to the intestinal mucosa and that they over
weeks differentiate into anti-inflammatory
macrophages. All subpopulations of intestinal dendritic cells are constantly being
replaced by their precursors in blood with a
very rapid turnover rate. Together, our results demonstrate that mononuclear phagocytes in the human gut consist of many
functionally distinct subsets. Importantly,
we find that plasma cells in the gut are
very long-lived (>> 1 year). This finding is
surprising and may have important implications for future vaccinations strategies.
|
ANNUAL REPORT 2014
|
Frode Jahnsen
Lymphocyte recruitment to peripheral
tissues is fundamental for immune surveillance and homeostasis, but the chemokines
and chemokine receptors responsible for
tissue-specific homing of T cells to the upper
airway mucosa have not been determined.
We found that CCL28 is preferentially expressed on endothelial cells in the mucosa
and its receptor CCR3 is expressed on the
majority of mucosal T cells. Functional studies indicate that CCL28-CCR3 interactions
are involved in the homeostatic trafficking
of CD4(+) T cells to the upper airways.
In an experimentally-induced human model
for allergic rhinitis we find that CD14+
monocytes are rapidly (within hours) recruited to the nasal mucosa in response to
allergen challenge in allergic patients. By
transcriptomic profiling we find that mononuclear phagocytic cells in the challenged
nasal mucosa produce several Th2-associated chemokines during the inflammatory reaction, suggesting that these cells, including
monocytes, are central players as proinflammatory cells in upper airway allergy recruiting and activating Th2 cells and eosinophils.
Melum GR, Farkas L, Scheel C, Van Dieren B,
Gran E, Liu YJ, Johansen FE, Jahnsen FL, Baekkevold ES (2014). A thymic stromal lymphopoietin-responsive dendritic cell subset
mediates allergic responses in the upper
airway mucosa. J Allergy Clin Immunol 134
(3), 613-621.e7
A role for CCL28-CCR3 in T-cell homing
to the human upper airway mucosa. Danilova E, Skrindo I, Gran E, Hales BJ, Smith
WA, Jahnsen J, Johansen FE, Jahnsen FL,
Baekkevold ES. Mucosal Immunol. 2015
Jan;8(1):107-14. doi: 10.1038/mi.2014.46.
Epub 2014 Jun 11.
AMBITIONS FOR 2015
• Study the blood monocyte compartment
in experimentally-induced celiac disease.
• Functional characterization of monocytes,
macrophages and dendritic cells in the
human small intestine.
• Explore the relationship of immune cells
and stromal cells in experimentally-induced allergic rhinitis.
• Explore the relationship of immune cells
and stromal cells in active celiac disease.
• Determine the longevity of resident memory T cells in the human small intestine.
• Identified monocytes as a central component of the inflammatory process in
allergic rhinitis
• Determined plasma-cell subsets and their
longevity in the human small intestine.
• Determined the half-life of monocytes,
macrophages and dendritic cells in the
human small intestine
• Defined a role for CCL28-CCR3 in T-cell
homing to the human upper airway
mucosa.
Jenum S, Grewal HM, Hokey DA, Kenneth
J, Vaz M, Doherty TM, Jahnsen FL, TB Trials
Study Group (2014). The frequencies of IFNγ+IL2+TNFα+ PPD-specific CD4+CD45RO+
T-cells correlate with the magnitude of the
QuantiFERON® gold in-tube response in a
prospective study of healthy indian adolescents. PLoS One 9 (7), e101224
|
ANNUAL REPORT 2014
|
21
MUNTHE
GROUP
22
We study B cell biology
in health, autoimmunity
and cancer. As
most B cell cancers
have autoreactive
specificities, the
autoimmunity and
cancer studies are
closely linked. We
have progressed to
study how Th cells in
patients can maintain
autoimmune B cells
as well as lymphoma
cells.
We are interested in how Th cells can
regulate B cell responses, both in health, in
autoimmunity and after malignant transformation. Our goal is to define the specificity
of Th cells, the mechanisms of collaboration,
to pinpoint targets for pharmacological
interventions and to study heterogeneity
between patients. We have made important
contributions to explain the pathogenesis
of CLL and would very much like to extend
these results to Multiple Myeloma.
We have the following research questions:
• How can Idiotype-specific Th cells drive
autoimmune B cell responses?
• How can Th cells drive the proliferation of
human lymphoma?
• What is wrong with BCR signalling in
CLL?
• What is the drive for myeloma proliferation in human patients?
• How can we identify which drugs can
abrogate lymphoma and myeloma proliferation?
• What allows reversal of B cell anergy in
CLL and reversal of anergy in anergic B
cell subsets in normals?
Aas-Hanssen, K., A. Funderud, K.M. Thompson, B. Bogen, and L.A. Munthe. 2014.
Idiotype-specific Th cells support oligoclonal expansion of anti-dsDNA B cells in
mice with lupus. Journal of immunology
193:2691-2698.
|
ANNUAL REPORT 2014
|
Ludvig A. Munthe
Jacobsen, J., O.A. Haabeth, A.A. Tveita, K.W.
Schjetne, L.A. Munthe, and B. Bogen. 2014.
Naive idiotope-specific B and T cells collaborate efficiently in the absence of dendritic
cells. Journal of immunology 192:4174-4183.
• We described and characterized Id-driven
T B collaboration as a drive for anti-dsDNA B cells in the systemic autoimmune
disease Lupus, demonstrating clonal
expansion in lupus-prone mice – both in
terms of BCR sequences and by demonstrating anti-dsDNA B cells in functional
assays and flow cytometry. Aas-Hanssen
et al, The Journal of Immunology 2014.
• We demonstrated a novel pathway for expansion and support of chronic lymphocytic leukemia (CLL) cells from patients,
Bürgler et al, The Journal of Immunology
2014. CLL patients have T helper (Th) cells
of the Th1, IFN-g secreting type that are
specific for CLL cell antigen. When mixed,
we show that Th1 cells activate CLL cells
in an IFN-g dependent manner and that
IFNg activates the T-Bet transcription
factor in CLL cells. With ChIP-analysis and
qPCR we identify T-Bet consensus sites in
intron I of the CD38 gene, demonstrating
a IFNG-JAK- T-bet -CD38 axis. Blocking
IFNG-g in xenograft experiments abrogated proliferation of cancer cells. We
thereby link Th cell activation, cytokine
profile and CLL cell response to the CD38
marker that is important for prognosis in
the patient group. We also demonstrated
that Th cells activate CLL cells to secrete
pro-inflammatory chemokines, further
attracting CLL cells.
• We extended the network of sample collection to South Eastern Norway, adding
to our biobank collection.
• We published with the Bogen group on
the utility of Vaccibodies in CLL (Ruffini et
al, J Transl Med, 2014), on Id-dependent
Th B cell collaboration (Jacobsen et al,
The Journal of Immunology 2014) and on
FAM46 gene variants predisposing to M
tuberculosis (Etokebe et al, PlosOne 2014).
We contributed to papers to be published
in early 2015.
• We published 8 clinical immunology
papers (Bazso et al., 2014; Bodolay et al.,
2014; Laczik et al., 2014; Nakken et al.,
2014; Senolt et al., 2014; Szodoray et al.,
2014; Vincze et al., 2014; Zold et al., 2014)
• We obtained funding from the Health Region South East to initiate a Personalized
Medicine initiative for CLL and myeloma
in 2015 (Kjetil Tasken, Geir Tjønnfjord;
Miljøstøtte, 9 million NOK).
• We achieved long term culture of CLL
cells ex vivo from patients, implemented
multiplexed phosphoflow in our analyses
• We initiated collaborations with two biotech companies.
• We will define how a small molecular
pathway inhibitor can have effect on CLL
cells and not normal B cells, pinpointing a
treatment strategy in this disease.
• We will demonstrate how primary myeloma cells from patients can be stimulated
to proliferate in vitro and in vivo.
• We will succeed in establishing ex vivo
culture of human primary myeloma cells.
• We will define how EBV infection may
play a part in disease progression in CLL.
• We will initiate a high throughput drug
screen for CLL (ex vivo culture).
AMBITIONS FOR 2015
• We will characterize allelic inclusion,
exclusion and exchange of VL and VH of
anti-dsDNA B cells in Lupus mice.
• We will present bioinformatics analyses
of Th cell antigens in murine Lupus.
• We will define the mechanism for how B
cell anergy is reversed in human anergic
B cells, suggest novel druggable targets.
|
ANNUAL REPORT 2014
|
23
SANDLIE
GROUP
24
The Sandlie group
studies the structure
and function of
antibodies and T-cell
receptors, the specific
detecting molecules of
the adaptive immune
system. The purpose
of the work is to
engineer antibodies
and antibody derived
molecules to be used
in therapy and as
research reagents.
Furthermore, one antibody receptor, the
neonatal Fc receptor (FcRn), also binds albumin, and we study how FcRn binding regulates the serum half life and biodistribution
of albumin and molecules bound to albumin.
We focus on two projects: A) Studies of the
interaction between Fc receptors, and in
particular FcRn, with IgG subclasses and
albumin. Key questions are how ligand binding elicits antibody effector functions and
regulate biodistribution and serum half-life.
B) Selection of antibodies for the detection
of complexes between antigenic peptides
and HLA molecules, as well as peptide – HLA
complexes for detection of specific T-cell
receptors. The focus is on engineering to
increase stability and affinity for molecules
that are characteristic of disease models in
groups at CIR.
Proteins in blood are short lived and normally degrade within a few hours or days,
but the two most abundant proteins, IgG and
albumin, are rescued from degradation and
have half-lives of three weeks. The rescue
mechanism depends on their interaction
with the neonatal Fc receptor (FcRn), and
it is crucial to understand how FcRn rescues IgG and albumin, and to transfer long
half-life to therapeutics, using the same
mechanism. We have worked in collaboration with Novozymes Ltd, UK, who has filed
several patent applications and developed
the Veltis® technology, a set of human albumin variants designed by us with greatly
increased binding affinity for FcRn. Biopharmaceuticals fused to a new albumin variant
|
ANNUAL REPORT 2014
|
Inger Sandlie
can have half-life of months, which will
decrease dose, dozing frequency and toxic
side effects. In 2014, we reported on the fine
mapping of the albumin FcRn interaction.
To ask questions regarding the nature of the
antigen presenting cell, the location and rate
of antigen presentation and the interaction
with T cells, specific detection molecules are
needed. Specific antibodies and soluble T-cell
receptors are new tools for such studies in
health and disease. We have explored how
phage display may be used to improve the
affinity of antibodies and the stability and
affinity of soluble T-cell receptors and MHC
class II molecules. We have displayed not
only soluble T cell receptors, but also MHC
class II molecules, so-called “Phagemers”,
which will be used as diagnostics for coeliac
disease. Furthermore, a spin-out company,
Nextera AS, commercialises and develops
the new phage display- and Phagemer technologies, and utilizes libraries of Phagemers
to search for disease causing proteins that
drive pathological T cell activation in autoimmune diseases and chronic infections.
Hallstensen RF, Bergseth G, Foss S, Jæger S,
Gedde-Dahl T, Holt J, Christiansen D, Lau
C, Brekke OL, Armstrong E, Stefanovic V,
Andersen JT, Sandlie I, Mollnes TE. Eculizumab treatment during pregnancy does
not affect the complement system activity
of the newborn. Immunobiology. 2014 Nov
13. pii: S0171-2985(14)00228-9. doi: 10.1016/j.
imbio.2014.11.003.
Sand KM, Bern M, Nilsen J, Dalhus B, Gunnarsen KS, Cameron J, Grevys A, Bunting K,
Sandlie I, Andersen JT. Interaction with both
domain I and III of albumin is required for
optimal pH-dependent binding to the neonatal Fc receptor (FcRn). J Biol Chem. 2014
Dec 12;289(50):34583-94. doi: 10.1074/jbc.
M114.587675. Epub 2014 Oct 24.
Sand KM, Dalhus B, Christianson GJ, Bern M,
Foss S, Cameron J, Sleep D, Bjørås M, Roopenian DC, Sandlie I, Andersen JT. Dissection
of the neonatal Fc receptor (FcRn)-albumin
interface using mutagenesis and anti-FcRn
albumin-blocking antibodies. J Biol Chem.
2014 Jun 13;289(24):17228-39. doi: 10.1074/
jbc.M113.522565. Epub 2014 Apr 24.
Andersen JT, Dalhus B, Viuff D, Ravn BT,
Gunnarsen KS, Plumridge A, Bunting K,
Antunes F, Williamson R, Athwal S, Allan
E, Evans L, Bjørås M, Kjærulff S, Sleep D,
Sandlie I, Cameron J. Extending serum halflife of albumin by engineering neonatal Fc
receptor (FcRn) binding. J Biol Chem. 2014
May 9;289(19):13492-502. doi: 10.1074/jbc.
M114.549832. Epub 2014 Mar 20.
• Increased our understanding of the
interaction between the serum half-life
regulating receptor, FcRn, and albumin.
Designed and characterized novel albumin
variants with increased binding to FcRn
that will be used as carriers of biopharmaceuticals to increase their serum half-life.
|
ANNUAL REPORT 2014
• Demonstrated that the interaction is hydrophobic, and the binding site for FcRn
on albumin overlaps with a high affinity
binding site for fatty acids. Thus, ligands
bound to albumin may well affect its
interaction with FcRn, which is important
for transport and deposition of ligands at
different body sites.
• Selected antibodies that bind specifically
to HLA DQ2.5 in complex with gluten
peptide.
AMBITIONS FOR 2015
• Design improved molecular trackers for
specific peptide – MHC complexes to be
used in studies of antigen presentation.
• Design molecular trackers for specific
T-cell receptors characteristic for gluten
specific T cells to be used in diagnostic
tests.
• Analyse the fine specificity of the T cell
response in coeliac disease.
• Understand basic mechanisms that govern
transcytosis and recycling of albumin and
IgG, and how both processes are altered
by ligand binding.
• Describe structural features of the constant regions of the human IgG subclasses
that are important for their effector functions, and characterize how IgG bound to
certain pathogens directs them to intra
cellular degradation and initiate signalling
that alerts the cell to convert to fighting
the infection.
|
25
SOLLID
GROUP
26
Our group is trying
to dissect the interplay
of environmental
and genetic factors in
chronic autoimmune
disorders. We are
concentrating on
coeliac disease as a
model to understand
the molecular
mechanisms leading
to chronic inflammatory
disease.
Ludvig M. Sollid
This disorder, caused by an inappropriate
immune response to cereal gluten proteins,
is characterised by a strong HLA association and presence of autoantibodies specific
for TG2. We have generated a large panel
of CD4+ T-cell lines and clones cultured
from intestinal biopsy specimens from
coeliac disease patients. Characterisation of
how these T cells recognise gluten protein
has led to interesting findings such as the
importance of protein structure on antigen
processing, how enzyme mediated posttranslational protein modification increases
antigenicity and how HLA binding specificity and peptide-MHC stability influence
T-cell priming. This knowledge reveals
general principles of immune regulation
that are applicable to other autoimmune
and chronic inflammatory diseases. Currently we have taken up a strong interest in
characterising the autoantibody response of
coeliac disease. This is the focus of an ERC
Advanced Grant project we undertake.
gen-specific cells: High throughput DNA
sequencing is implemented to monitor and
follow adaptive immune responses.
Amundsen SS, Viken MK, Sollid LM, Lie BA
(2014) Coeliac disease-associated polymorphisms influence thymic gene expression.
Genes. Immun., 15(6):355-60.
Qiao SW, Christophersen A, Lundin KE,
Sollid LM (2014) Biased usage and preferred
pairing of – and -chains of TCRs specific for
an immunodominant gluten epitope in coeliac disease. Int. Immunol., 26(1):13-9.
Sollid LM, Pos W, Wucherpfennig KW (2014)
Molecular mechanisms for contribution of
MHC molecules to autoimmune diseases.
Curr. Opin. Immunol., 31:24-30.
Structure and function of TG2: We are trying to understand where and how TG2 is
active in the intestinal coeliac lesions.
Christophersen A, Ráki M, Bergseng E,
Lundin KE, Jahnsen J, Sollid LM, Qiao SW
(2014) Tetramer-visualized gluten-specific
CD4+ T cells in blood as a potential diagnostic marker for coeliac disease without oral
gluten challenge. United. European. Gastroenterol. J., 2(4):268-78.
Gluten-reactive T cells: We are studying TCR
specificity and function of gluten-reactive T
cells. MHC tetramers are key tools in these
studies.
B cells and plasma cells: We are studying
the specificity of human recombinant antibodies cloned from immunoglobulin genes
of single TG2-specific or gluten-specific
plasma cells isolated from gut biopsies.
Characterisation of BCR and TCR of anti-
|
ANNUAL REPORT 2014
|
Iversen R, Mysling S, Hnida K, Jørgensen TJ,
Sollid LM (2014) Activity-regulating structural changes and autoantibody epitopes in
transglutaminase 2 assessed by hydrogen/
deuterium exchange. Proc. Natl. Acad. Sci.
U. S. A., 111(48):17146-51.
Dørum S, Bodd M, Fallang LE, Bergseng E,
Christophersen A, Johannesen MK, Qiao SW,
Stamnaes J, de Souza GA, Sollid LM (2014)
HLA-DQ molecules as affinity matrix for
identification of gluten T cell epitopes. J. Immunol., 193(9):4497-506.
Steinsbø Ø, Henry Dunand CJ, Huang M,
Mesin L, Salgado-Ferrer M, Lundin KE, Jahnsen J, Wilson PC, Sollid LM (2014) Restricted
VH/VL usage and limited mutations in
gluten-specific IgA of coeliac disease lesion
plasma cells. Nat. Commun., 5:4041.
Lundin KE, Sollid LM. Advances in coeliac
disease (2014) Curr. Opin. Gastroenterol.,
30(2):154-62.
• Monoclonal antibodies were cloned from
single gluten-specific plasma cells isolated
from coeliac lesions (Nat Comm 2014).
Gluten-specific IgA were found to have
restricted VH/VL usage and limited numbers of mutations.
• Completed studies using hydrogen/deuterium exchange to assess structural
changes induced by Ca2+, GTP, cysteine
oxidation and by the binding of transglutaminase 2 (TG2) autoantibodies of
coeliac disease patients on TG2 (PNAS
2014). Binding of Ca2+ and GTP stabilised
distinct regions in the catalytic core and
C-terminal domains of TG2 and oxidation prevented the Ca2+-induced changes.
Binding of TG2 autoantibodies resulted
in pronounced allosteric effects on TG2
structure.
• Used proteomics to characterise the endogenous peptide ligands of HLA-DQ2.5,
HLA-DQ2.2 and HLA-DQ7.5 (Immunogenetics 2015) and to identify (novel) gluten
T-cell epitopes that selectively bind to
HLA-DQ2.5 and HLA-DQ2.2 (J Immunol
2014). The binding motifs of HLA-DQ2.5
|
ANNUAL REPORT 2014
and HLA-DQ2.2 were found to be different where position P3 was a major
anchor site only in HLA-DQ2.2. This data
fit with the finding that the three known
HLA-DQ2.2-restricted gluten epitopes all
harbour serine at P3.
• Measured frequency of gluten-reactive T
cells in blood of coeliac disease patients
and healthy controls by HLA tetramer
staining (United European Gastroenterol J
2014). Showed proof-of principle that the
enumeration of gluten-tetramer binding
effector memory T cells in blood may be
used in coeliac disease diagnosis.
AMBITIONS FOR 2015
• Continue with high throughput sequencing of B-cell receptors (BCR) and T-cell
receptors (TCR) as well as undertaking
paired BCR VH–VL and TCR Va–Vb sequencing from single cells. Complete the
study on paired TCR repertoire analysis of
DQ2.5-glia-α2 and DQ2.5-glia-ω2-reactive
T cells.
• Complete the structural studies of TG2specific autoantibodies of coeliac disease,
and in complex with TG2.
• Perform blinded study on using tetramerstaining of gluten-reactive T cells in blood
as potential diagnostic tool in differentiating coeliac disease patients on gluten-free
diet and healthy controls.
• Perform in vitro studies to investigate
cooperation between TG2-specific B cells
and gluten-reactive T cells.
|
27
28
ABOUT
|
ANNUAL REPORT 2014
|
29
|
ANNUAL REPORT 2014
|
FACTS
AND
FIGURES
30
FACTS AND FIGURES
Centre for Immune Regulation (CIR) was
established in December 2007 as a Centre
of Excellence appointed by the Research
Council of Norway. Following a successful
midterm evaluation, CIR will continue to operate as a CoE till the end of 2017. CIR is also
a FOCIS (Federation of Clinical Immunology
Societies) Center of Excellence.
Our host institution is the University of
Oslo. Oslo University Hospital is an equal
consortium partner. The centre is organised
directly under the Faculty of Medicine and
the centre Director reports to the Dean. CIR
comprises research groups from the Faculty
of Mathematics and Natural Sciences, the
Faculty of Medicine and from Oslo University Hospital. Centre staff is employed at
the Department of Biosciences, the Department of Immunology and the Department of
Pathology.
107 persons, producing 60.5 person years,
are involved in research at CIR.
CIR actively recruits international talents
and currently 20 nationalities are represented at the centre.
The overall gender balance at CIR is 37/63
with an overweight of female members
among postdocs, PhD students, master students and technicians.
|
ANNUAL REPORT 2014
|
THE RESEARCH GROUPS
CIR consists of six research groups headed
by professors, Ludvig M. Sollid, Inger Sandlie, Oddmund Bakke, Bjarne Bogen, Frode
L. Jahnsen and Ludvig A. Munthe. Professor
Ludvig A. Munthe joined CIR as a new group
leader in January, 2014. Sollid’s group includes the group of Gustavo de Souza, head
of the proteomics core facility and projects.
Bakke’s group includes the group of Alexandre Corthay and Sandlie’s group includes
the group of Jan Terje Andersen.
MANAGEMENT
The centre is headed by Director Ludvig M.
Sollid and Deputy Director Inger Sandlie.
The centre management is supported by an
administrative coordinator, Lise Kveberg.
The Director has the daily responsibility for
project management, administration and
delivery.
THE CIR BOARD
The governing board of CIR has four members; two from the University of Oslo (UiO)
and two from Oslo University Hospital
(OUS). The board is appointed by UiO.
• Hilde I. Nebb (chair), Dean of Research,
Faculty of Medicine, UiO.
• Svein Stølen, Dean of Research, Faculty of
Mathematics and Natural Sciences, UiO.
• Erlend B. Smeland, Director of Research,
Innovation and Education, OUS.
• John Torgils Vaage, Head of the Department of Immunology, OUS.
The authority of the board is to ensure that
the intentions and terms of contract described in the Centre of Excellence agreement are fulfilled. Furthermore, the board
approves the annual budget and ensure that
centre activities are completed as outlined
in the project description and funding plan,
within the adopted time frame.
SCIENTIFIC ADVISORY BOARD
CIR has a scientific advisory board (SAB)
consisting of European world-class scientists. The SAB’s mandate is to critically
evaluate and advice on the centre’s scientific performance and progress.
• Professor Søren Buus, University of Copenhagen, Denmark.
• Professor Rikard Holmdahl, Karolinska
Institutet, Stockholm, Sweden.
• Professor Sirpa T. Jalkanen, University of
Turku, Finland.
FOCIS COE CLINICAL ADVISORY BOARD AND
LAY ADVISORY BOARD
As a Federation of Clinical Immunology
Societies (FOCIS) Centre of Excellence (FCE),
CIR has established two advisory boards.
The clinical advisory board is responsible
for facilitating translational research at CIR.
|
ANNUAL REPORT 2014
• Head physician Knut E. Lundin (chair,
gastroenterologist, OUS).
• Professor II Geir E. Tjønnfjord (haematologist, OUS and UiO).
• Professor Knut Dahl-Jørgensen (paediatrician, OUS and UiO).
• The lay advisory board focuses on strategic development, fundraising and
community outreach.
• The Director of the Norwegian Coeliac
Society.
• The Secretary General of the Norwegian
Asthma and Allergy Association.
• The Secretary General of the Norwegian
Diabetes Association.
31
FUNDING (1000 NOK)
2014
Research Council of Norway (RCN) – CoE 1
11050
University of Oslo (UiO) 2
19686
Oslo University Hospital (OUS) 3
9086
Other funding from RCN
7323
South-Eastern Norway Regional Health
12811
Private funding 4
2857
International funding 5
7749
Total funding
1 Centre of Excellence grant.
2Including value of personnel funded by UiO and indirect costs of infrastructure.
3Including value of personnel funded by OUS and indirect costs of infrastructure.
4Including grants from the Norwegian Cancer Society, and others.
5Including ERC advanced grant, EU grants, and others.
Compared to 2013, the total funding is increased in 2014.
|
70562
STAFF
AND
STUDENTS
Peter Szoroday
Researcher
OUS
OUS
Dong Wang
Researcher
RCN-CIR
UiO
Name
Position
Funding*Employer*
Frode M. Skjeldal
Senior engineer
UiO
Linda Haugen
Senior engineer
UiO
UiO
Kahsai Beraki
Senior engineer
UiO
UiO
TECHNICIANS
GROUP LEADERS
Funding*Employer*
Ingrid Kjos
Staff engineer
Hilde Omholt
Senior engineer
UiO
RCN-CIR
UiO
NCS
OUS
S-EN RHA
OUS
Marte Fauskanger
Research assistent
Aaste Aursjø
Senior engineer
UiO
UiO
Kathrine Hagelsteen
Biomedical Laboratory Scientist UiO
UiO
OUS
Linda I. Solfjell
Biomedical Laboratory Scientist OUS
Kjersti Thorvaldsen Hagen
Biomedical Laboratory Scientist S-EN RHA
OUS
Hege Eliassen
Senior Executive Officer
UiO/OUS
UiO/OUS
Sara Halmøy Bakke
Staff engineer
UiO
UiO
Name
Position
Oddmund Bakke
Professor
UiO
UiO
Bjarne Bogen
Professor
UiO/OUS
UiO/OUS
Bjørg Simonsen
Frode L. Jahnsen
Professor
UiO/OUS
UiO/OUS
Maria Ekman Stensland
Inger Sandlie
Professor
UiO
UiO
Martin McAdam
Research Technician
Ludvig M. Sollid
Professor
RCN-CIR/ERC
UiO
Stine Rosenqvist Lund
Engineer
Ludvig A. Munthe
Professor
UiO
UiO
Sathiyaruby Sivaganesh
Staff engineer
UiO
UiO
Marie K Johannesen Senior engineer
UiO
UiO
Staff engineer
S-EN RHA
OUS
Staff engineer
S-EN RHA
UiO
RCN
OUS
S-EN RHA
OUS
CIR – Centre for Immune
Regulation
ERC – European Research
Council, Advanced grant
EU – European Union
S-EN RHA – South-Eastern
Norway Regional Health
Authority
NCS – Norwegian Cancer
Society
OUS – Oslo University
Hospital
RCN – Research Council of
Norway
ImmusanT – Biotechnology
company, UK
UiO – University of Oslo
UEG – United European
Gastroenterology
The list of CIR staff and
students include both members that left and joined the
Centre during 2014. Several
CIR members have changed
employer, position and funding body during 2014. The
listed funding body, position
and employer refer to the
status per December 2014.
ADMINISTRATION
RESEARCH SCIENTISTS
32
Name
Position
Funding*Employer*
Per Brandtzæg
Professor emeritus
Name
Position
Funding*Employer*
Lise Kveberg
Senior advisor
RCN-CIR
UiO
Espen Bækkevold
Researcher
S-EN RHA
OUS
POSTDOCS
Alexandre Corthay
Researcher
RCN
OUS
Name
Gerbrand Koster
Researcher
RCN
UiO
Cinzia A. M. Progida
RCN/CIR/UiO/NCS
Knut E.A. Lundin
Consultant
S-EN RHA
OUS
Cathrine Hayward
UiO
UiO
Geir Åge Løset
Researcher
RCN
UiO
Anders A Tveita
NCS
OUS
Ingrid Olsen
Researcher
RCN
UiO
Johanne Jacobsen
S-EN RHA
OUS
Shuo-Wang Qiao
Researcher
UiO
UiO
Ole-Audun W. Haabeth
S-EN RHA
OUS
Funding*Employer*
UiO
Gustavo de Souza
Researcher
UiO
UiO
Peter C. Huszthy
RCN
UiO
Keith Thompson
Researcher
UiO
UiO
Lisa M. Gruber
S-EN RHA
OUS
Inger Øynebråten
Researcher
S-EN RHA
OUS
Ole J.B. Landsverk
S-EN RHA
OUS
Jan Terje Andersen
Researcher
RCN
OUS
Kristin Gunnarsen
S-EN RHA
OUS
CENTRE PERSONNEL 2014
CIR STAFF DEVELOPMENT
GENDER BALANCE STAFF
35
140
29
30
GENDER DISTRIBUTION
20
18
120
16
25
18
12
10
60
4
20
ANNUAL REPORT 2014
2
0
|
n
tio
tra
is
in
n
tu
le
up
ro
Male
Ad
m
Head count
* Headcount includes unpaid MSc/
MD students and staff that left or
joined CIR during 2014.
G
tra
is
Man years
de
nt
0
2014
ia
2013
rs
2012
ic
2011
te
2010
hn
2009
as
2008
tio
n
ns
ic
m
in
Ad
hn
en
t
|
Te
c
ud
st
D
/M
Sc
M
|
ia
s
s
ud
en
s
st
D
er
s
td
oc
Po
s
ch
se
ar
Re
Ph
G
ro
up
le
ad
er
s
0
M
1
en
t
5
63%
6
40
6
Te
c
10
37%
8
ud
13
St
15
18
14
80
ad
er
Re
se
ar
ch
er
Po
st
do
c
Ph
D
st
ud
en
t
20
20
100
ANNUAL REPORT 2014
Female
|
33
Peng Lei
RCN
UiO
Elin Bergseng
RCN
UiO
Jorunn Stamnæs
ERC
UiO
Siri Dørum
RCN-CIR
UiO
Fleur du Pre
S-EN RHA
OUS
Omri Snir
ERC/S-EN RHA
UiO
Bishnuedo Roy
ERC
UiO
Xi Chen
S-EN RHA
OUS
Rasmus Iversen
ERC
UiO
Britt Nakken
S-EN RHA
OUS
Astrid E. V. Tutturen
RCN-CIR
UiO
NATIONAL
Magnar Bjørås, Dept. of Microbiology,
Oslo Univ. Hosp. and Univ. of Oslo
Heidi Kiil Blomhoff, Institute of Basic
Medical Sciences, University of Oslo
Rune Blomhoff, Institute of Basic Medical
Sciences, University of Oslo
Bjørn Dalhus, Dept. Medical Biochemistry,
Univ. of Oslo and Oslo Univ. Hospital
Ralph Dollner, Department of
PHD STUDENTS
34
COLLABORATION
Otorhinolaryngology, Head and Neck Surgery,
NameFunding* Employer*
Oslo University Hospital
Henrik Aamodt
OUS
OUS
Terje Espevik, Norwegian University of Science
Kristin Aas-Hanssen
RCN/S-EN RHA
UiO
and Technology, Trondheim
Axel Berg-Larsen UiO
UiO
Peter Gaustad, Dept. of Medical Microbiology,
Malin C. Bern
RCN
UiO
University of Oslo and Oslo University Hospital
Anna Bujko
S-EN RHA
OUS
Tobias Gedde-Dahl, Dept. of Haematology,
Inês Cardoso
EU
UiO
Asbjørn Christophersen
S-EN RHA/ImmusanT/RCN
Marita Borg Distefano
UiO
UiO
Harleen Grewal, Gades Institute, University
Stian Foss
UiO
UiO
of Bergen and Haukeland University Hospital
Ibon Eguiluz Gracia
S-EN RHA
OUS
Krzysztof Grzyb, Dept. of Pathology, Oslo
Algirdas Grevys
UiO
UiO
University Hospital
Kathrin Hnida
EU
UiO
Guttorm Haraldsen, Dept. of Pathology,
Christina Hoffmann
RCN-CIR
UiO
University of Oslo and Oslo University Hospital
Lene Støkken Høydahl
RCN
UiO
Are Holm, Dept. of Respiratory Medicine,
Shiva Dahal Koirala
RCN-CIR
UiO
Dorota Joanna Konorska
RCN-CIR
UiO
Harald Holte, Dept. of Oncology,
Ana Kucera
UiO
UiO
Duarte Nunes De C Mateus
UiO
UiO
Jørgen Jahnsen, Department of Medicine,
Guro Reinholt Melum
S-EN RHA
OUS
Akershus University Hospital
Nadia Mensali
OUS/UiO
UiO
Kjetill S. Jacobsen, Centre for Ecological and
Elisabeth Müller
UiO
UiO
Evolutionary Synthesis, University of Oslo
Jeannette Nilsen
RCN
OUS
Knut-Dahl Jørgensen, Dept. of Pediatrics,
Nicolay Rustad Nilssen
S-EN RHA
OUS
Anna Parente Ribes
NCS/UiO
UiO
Mari Kaarbø, Dept. of Microbiology, University
Louise Risnes
S-EN RHA
OUS
of Oslo and Oslo University Hospital
Kine Marita K. Sand UiO
UiO
Benedicte A. Lie, Dept. of Medical Genetics,
Vikas K. Sarna
S-EN RHA
OUS
Fredrik Hellem Schesvold
NCS
OUS
Fridtjof Lund-Johansen, Dept. of Immunology,
Øyvind Steinsbø
UEG/S-EN RHA/OUS
UiO /OUS
UiO /OUS
Einar Gran, Lovisenberg Hospital, Oslo
Trond Leren, Dept. of Medical Genetics,
STUDENTS
NameStudy
NameStudy
Terje E. Michaelsen, School of Pharmacy, Dept.
Astri Frafjord
MSc
Mira Halvorsen Børstad
MSc
of Pharmaceutical Chemistry, University of Oslo
Shuai Guo
MSc
Nora Valeur MSc
Karsten Midtvedt, Dept. of Internal Medicine,
Heidi Anine Korsmo
MSc
Sofie Navelsaker MSc
Álvaro Sahún Español
BSc
Hanna Noordzij MSc
Tom Eirik Mollnes,
Branislava Stankovic
MSc
Ina Hodnebrug
MSc
Dept. of Immunology, University of Oslo
Merete Storflor
MSc
Rahel Frick
MSc
J. Preben Morth, Centre for Molecular Medicine,
Sanjib Halder
MSc
Heidrun Elisabeth Lode
MSc
University of Oslo
Melanie Manzke
MSc
Camilla Myklebust
MSc
Johanna Olweus, Institute for Cancer Research,
Martine Schrøder
MSc
Sowmya Subbana
MSc
Norbert Roos, Dept. of Molecular Biosciences,
Patrick Holt,
University of Oslo
Telethon Institute of Child Health Research, AU
Anne Simonsen, Institute of Basic Medical Sciences,
Ann Hosmalin, Cochin Institute, FR
University of Oslo
Bertrand Huard, University of Geneva, CH
Ingebjørg Skrindo, Department of
Bana Jabri, University of Chicago, US
Otorhinolaryngology, Ahus
Leo C. James, Medical Research Council Laboratory
Anne Spurkland, Institute of Basic Medical
of Molecular Biology, UK
Sciences, University of Oslo
Franziska Jundt,
Harald Stenmark, Centre for Cancer Biomedicine,
Charite – Universitätsmedizin BerlinDE
Univ. of Oslo and Oslo Univ. Hospital
Thomas J.D. Jørgensen,
Bernt Thiede, Biotechnology Center,
University of Southern Denmark, DK
University of Oslo
John Kappler, National Jewish Health, US
Geir Tjønnfjord, Dept. of Haematology,
Chaitan Khosla, Stanford University, US
Chu-Young Kim,
Sheraz Yaqub, Dept. of Surgery,
National University of Singapore, SI
Frits Koning, Leiden University Medical Center, NL
Einar-Martin Aandahl, Dept. of Surgery,
Wayne Lencer, Harvard Medical School, US
Ana-Maria Lennon-Dumenil,
Ole Øyen, Dept. of Surgery,
Institut Curie, Paris, FR
Wiebke Ludwig-Peitsch,
Researchers at Nextera AS, Oslo Innovation Centre
Klinik für Dermatologie, DE
Bernard Malissen, Centre d’Immunologie de
INTERNATIONAL
Marseille-Luminy, FR
William Agace, Lund University, SE
Kristiina Malmstrøm, Helsinki University, FI
Christian Brix Andersen, Aarhus University, DK
Rudolf Manz, University of Lubeck, DE
Francesco Annunziato, University of Florence, IT
Markku Mäki, University of Tampere, FI
Richard S. Blumberg, Harvard Medical School, US
Jeffery Miner,
Kurt Bommert, University of Würzburg, DE
Washington University School of Medicine, US
Anthony Bosco, Telethon Institute of Child
Jacques Neefjes, Netherlands Cancer Institute, NL
Health Research, AU
Morten Nielsen,
Cecilia Bucci, University of Salento, IT
Technical University of Denmark, DK
Søren Buus, University of Copenhagen, DK
Morten S. Nielsen, University of Aarhus, DK
Jo Caers, Centre Hospitalier Universitaire
Hugh Thomson Reyburn,
de Liège, BE
Spanish National Center for Biotechnology, ES
Jason Cameron, Novozymes Biopharma Ltd., UK
Paul Roche, NIH, US
Inhak Choi, University of Busan, KR
Derry C. Roopenian, The Jackson Laboratory, US
Matthew Collin, Institute of Cellular Medicine,
Daniele Sblattero, University of Piemonte, IT
Newcastle University
Hauke Smidt, Wageningen University, NL
Shaodong Dai, National Jewish Health, US
Dimitri Svergun,
Marc Dalod, Centre d’Immunologie de
European Molecular Biology Laboratory, DE
Marseille-Luminy FR
Mario Vaz, St. Johns Research Institute, IN
Morten Dziegiel, Rigshospitalet –
Gestur Vidarsson, Sanquin Research,
Copenhagen University Hospital, DK
University of Amsterdam, NL
Tatiana Efimova,
Patrick C. Wilson,
Washington University School of Medicine, US
University of Chicago, US
Caroline Ekblad, Affibody AB, SE
Cisca Wijmenga,
Peter M. Elias, University of California
University Medical Center Groningen, NL
San Francisco, US
Jenny Woof, University of Dundee, UK
Laszlo Fesus, University of Debrecen, HU
Anna Wu, University of California
Mattias Forsell, Karolinska Institutet, SE
Los Angeles, US
Donald Forthal, University of California,
Kai W. Wucherpfennig,
California, US
Dana-Farber Cancer Institute, US
Johan Garssen, University of Utrecht and Danone
Hideo Yagita, Jutendo University, JP
Research Centre for Specialised Nutrition, NL
Gur Yaari, Bar-Ilan University , IS
Georg Georgiou, University of Texas, US
Dov Zipori, Weizmann Institute, IS
Mariano Grasselli, Universidad Nacional de
Quilmes-IMBICE, AR
|
ANNUAL REPORT 2014
|
|
ANNUAL REPORT 2014
|
35
EDUCATION
AND CAREER
DEVELOPMENT
PHD
A large number of PhD students have graduated from CIR. The ambition has been to
educate 35 new PhDs during this 10 years
period. A total of 33 PhD students have
already successfully defended their thesis
so this goal is almost achieved. In 2014, two
female students defended their thesis:
ASTRID ELISABETH VOORHAM TUTTUREN, “Enrichment and identification of
citrullinated proteins in biological samples”. Supervisor: Ludvig M. Sollid.
36
SYNNE JENUM, “Mycobacterium tuberculosis infection and disease – a contribution
to the understanding of immunological
diagnostics in children”. Supervisor: Frode
Jahnsen.
COMPLETED PHD DEGREES AT CIR
PER YEAR FROM 2008 TO 2014
8
7
6
5
4
3
2
1
0
2008
|
2009
2010
ANNUAL REPORT 2014
2011
|
2012
2013
2014
MSC
In 2014, 5 CIR master students graduated
from the University of Oslo. Two foreign
students performed their work for MSc
degree at CIR and graduated in Italy and
Netherland respectively.
Jeanette Nilsen
Astri Frafjord
Heidi Anine Korsmo
Mira Halvorsen Børstad
Martin Mc Adam
Jeta Sadikaj
Brenda van Dieren
Álvaro Sahún Español did a project at CIR
for a BSc degree in Spain.
applicants by the centre’s scientific advisory board, financial support was granted for
two years to two selected talents.
This has been a big success. The candidates
either received career grants for 2015 or
scored at the top range in the evaluation of
their applications.
The gender equality program will be continued in 2015 and 2016 and the new career
development grants for female scientists
were announced in the end of 2014.
CAREER DEVELOPMENT AND
OPPORTUNITIES
CIR continues to support the career development of our talents. In 2014 the Medical Faculty has through the “phasing in
scheme” announced an associate professorship for a junior faculty member within
CIR. The selection board has now submitted
their recommendation, and we hope the
position will be filled before the summer of
2015.
Two young CIR scientists, Cinzia Progida
and Anders Tveita, received career grants
from the Norwegian Cancer Society and
Progida also received a “Young researcher
career grant” from the Research Council of
Norway.
37
GENDER EQUALITY PROGRAM
At CIR and generally in molecular biomedical research there is a high proportion of female PhD students and postdocs, while the
majority of the senior scientists and group
leaders are male. CIR and the University
of Oslo value gender diversity and aim to
increase the number of female researchers
in senior scientist positions. Women, more
so than men, leave academia during their
postdoctoral engagements and transition to
independent researchers. CIR acknowledges
that the centre, our host institution and
other academic institutions nationally and
abroad are at risk of losing many talents,
possessing valuable and highly specialised
competency.
In 2013, in line with the gender diversity
strategy of the University of Oslo, CIR provided two development grants to support
the career of female scientists. CIR has
obtained earmarked funding from the Research Council of Norway (RCN) to launch
this program. Following an evaluation of
|
ANNUAL REPORT 2014
|
38
ACTIVITIES
|
ANNUAL REPORT 2014
|
39
|
ANNUAL REPORT 2014
|
VISITING
PROFESSOR
PROGRAM
One of the core activities at CIR is the Visiting Professor program. CIR scientists have
an extensive international network which
has made it possible to attract some of the
world’s most important scientists in medical sciences to Oslo. The invited professors
stay for one week at CIR. During this week
they engage in scientific discussions with
researchers, supervision of CIR students
and give two public lectures for the whole
scientific environment at the University of
Oslo and the Oslo University hospital. These
visits have resulted in fruitful collaborations
resulting in joint publications, researcher
mobility and new ideas. A total of twelve
professors have been included in the Visiting Professor program, and many of them
have visited us twice.
40
Susan K. Pierce
Mark M. Davis
In 2014, Susan K. Pierce (NIAID, NIH, USA)
revisited CIR for her second time in June and
Mark M. Davis (Stanford University, USA)
joined the Visiting Professor program in
August.
We are very pleased to announce that Mark
M. Davis and Bana Jabri (University of
Chicago, USA) will revisit CIR in 2015, and
Bernhard Malissen (Centre d’Immunologie
de Marseilles-Luminy, France) will join the
Visiting Professor faculty in 2015 and has accepted to visit CIR in June. We are very much
looking forward to their visits.
New Visiting Professors are nominated by CIR
staff and will be invited to CIR in the future.
SUSAN K. PIERCE
Dr. Pierce works at the National Institute
of Allergy and Infectious Diseases, NIH, US.
Pierce focuses her work on B-cell receptor signaling and trafficking as well as on
the acquisition and maintenance of immunological memory in B cells. Her group
studies the regulation of these processes
during immune responses to infections
and vaccination and has a special interest
in the immunological memory response
to the malaria parasite. During her visit in
June, Pierce gave two guest lectures entitled
“Regulating the initiation of antigen-driven
B cell responses" and “The acquisition of immunity in malaria”.
|
ANNUAL REPORT 2014
|
MARK M. DAVIS
Dr. Davis works at the Stanford University
in California, US. His focus is to understand
the characteristics of a healthy humane immune system. Davis and his research group
are trying to define what a normal immune
response look like at the molecular and
cellular level. There is no easy test to look
for normal function of a patient’s immune
system, and one goal of Davis’ research is
to generate a simple battery of tests to be
performed on a blood sample that can give
information about the health status of your
complex immune system. The future aim
is to be able to give optimal treatment to
patients and customized vaccines to older
people. During his visit at CIR in August,
Davis gave two lectures. One was entitled
“Immunology taught by humans” and the
other was part of a minisymposium on T
cells in health and disease and was entitled
“Molecular aspects of T cell recognition and
applications to human responses”.
41
MINISYMPOSIUM
T CELLS IN HEALTH AND DISEASE / AUG 27
Contributors and titles:
Mark M. Davis, Stanford University, USA.
“Molecular aspects of T cell recognition and
applications to human responses”.
Yueh-Hsiu Chien, Stanford University, USA.
“Gamma delta T cells: First line of defense
and beyond”.
Shuo-Wang Qiao, Centre for Immune Regulation, University of Oslo. “The CD4+ T-cell
response to gluten in celiac disease.
Geir Åge Løset, Centre for Immune Regulation, University of Oslo and Nextera AS.
“CD4+ TH-cell epitope discovery using MHC
class II displayed on filamentous bacteriophages”.
WORK PACKAGE
(WP) SYMPOSIA
In CIRs research plan for the last five years
(2013-2017) we introduced a new strategy to
enhance scientific interaction between the
research groups. Projects were organized
into four work packages (WP) with common research focus. The WPs bridge disease
models and cross lab-boundaries and will
hopefully enhance sharing of knowledge
and skills between the scientists and students. The four main themes for the WPs
are:
WP1 – Function of APCs in autoimmunity
and allergy
WP2 – T-cell repertoire in autoimmunity
and allergy
WP3 – Pathogenic T-B collaboration
WP4 – Pathogenic and regulatory antibodies
by attendees, and discussion of future WPactivities.
WP4 SYMPOSIUM / OCT 16
Title: Generation of recombinant antibodies
and derived fragments
Program: Introduction by the WP coordinator
Jan Terje Andersen.
Stian Foss: “Antibody production using the
HEK293E cell line”
Bjørg Simonsen: “Antibody production using
the HEK293E/F cell lines”
Xi Chen: “Eukaryotic expression of antibody
fragments and characterization”
Kristin S. Gunnarsen/Lene Støkken Høydahl:
“Prokaryotic expression of antibody fragments and characterization”
WP1 SYMPOSIUM / MAY 27
Goal: Establishment of a competence/technology “database”.
Program: Introduction by the WP coordinator Espen S. Bækkevold, short presentations
|
ANNUAL REPORT 2014
|
GUEST
LECTURES
CIR organizes a series of guest lectures.
Most lectures are hosted by a postdoc
invitation committee. The 2014 committee
consisted of Omri Snir, Lisa M. Gruber, Cinzia Progida, Kristin S. Gunnarsen and Peter
C. Huszthy.
Matthew Collin
Ralf Küppers
IN 2014, CIR ORGANIZED 8 GUEST
LECTURES:
Jacques Neefjes, a former member of the CIR
Visiting Professor faculty from the Netherlands Cancer Institute in Amsterdam, visited
us in June and gave a lecture entitled "How
Salmonella causes cancer and the epidemics
of gallbladder carcinoma in India". Professor Neefjes is a cell biologist who has made
large contributions to the detailed understanding of antigen presentations by MHC
molecules.
Ana-Maria Lennon-Dumenil
Kunchithapadam Swaminathan visited CIR
in June and gave a lecture entitled “Happy
marriages among biophysical techniques”.
Professor Swaminathan is a structural
biologist which heads a research group at
the National University of Singapore. His research is focused on cell signaling and gene
regulation in human diseases and in his talk
he introduced us to the strength and limitations to some of the contemporary biophysical techniques.
42
Matthew Collin visited CIR in June and gave
a lecture entitled “Human dendritic cells in
health and disease”. Professor Collin heads
a research group at the Newcastle University and the Director of adult bone marrow
transplantation at the Northern Centre for
bone marrow transplantation. The focus of
his research is to understand the origin and
function of human dendritic cells.
Gur Yaari
Gabriel D. Victora
Patrick Holt visited CIR in June and gave a
lecture entitled "Treg-mediated control of
IgE-mediated acute phase responses??”.
Professor Holt is the head of the Division
of Cell Biology at the Telethon Institute and
University of Western Australia in Perth,
and heads a research group with focus on
the pediatric immune system in relation to
asthma and allergy.
pects of CLL pathogenesis”. Professor Küppers heads a research group at the Institute
of Cell Biology (Cancer Research) at University of Duisburg-Essen in Essen, Germany.
Their research aims at understanding the
pathogenesis of B cell tumors by comparing
the gene expression profile of the B cell lymphomas or leukemias with the B cell subsets
they originate from.
Ana-Maria Lennon-Dumenil visited CIR in
October and gave a lecture entitled “Coordinating cell migration with function: the
example of dendritic cells”. Dr. LennonDumenil heads a research group at the
Institut Curie in Paris, France, which aims to
identify the molecular mechanisms involved
in the space and time-related control of the
function of antigen-presenting cells.
Gur Yaari visited CIR in November and gave
a lecture entitled: “Mining B cell repertoire
dynamics from next-generation sequencing
studies”. Dr. Yaari heads a research group
at the Bar-Ilan University in Israel which
develops computational and statistical tools
to process and analyze high-throughput
biological data in order to obtain meaningful
biological insights into the adaptive immune
system.
Gabriel D. Victora visited CIR in December and gave a lecture entitled: “Darwin in
miniature: antibody evolution in germinal
centers”. Dr. Victora is a young scientist
from the Whitehead Institute for Biomedical Research, MIT, Cambridge, MA, US. He
presented several cutting edge techniques
used in his laboratory to study the generation of germinal centers in lymph nodes. His
studies are important to understand the dynamics and regulation of germinal center B
cells and have implications for how vaccines
work, but also for the development of allergies, autoimmune diseases and lymphomas.
In collaboration with the KG Jebsen Centre
for Research on Influenza Vaccines (JIV) and
Norwegian Society for Immunology (NSI)
we arranged a guest lecture by:
Simon J. Draper from the Blood-Stage Malaria Group Jenner Institute at the University of Oxford, UK. Title: “Development of
broadly-neutralising vaccines against the
blood-stage infection of human malaria”.
Ralf Küppers visited CIR in September and
gave a lecture entitled “Generation and
function of human memory B cells and as-
|
ANNUAL REPORT 2014
|
INTERNAL
ACTIVITIES
PROJECT MEETINGS
Once a month, all CIR members participates in a project meeting where research
projects are presented to other colleagues
within CIR. This is a great opportunity to
have scientific discussions, critical review of
recent data, and initiate new collaborations.
It also provides a friendly venue where less
experienced junior scientists can practice
presentation of experimental data. The project meeting is one of the key events which
gather all CIR members, and it is important for building centre identity. After the
project presentation pizza and soft drinks
are served, and the scientific discussions
continue in a more relaxed atmosphere.
RETREAT
August 18-19 2014, CIR arranged a retreat
to Soria Moria in Oslo. A total of 80 people
attended the conference. Attendants were
the members of CIR and the scientific advisory board. Members of the CIR centre board
were also present during parts of the program. Two international keynote speakers
were invited. Rudolf Valenta (Medical University of Vienna) presented “From allergen
genes to new forms of diagnosis and therapy
of allergy”, and Rikard Holmdahl (Karolinska
Institutet, Stockholm), member of the CIR
scientific advisory board, gave a talk entitled “From genes to oxidation inflammation
pathways”. The talks of the keynote speakers were excellent and were followed by 15
very good selected oral presentations and 23
poster presentations by young CIR scientists. The program was divided into seven
sessions which were chaired by researchers
at CIR: Keynote lectures (Wang Dong and
Alexandre Corthay), “Immune cells and their
responses in the gut” (Inger Øynebråten),
“T and B cells and extracellular molecules
in celiac disease” (Anders Tveita), “Protein
engineering and approaches to regulate
immune responses” (Shuo-Wang Qiao), “Immune cells and responses in tumor pathogenesis” Espen Bækkevold), and “Anti-tumor
responses, and “Transport and signalling
pathways” (Jan Terje Andersen). The organizing committee did an excellent job and
consisted of Wang Dong, Fleur De Pré, Marte
Hotvedt Hauskanger, Ibon Eguiluz Gracia,
Elisabeth Müller, Nicolay Rustad Nilssen and
Anders Sandvik.
|
ANNUAL REPORT 2014
Centre for Immune Regu
lation
(CIR)
CIR Retreat 2014
Program and abstracts
August 18–19, 2014
Soria Moria Hotel, Oslo
This material is confide
ntial and is only for internal
use
at the Centre for Immune
Regulation
CIR_Abstract_book_201
4.indd 1
12.08.14 11:22
|
43
44
PUBLICATIONS
|
ANNUAL REPORT 2014
|
|
ANNUAL REPORT 2014
|
45
PAPERS IN
SCIENTIFIC
JOURNALS
Borg M, Bakke O, Progida C (2014) A novel
interaction between Rab7b and actomyosin reveals a dual role in intracellular transport and
cell migration. J Cell Sci, 127 (22), 4927-39
Aas-Hanssen K, Funderud A, Thompson KM,
Bogen B, Munthe LA (2014) Idiotype-specific
Th cells support oligoclonal expansion of antidsDNA B cells in mice with lupus. J Immunol,
193 (6), 2691-8
Amundsen SS, Viken MK, Sollid LM, Lie BA
(2014) Coeliac disease-associated polymorphisms influence thymic gene expression.
Genes Immun, 15 (6), 355-60
Andersen JT, Dalhus B, Viuff D, Ravn BT, Gunnarsen KS, Plumridge A, Bunting K, Antunes
F, Williamson R, Athwal S, Allan E, Evans
L, Bjørås M, Kjærulff S, Sleep D, Sandlie I,
Cameron J (2014) Extending serum half-life of
albumin by engineering neonatal Fc receptor
(FcRn) binding. J Biol Chem, 289 (19), 13492502
Bagherifam S, Skjeldal FM, Griffiths G, Mælandsmo GM, Engebråten O, Nyström B, Hasirci V, Hasirci N (2014) pH-Responsive Nano
Carriers for Doxorubicin Delivery. Pharm Res.
Oct 7.
46
Bakke O, Progida C. (2014). Emerging regulators of endosomal dynamics during mitosis.
Cell Cycle.13(3):, 349-50
Bazso A, Bazso T, Szodoray P, Poor G, Kiss E
(2014) Aseptic necrosis at multiple localisations
in a lupus patient with lymphoma. Osteoporosis international: a journal established as result
of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 25:1415-1417.
Cover page from Borg et
al. 2014, Journal of Cellular
Science, 127 (22), 49274939. Reproduced with
permission.
Binsfeld M, Beguin Y, Belle L, Otjacques E,
Hannon M, Briquet A, Heusschen R, Drion P,
Zilberberg J, Bogen B, Baron F, Caers J (2014)
Establishment of a murine graft-versus-myeloma model using allogeneic stem cell transplantation. PLoS One, 9 (11), e113764
|
ANNUAL REPORT 2014
|
Corthay A (2014) Does the immune system
naturally protect against cancer? Front Immunol, 5, 197
De Luca M, Cogli L, Progida C, Nisi V, Pascolutti R, Sigismund S, Di Fiore PP, Bucci C
(2014) RILP regulates vacuolar ATPase through
interaction with the V1G1 subunit. J Cell Sci.
127(Pt 12), 2697-708.
Dhanasekaran S, Jenum S, Stavrum R, Ritz C,
Kenneth J, Vaz M, Doherty TM, Grewal HM,
TB Trials Study Group (Jahnsen FL)(2014)
Concordant or discordant results by the tuberculin skin test and the quantiFERON-TB test
in children reflect immune biomarker profiles.
Genes Immun, 15 (5), 265-74
Dhanasekaran S, Jenum S, Stavrum R, Wiker
HG, Kenneth J, Vaz M, Doherty TM, Grewal
HM, TB Trials Study Group (2014) Effect
of non-tuberculous Mycobacteria on host
biomarkers potentially relevant for tuberculosis management. PLoS Negl Trop Dis, 8 (10),
e3243
Dørum S, Bodd M, Fallang LE, Bergseng E,
Christophersen A, Johannesen MK, Qiao SW,
Stamnaes J, de Souza GA, Sollid LM (2014)
HLA-DQ molecules as affinity matrix for identification of gluten T cell epitopes. J Immunol,
193 (9), 4497-506
Etokebe GE, Bulat-Kardum L, Munthe LA,
Balen S, Dembic Z (2014) Association of
variable number of tandem repeats in the
coding region of the FAM46A gene, FAM46A
rs11040 SNP and BAG6 rs3117582 SNP with
susceptibility to tuberculosis. PLoS One. Mar
13;9(3):e91385.
Fenaroli F, Westmoreland D, Benjaminsen J,
Kolstad T, Skjeldal FM, Meijer AH, van der
Vaart M, Ulanova L, Roos N, Nyström B, Hildahl J, Griffiths G. Nanoparticles as drug delivery system against tuberculosis in zebrafish
Lundin KE (2014) Non-celiac gluten sensitivity
- why worry? BMC Med, 12, 86
Haabeth OA, Tveita AA, Fauskanger M,
Schjesvold F, Lorvik KB, Hofgaard PO, Omholt
H, Munthe LA, Dembic Z, Corthay A, Bogen
B (2014) How Do CD4(+) T Cells Detect and
Eliminate Tumor Cells That Either Lack or Express MHC Class II Molecules? Front Immunol,
5, 174
Makharia GK, Mulder CJ, Goh KL, Ahuja V, Bai
JC, Catassi C, Green PH, Gupta SD, Lundin KE,
Ramakrishna BS, Rawat R, Sharma H, Sood
A, Watanabe C, Gibson PR, World Gastroenterology Organization-Asia Pacific Association of Gastroenterology Working Party on
Celiac Disease (2014) Issues associated with
the emergence of coeliac disease in the Asia–
Pacific region: a working party report of the
World Gastroenterology Organization and the
Asian Pacific Association of Gastroenterology.
J Gastroenterol Hepatol, 29 (4), 666-77
Hjelle AM, Apalset E, Mielnik P, Bollerslev J,
Lundin KE, Tell GS (2014) Celiac disease and
risk of fracture in adults--a review. Osteoporos Int, 25 (6), 1667-76
Iversen R, Mysling S, Hnida K, Jørgensen TJ,
Sollid LM (2014) Activity-regulating structural changes and autoantibody epitopes in
transglutaminase 2 assessed by hydrogen/
deuterium exchange. Proc Natl Acad Sci U S
A, 111 (48), 17146-51
Jabri B, Chen X, Sollid LM (2014) How T cells
taste gluten in celiac disease. Nat Struct Mol
Biol, 21 (5), 429-31
Jacobsen J, Haabeth OA, Tveita AA, Schjetne
KW, Munthe LA, Bogen B (2014) Naive
idiotope-specific B and T cells collaborate
efficiently in the absence of dendritic cells. J
Immunol, 192 (9), 4174-83
Jenum S, Grewal HM, Hokey DA, Kenneth
J, Vaz M, Doherty TM, Jahnsen FL, TB Trials Study Group (2014) The frequencies of
IFNγ+IL2+TNFα+ PPD-specific CD4+CD45RO+
T-cells correlate with the magnitude of the
QuantiFERON® gold in-tube response in a
prospective study of healthy indian adolescents. PLoS One, 9 (7), e101224
Knudsen Sand KM, Landsverk OJ, Berg-Larsen
A, Bakke O, Gregers TF (2014) The humanspecific invariant chain isoform Iip35 modulates Iip33 trafficking and function. Immunol
Cell Biol, 92 (9), 791-8
Laczik R, Soltesz P, Szodoray P, Szekanecz Z,
Kerekes G, Paragh G, Rajnavolgyi E, Abel G,
Szegedi G, Bodolay E (2014) Impaired endothelial function in patients with undifferentiated connective tissue disease: a follow-up
study. Rheumatology 53:2035-2043.
Lin M, Du L, Brandtzaeg P, Pan-Hammarström
Q (2014) IgA subclass switch recombination in
human mucosal and systemic immune compartments. Mucosal Immunol 7 (3), 511-20
|
ANNUAL REPORT 2014
Melum GR, Farkas L, Scheel C, Van Dieren
B, Gran E, Liu YJ, Johansen FE, Jahnsen FL,
Baekkevold ES (2014) A thymic stromal
lymphopoietin-responsive dendritic cell subset mediates allergic responses in the upper
airway mucosa. J Allergy Clin Immunol, 134
(3), 613-621.e7
Cover from Nature Structural
& Molecular Biology, Volume
21 No 5. Reproduced with
permission
Nakken B, Bodolay E, Szodoray P (2014).
Cytokine Milieu in Undifferentiated Connective Tissue Disease: a Comprehensive Review.
Clinical reviews in allergy & immunology
47
Rahman MA, Kristiansen PE, Veiseth SV,
Andersen JT, Yap KL, Zhou MM, Sandlie I,
Thorstensen T, Aalen RB (2014) The arabidopsis histone methyltransferase SUVR4 binds
ubiquitin via a domain with a four-helix bundle structure. Biochemistry, 53 (13), 2091-100
Sand KM, Bern M, Nilsen J, Dalhus B, Gunnarsen KS, Cameron J, Grevys A, Bunting K,
Sandlie I, Andersen JT (2014) Interaction with
Both Domain I and III of Albumin Is Required
for Optimal pH-dependent Binding to the
Neonatal Fc Receptor (FcRn). J Biol Chem, 289
(50), 34583-94
Cover from Proc Natl Acad
Sci U S A, 111 (48). Reproduced with permission
Sand KM, Dalhus B, Christianson GJ, Bern
M, Foss S, Cameron J, Sleep D, Bjørås M,
Roopenian DC, Sandlie I, Andersen JT (2014)
Dissection of the neonatal Fc receptor (FcRn)albumin interface using mutagenesis and
anti-FcRn albumin-blocking antibodies. J Biol
Chem, 289 (24), 17228-39
Schwarzer R, Nickel N, Godau J, Willie BM,
Duda GN, Schwarzer R, Cirovic B, Leutz A,
Manz R, Bogen B, Dörken B, Jundt F (2014)
Notch pathway inhibition controls myeloma
bone disease in the murine MOPC315.BM
model. Blood Cancer J, 4, e217
p
Bodolay E, Prohaszka Z, Paragh G, Csipo I,
Nagy G, Laczik R, Demeter N, Zold E, Nakken
B, Szegedi G, Szodoray P (2014) Increased levels of anti-heat-shock protein 60 (anti-Hsp60)
indicate endothelial dysfunction, atherosclerosis and cardiovascular diseases in patients
with mixed connective tissue disease. Immunologic research 60:50-59.
Christophersen A, Ráki M, Bergseng E, Lundin
KE, Jahnsen J, Sollid LM, Qiao SW (2014) Tetramer-visualized gluten-specific CD4+ T cells
in blood as a potential diagnostic marker for
coeliac disease without oral gluten challenge.
United European Gastroenterol J, 2 (4), 268-78
embryos: direct visualization and treatment
(2014) ACS Nano, Jul 22;8(7):7014-26.
|
Senolt L, Grassi W, Szodoray P (2014) Laboratory biomarkers or imaging in the diagnostics
of rheumatoid arthritis? BMC medicine 12:49.
Skrede S, Steinsland H, Sommerfelt H, Aase
A, Brandtzaeg P, Langeland N, Cox RJ, Saevik
M, Wallevik M, Skutlaberg DH, Tellevik MG,
Sack DA, Nataro JP, Guttormsen AB (2014)
Experimental infection of healthy volunteers
with enterotoxigenic Escherichia coli wildtype strain TW10598 in a hospital ward. BMC
Infect Dis, 14, 482
Solberg LB, Brorson SH, Stordalen GA, Bækkevold ES, Andersson G, Reinholt FP (2014)
Increased tartrate-resistant Acid phosphatase
expression in osteoblasts and osteocytes in
experimental osteoporosis in rats. Calcif Tissue Int 94 (5), 510-21
Sollid LM, Pos W, Wucherpfennig KW (2014)
Molecular mechanisms for contribution of
MHC molecules to autoimmune diseases.
Curr Opin Immunol, 31C, 24-30
48
Steinsbø Ø, Henry Dunand CJ, Huang M,
Mesin L, Salgado-Ferrer M, Lundin KE, Jahnsen J, Wilson PC, Sollid LM (2014) Restricted
VH/VL usage and limited mutations in
gluten-specific IgA of coeliac disease lesion
plasma cells. Nat Commun, 5, 4041
Szodoray P, Hajas A, Toth L, Szakall S, Nakken
B, Soltesz P, Bodolay E (2014) The beneficial
effect of plasmapheresis in mixed connective
tissue disease with coexisting antiphospholipid syndrome. Lupus 23:1079-1084.
Toft-Hansen H, Rasmussen KS, Staal A,
Roggen EL, Sollid LM, Lillevang ST, Barington
T, Husby S (2014) Treatment of both native
and deamidated gluten peptides with an endo-peptidase from Aspergillus niger prevents
stimulation of gut-derived gluten-reactive
T cells from either children or adults with
celiac disease. Clin Immunol, 153 (2), 323-31
Tutturen AE, Fleckenstein B, de Souza GA
(2014) Assessing the citrullinome in rheumatoid arthritis synovial fluid with and without
enrichment of citrullinated peptides. J Proteome Res, 13 (6), 2867-73
Tveita AA, Haabeth OA, Bogen B (2014)
Limitations of bystander killing in Th1/M1
immune responses against a secreted tumor
antigen. OncoImmunology, 3 (9), e954953
Tveita AA, Schjesvold FH, Sundnes O,
Haabeth OA, Haraldsen G, Bogen B (2014)
Indirect CD4+ T-cell-mediated elimination of
MHC II(NEG) tumor cells is spatially restricted and fails to prevent escape of antigen-negative cells. Eur J Immunol, 44 (9), 2625-37
Vincze M, Der H, Kerekes G, Szodoray P,
Zeher M, Danko K, Soltesz P (2014) Decreased flow-mediated dilatation with
increased arterial stiffness and thickness as
early signs of atherosclerosis in polymyositis
and dermatomyositis patients. Clinical rheumatology 33:1635-1641.
Wong D, Winter O, Hartig C, Siebels S,
Szyska M, Tiburzy B, Meng L, Kulkarni U,
Fähnrich A, Bommert K, Bargou R, Berek C,
Chu VT, Bogen B, Jundt F, Manz RA (2014)
Eosinophils and megakaryocytes support the
early growth of murine MOPC315 myeloma
cells in their bone marrow niches. PLoS One,
9 (10), e109018
Zold E, Bodolay E, Dezso B, Soos G, Nakken
B, and Szodoray P (2014) Mixed connective
tissue disease associated with autoimmune
hepatitis and pulmonary fibrosis. The Israel
Medical Association journal: IMAJ 16:733-734.
ANNUAL REPORT 2014
|
Dooper M, Myrset HR, Bogen B: New fusion
proteins for the treatment of allergic diseases
(US application/PCT international application
no. 13/666,023, Canadian Patent Application
No. 2,794,051).
PATENTS
Johansen FE, Sandvik A and Engstad RE:
Methods of treating or preventing inflammatory disease of the intestinal tract (PCT/
GB2008/003850).
Andersen JT and Sandlie I (with Novozymes):
Albufuse2 Domain III extreme C-terminal
(EP11164955.4).
Andersen JT and Sandlie I (with Novozymes): Albumin derivatives and variants
(WO2011124718 A1).
Albumin variants (EP10159450.5).
Albumin variants (WO2011051489 A2).
Andersen JT and Sandlie I: Modulation of
albumin half-life (EP9174698.2).
OTHER PAPERS
Albufuse mutations (EP11164989.3).
Moum B, Lundin KE (2014) Biosimilar medicines in inflammatory bowel disease. Tidsskr
Nor Laegeforen, 134 (8), 819-20
Andersen JT and Sandlie I: Albumin combination mutants (EP12177916.9 and EP12191859.9).
Frich J, Lundin KE, Os I (2014) [The grading
system--balancing various interests] Tidsskr
Nor Laegeforen, 134 (1), 14-5
Frich J, Lundin KE, Os I (2014) [J. Frich and
colleagues reply] Tidsskr Nor Laegeforen, 134
(5), 496; discussion 497
BOOKS AND BOOK
CHAPTERS
Andersen J.T., Hjelstuen O.K. and Sandlie I.
Medical technology - meeting tomorrow’s
healthcare challenges, edited by John Grue
and Anne-Brit Kolstø. Chapter: From basic
research to innovation. Novus forlag, 2014.
(ISBN 978-82-7099-791-6).
Brandtzaeg P, Eskeland S. Bevisvurdering og
juss eller “vitenskap og galskap”. s. 17-29. I:
|
Festskrift til Fredrik Fasting Torgersen (Red.:
Eskeland KO, Mossig H, Os Simonsen Ø,
Steen T, Holck P). SpreDet Forlag, Oslo, 2014
(ISBN: 978-82-93277-13-2).
Andersen JT, Bern M and Sandlie I: Albumin
variants fused to immunogens (AlbuVax)
for improved transcellular delivery, US
61/936,442. Filed 06.02.2014
Bogen B and Braathen R: Heterodimeric vaccine molecules (U.S. Provisional Patent Application Serial No. 61/695,639).
Bogen B and Hofgaard PO: A novel mouse
model for multiple myeloma (MOPC315.BM)
that allows noninvasive spatiotemporal detection of osteolytic disease (U.S. Provisional
Patent Application Serial No. 61/708,310).
Bogen B, Fossum E and Grødeland G: Vaccibodies targeted to cross-presenting dendritic
cells (US serial no: 61538,186).
Di Niro R, Sollid LM and Wilson PC: Identification of antibodies in mucosal cells (US provisional, US61/352/467).
|
ANNUAL REPORT 2014
Løset GÅ and Sandlie I: Multivalent phage display systems and methods (WO2011/036555).
Løset GÅ, Frigstad T, Sandlie I and Bogen B:
Disulphide bond-stabilized functional soluble
MHC class II heterodimers (WO2011/101681).
Løset GÅ: pVII phage display
(WO2009/024591).
Løset GÅ: Signal sequence-independent pIX
phage display (WO2010/097411).
Mollnes TE, Espevik T, Sandlie I, Gunnarsen
JT, Lau C. A humanized antibody against CD14,
PCT/US14/31402. Filed 21.03.2014,
Munthe LA, Carlsen H, Blomhoff R and Bogen
B: Triple transgenic mouse model of autoimmune disease and NF-kB in vivo imaging (US
provisional, US61/262/968).
Reiersen H, Løset GÅ, Hagemann UB and
Owen D: Method for screening phage display
libraries against each other (WO2010/097589).
Ruffini PA, Fredriksen A and Bogen B: Homodimeric protein constructs (WO2010/61358513,
EP10167291.3).
Sandlie I, Andersen JT and Bern M: Albumin
variants fused to immunogens (AlbuVax) for
improved transcellular delivery (61033-13082US-P).
Sandlie I, Andersen JT and Foss S: A human
IgG1 mutant with improved binding to tripartite motif-containing protein 21 (TRIM21)
(61500-13035-US-P).
Sandlie I, Andersen JT and Sand KMK: Human
albumin mutants with decreased binding to
FcRn (2132-13083-US-P).
Sollid LM, Qiao SW, Christophersen A and
Lundin KEA: Detection of gluten specific T cells
(U.S. Provisional Patent Application Serial No.
61/823,072).
|
49
50
DISSEMINATION
|
ANNUAL REPORT 2014
|
|
ANNUAL REPORT 2014
|
51
INVITED
LECTURES
Koster G: “Membrane nanotube formation
by proteins - regulation by force and curvature” University of California Berkeley.
February 20, USA
Andersen, JT. Life Science workshop at Oslo
University Hospital, June 10, Oslo, Norway
Andersen, JT. CRS Workshop Albumin: The
Next Generation Protein Therapeutic at the
Controlled Release Society's Annual Meeting and Exposition in Chicago, July 13-16,
Illinois, USA
Alexandre Corthay
52
Lundin KE: «HLA tetramers in the diagnosis
of CDV. Prolamin Working Group meeting,
September 26, Nantes, France
Sollid LM: «Immunopathogenesis of celiac
disease». Columbia University Conference:
Development of Therapies for celiac disease,
March 20-21, New York, USA
ORAL
PRESENTATIONS
Bakke, O. Invariant chain (Ii), a multifunctional molecule, its role in sorting and Ii as a
vehicle for antigen loading onto MHC I and
MHCII. 8th International Workshop on Antigen Processing and Presentation, June 10-13,
Philadelphia, PA, USA
Bujko A: Monocytes differentiate into macrophages and lymph node-homing dendritic
cells in human gut, World Immune Regulation Meeting VIII-2014, March 19-22, Davos,
Switzerland (oral and poster presentation).
Andersen, JT. Seminar October 21. Department of Microbiology, University of Oslo,
Oslo University Hospital, Rikshospitalet,
Norway
Lundin KE: «Celiac disease. Lecture at
Postgrauduate training programme»,22nd
European Gastroenterology Week, October
18-22, Vienna, Austria
Sollid LM: « Celiac disease: Interplay of
autoimmunity and food hypersensitivity».
Stanford Institute of Immunity, Transplantation and Infection Special Seminar, April
2, Stanford, USA
Andersen, JT: Intracellular antibody sensing
in the battle against infection. Norwegian
Society for Immunology 32nd annual meeting, November 13, Oslo, Norway
Lundin KE: «Round table discussion - Should
asymptomatic CD patients be treated?».
22nd European Gastroenterology Week,
October 18-22, Vienna, Austria
Sollid LM: «Celiac disease: When food is the
problem». Gordon Research Conference: Immunochemistry & Immunobiology, June 1-6,
Newry, USA
Bujko A: Monocytes differentiate into macrophages and lymph node-homing dendritic
cells in human gut, 13th International Symposium on Dendritic Cells, September 14-18,
Tours, France
Bogen B:” How do CD4+ T cells eliminate
tumor cells that lack MHC class II molecules? “. Norwegian Cancer Symposium,
June 10-12, Oslo, Norway
Lundin KE: «Celiac disease – state of the art
and unmet clinical needs». Gastroenterologi
i fokus. November 20, Stockholm, Sweden
Sollid LM: «Immune control of celiac disease». 42nd Annual Meeting of the Scandinavian Society of Immunology, June 11-14,
Reykjavik, Iceland
Bækkevold ES: Human airway mucosal DCs
respond to TSLP and induce Th2 responses.
8th World Immune Regulation Meeting
March 19-22, Davos, Switzerland
Sollid LM: «Transglutaminase 2: autoantibody target and generator of T-cell
epitopes». Gordon Research Conference:
Transglutaminases in Human Disease Processes, June 29-July 4, Barga, Italy
Bækkevold ES: Novel concepts to investigate
immunopathology in organ rejection. Medisinsk fakultets 200-års jubileum, September 10,
Oslo universitetssykehus Rikshospitalet, Oslo
Bogen B: “A Novel Mouse Model for Multiple
Myeloma (MOPC315.BM)”. Department of
Hematology, Mount Sinai Hospital/ Icahn
School of Medicine, December 17, New York,
USA
Jan Terje Andersen
Lundin KE: «Controversies about biosimilars». Annual GEDII meeting, January 17,
Lisboa, Portugal
Sollid LM: «Coeliac disease: Food hypersensitivity coupled with autoimmunity». 12th
EAACI Immunology Winter School: Basic
immunology research in allergy and clinical immunology. January 30-Feb 2, Poiana
Brasov, Romania
Brandtzæg P. NSI Honorary Member Lecture: “The advent of immunological research
in Norway and NSI as a catalyst”. November
13, Oslo, Norway
Corthay A “What is inflammation? An
immunologist’s perspective”. Norwegian
Inflammation Network seminar “Sufficient
options to treat inflammation? Looking at
the pipeline of the pharmaceutical industry”, October 29, Oslo, Norway
Corthay A “Can tumor-specific Th2 cells be
used to treat cancer?”. Norwegian Cancer
Symposium 2014 – Harnessing Innate and
Adaptive Immunity in Cancer Therapy, June
10-12, Oslo, Norway
Corthay A “Cancer prevention by the immune system: role of CD4+ T cells, macrophages, and interleukin-1”. 11th International Conference on Innate Immunity, June
1-6, Olympia, Greece
|
ANNUAL REPORT 2014
|
Sandlie I: Half-life extension by albumin or
Fc-fusion. Gordon Conference on Antibody
Biology and Engineering, March 23-28, Tuscany, Italy
Sandlie I: Tailoring the Lifespan of Biopharmaceuticals by Targeting the Neonatal
Fc Receptor (FcRn), KTH, Royal Institute of
Technology, School of Biotechnology, May
23, Stockholm, Sweden
Sandlie I: New perspective on IgG function.
December 15. Department of Pathophysiology, Infectiology and Immunology, Medical
University of Vienna, Vienna, Austria
Sandlie I: Fra Grunnforskning til Innovasjon.
Det Norske Vitenskapsakademi (January 29)
and Cutting Edge Konferansen Oslo Innovation Week October 10, Oslo, Norway
Sandlie I: Strategier for å bygge produktive
fagmiljøer. Odontologisk fakultets strategiseminar, April 9, Praha, Czech Republic
Sollid LM: «Antigen recognition (B and T
cell mechanisms». JDRF/Wellcome Trust
Frontier Meeting. Common Mechanisms
of Autoimmune Diseases, January 27-28,
London, UK
Sollid LM: «Small bowel, celiac disease and
adaptive immunity». Falk Symposium no
193: Celiac Disease and other small bowel
disorders, September 5-6, Amsterdam, the
Netherlands
Sollid LM: «The antibody response of celiac
disease». 18th Germinal Centre Conference,
September 11-14, Uddevalla, Sweden
Espen Bækkevold
Hnida K, Stamnaes J, Chen X, Iversen R and
Sollid LM «Functional implications of celiacautoantibodies-transglutaminase interactions». Gordon-Merck Research Seminar
Antibody Biology & Engineering, March
22-23, Barga, Italy
Jenum S: Characterization of Mycobacterium Tuberculosis specific T cells – clues to
protective immunity? Årsmøte, Norsk Flowcytometri Forening, April 30, Norway
Sollid LM: «New insights into the pathogenesis of coeliac disease: Gluten-gene-environmental interactions». 22nd European
Gastroenterology Week, October 18-22,
Vienna, Austria
Koster G: “Forces of membrane nanotubes
in vitro and in vivo – regulation by physical
membrane properties” Norsk biofysikkmøte,
March 6, Soria Moria, Oslo, Norway
Sollid LM: «Triggers and Drivers of autoimmunity: Lessons from coeliac disease». 22nd
European Gastroenterology Week, October
18-22, Vienna, Austria
Kucera A. “Invariant chain as a vaccination vehicle for loading of MHC I”. Annual
meeting, Norwegian Society of Immunology,
November 13, Oslo, Norway
Stankovic B. “Immune Cell Composition in
Human Non-Small Cell Lung Cancer”. Annual meeting, Norwegian Society of Immunology, November 13, Oslo, Norway
|
ANNUAL REPORT 2014
53
|
Kathrin Hnida
Steinsbø Ø. «Binding motifs of gluten-specific antibodies from celiac disease patients».
Annual meeting, Norwegian Society of
Immunology, November 13, Oslo, Norway
Steinsbø Ø: «Restricted VH/VL usage and
limited mutations in gluten-specific IgA of
coeliac disease lesion plasma cells”. Award
for excellent article published first half of
2014 Oslo University Hospital November 21,
Oslo, Norway
Wang, D: “Autologous bone marrow Th cells
can support multiple myeloma cell proliferation in vitro and in vivo”. Annual Meeting of the Federation of Clinical Immunology
Societies (FOCIS), June 25-28, Chicago, USA.
(oral and poster presentation, poster prize
winner)
POSTER
PRESENTATIONS
Borg M, Bakke O, Progida C: “A novel Rabactomyosin interaction reveals a dual role in
intracellular transport and cell migration”.
14th International Advanced Light Microscopy Meeting. May 20-23, Oslo, Norway
54
Marita Borg Stefano
Borg M, Bakke O, Progida C,: “A novel
interaction between Rab7b and actomyosin
cytoskeleton reveals multiple functions in
intracellular transport and cell migration”.
1st International Meeting “Building The
Cell”. September 24-26, Paris, France
Cardoso I, Stamnaes J, Iversen R, Sollid LM.
«TG2 interactions with extracellular matrix proteins as probed with celiac disease
antibodies». Gordon Research Conference:
Transglutaminases in Human Disease Processes, June 29-July 4, Barga, Italy
Linda Haugen
Gruber LM: Human small intestinal SIRPa+CD103+ dendritic cells display putative
immunoregulatory features. 13th International Symposium on Dendritic Cells, September 14-18, Tours, France
Gruber LM: Human small intestinal
SIRPa+CD103+CD1a+ dendritic cells display
putative immunoregulatory features. 32nd
Annual Meeting of the Norwegian Society
for Immunology, November 13, Oslo, Norway
Haugen LH, Skjeldal FM, Bergeland T, Bakke
O. Growth factor-induced phosphoraylation
of Eps15 and Hrs regulates their binding to
endosomes and RTK degradation, European
Light Microscopy Meeting, May, Oslo, Norway
Hnida K, Stamnaes J, Chen X, Iversen R and
Sollid LM «Epitope-dependent effect of celiac
anti-TG2 hmAbs on preventing TG2 oxidation». Gordon-Merck Research Seminar Antibody Biology & Engineering, March 22-23
and Gordon Research Conference, Antibody
Biology & Engineering, March 23-28, Barga,
Italy
Hnida K, Chen X, Iversen R, Graewert MA,
Svergun D and Sollid LM « Structural basis
for antigen recognition of Transglutaminase
2 specific autoantibodies in celiac disease».
Gordon Research Conference: Transglutaminases in Human Disease Processes, June
29-July 4, Barga, Italy
Iversen R: «Gluten, antibodies and TG2:
mechanisms for generation of autoantibodies in celiac disease». 18th Germinal Centre
Conference, September 11-14, Uddevalla,
Sweden
McAdam. M. Engineering of novel antibodies
for targeted anti-viral therapy. Norwegian
Society for Immunology annual meeting,
November 13, Oslo, Norway
Eguíluz-Gracia I, Melum GR, Döllner R, Bækkevold ES, Jahnsen FL: Experimentally-induced early recruitment of CD14+ monocytes
in human allergic rhinitis. EAACI Winter
School on Basic Research in Allergy and
Clinical Immunology, January 30-February 2,
Poiana Brasov, Romania
Nilsen J, Høydahl LS, Gunnarsen KS, Qiao
SW, Sollid LM, Sandlie I, Løset GÅ. Affinity maturation of a T cell receptor by use of
phage display and deep sequencing. Norwegian Biochemical Society Contact Meeting,
January 23-26, Røros, Norway
Algirdas Grevys: Fc-engineering of human
IgG1 for altered binding to the neonatal
Fc receptor affects Fc effector functions.
Gordon Research Conference (GRC), March
23-28, Lucca (Barga), Italy
Nilsen J, Sand KMK, Bern M, Dalhus B, Sandlie I, Andersen JT. The impact of albumin DI
on FcRn cross-species binding. Norwegian
Society for Immunology annual meeting,
Nov 13, Oslo, Norway
|
ANNUAL REPORT 2014
|
Progida C, Borg M, Koster G, Bakke O:
“Rab7b at the intersection of intracellular
trafficking and cell migration”. 9th EMBO/
Annaberg Workshop “Protein and lipid function in secretion and endocytosis”. January
14-19, Goldegg am See, Austria
Progida C, Borg M, Bakke O: “Rab7b and
the actomyosin cytoskeleton: novel roles in
intracellular trafficking and cell migration”.
Conference “The Dynamic Cell 2014”. September 4-7,Cambridge, UK
Snir O, Mesin L, Lundin KE, Yaari G and Sollid LM. «Analysis of celiac disease autoreactive gut-plasma cells and their corresponding memory compartment in peripheral
blood using high-throughput sequencing».
18th Germinal Center Conference, September
11-14, Uddevalla, Sweden
Steinsbø Ø: «Restricted VH/VL usage and
limited mutations in gluten-specific IgA of
coeliac disease lesion plasma cells». 18th
Germinal Centre Conference, September 1114, Uddevalla, Sweden
PRESENTATIONS
TO A TARGETED
AUDIENCE AND
THE PUBLIC
Christophersen A. «HLA tetramer to understand and diagnose celiac disease. Lecture
at the 200-year anniversary seminar of the
Faculty of Medicine, September 10, University of Oslo, Norway
Lundin KE: «Cøliaki og glutensensitivitet
uten cøliaki». Foredrag på årsmøtet for
Buskerud NCF, February 18, Hokksund,
Norway
Lundin KE: «Non coeliac gluten sensitivity».
Lecture at Nordic-baltic AOESC meeting,
Scandic KNA Hotel, Oslo, Norway
Lundin KE: «Non-coeliac gluten sensitivity».
Foredrag på 40-års jubileum, April 26, Norsk
Cøliakiforening, Hotel Bristol, Oslo, Norway
Wang D, Fløisand Y, Tveita A, Thoresen AS,
Bürgler S, Parente-Ribes A, Hofgaard P,
Bogen B, Tjønnfjord G, Dalgaard J, Munthe L.
“Autologous bone marrow Th cells can support multiple myeloma cell proliferation in
vitro and in vivo”. 1st International Winter
Symposium on Immunobiology: Metabolism,
Cancer, Auto immunity and Drug Discovery,
October, Seefeld, Austria
Lundin KE: «Cøliaki og fremtiden». Foredrag
på 40-års jubileum, June 26, Norsk Cøliakiforening, Hotel Bristol, Oslo, Norway
OTHER
Lundin KE: «Cøliaki». Foredrag på samling
for Norsk Cøliakiforenings Ungdommer Hotell Rica Park Hotell, November 22, Drammen, Norway
Andersen, JT. Chair for Gordon Research
seminars (GRS), Gordon Research Conference (GRC) pre-seminar for young investigators in Antibody Biology & Engineering:
Next-Generation Antibodies: From Biology
to Therapeutics, March 23-28, Renaissance
Tuscany Il Ciocco Resort, Lucca (Barga), Italy
Bakke, O and research group. Main organizer of 14th annual meeting of the European
Light Microscopy Initiative (ELMI), Oslo, May
20-23, http://www.mn.uio.no/ibv/forskning/
aktuelt/arrangementer/konferanser/2014/
elmi2014/
Lundin KE: «Glutensensitivitet uten cøliaki»,
Foredrag på Med Fak 200 års jubileumsseminar, May 24, Gamle Festsal, Oslo, Norway
Lundin KE: «Cøliaki». Foredrag på ungdoms
leir NCFU, June 23, Elverum, Norway
Progida C; “How do intracellular compartments communicate?” Lab14, October 29,
Lillestrøm, Norway
Progida C; “How do intracellular compartments communicate?” Lab Norges medlemsmøte, November 27, Oslo, Norway
Qiao SW: «Cøliaki – alltid glutenfritt?» Foredrag på Med Fak 200 års jubileumsseminar,
May 24, Oslo, Norway
Qiao SW: «Cøliaki og gluten-intoleranse - Er
gluten kilden til alt ondt?» Forskningsdagene, September 21, Oslo, Norway
|
ANNUAL REPORT 2014
Øyvind Steinsbø
|
55
Rasmus Iversen
MEDIA
COVERAGE
«Cinzia Progida vant Lab Norges forskningspris» at http://messe.no/no/Lab/Nyheter/
Cinzia-Progida-vant-Lab-Norges-forskningspris/
Lundin KE: Paneldeltager i Dagsnytt 18 om
glutensensitivitet: http://radio.nrk.no/serie/
dagsnytt-atten/nmag03003714/21-02-2014.
«Mie (10) og Filippa (12) mistet mamma –
nå har de samlet inn 600.000 kroner til
kreftsaken». TV2 and the Norwegian Cancer
Society visited Audun Tveita at his home
in relation to his research grant from the
Norwegian Cancer Society. http://www.tv2.
no/2014/10/28/nyheter/innsamling/kreft/
armband/6170879
Inger Sandlie, Jan Terje Andersen and colleagues. "The Research Race to Make Drugs
More Efficient". Wall Street Journal May 6.
Featuring technology developed by CIR in
collaboration with Novozymes.
“Jakter på WOW-effekten”. Geir Åge Løset
and Inger Sandlie. http://www.mn.uio.no/
forskning/aktuelt/aktuelle-saker/2014/jakter-pa-wow-effekten.html
56
«Lanserte HelseOmsorg21 på OUS Rikshopitalet». The Prime Minister Erna Solberg and
Minister of Health and Care Services Bent
Høie visited CIR. http://www.oslo-universitetssykehus.no/aktuelt_/nyheter_/Sider/
Lanserte-HelseOmsorg21-på-OUS-Rikshospitalet.aspx
“Sykehuset hedrer forskere”. Ludvig Sollid
honored with Excellent Researcher Award.
http://www.oslo-universitetssykehus.no/
aktuelt_/nyheter_/Sider/forskningspriser-august14.aspx
Cinzia Progida
“Miljonpris til Norges mest citerade forskare”. Per Brandtzæg. Press release at
Lunds Universitet on Fernströmstiftelsens
Nordiska Pris: http://www.lu.se/article/miljonpris-till-norges-mest-citerade-forskare,
and story in Dagens medisin: http://www.
dagensmedisin.no/nyheter/per-brandtzaghedres-med-millionpris/
Annual Report
2010
Centre for
Immune Regulation (CIR)
“UiOs mest oppfinnsomme forsker», Inger
Sandlie. Uniforum. http://www.uniforum.
uio.no/nyheter/2014/10/uios-mest-oppfinnsomme-forsker.html
«Synliggjør nanoverdenen». Oddmund
Bakke in Finansavisen, Oct 9.
«Nobelpris kjemi», NRK Radio live at
Oddmund Bakkes lab, Oct 9. http://
radio.nrk.no/serie/ekko-hovedsending/
MDSP25020114/09-10-2014
|
ANNUAL REPORT 2014
|
M
1
Ø M E R KE
T
ILJ
24
IR
Redaktør: Lise Kveberg, UiO
Foto: Øystein H. Horgmo, UiO
Design: Millimeterpress/Lise Myhre
Trykk: Rolf Ottesen
8
Trykksak 6
1
Anders Tveita
C
CENTRE FOR
IMMUNE REGULATION (CIR)
Visiting address
Oslo University
Hospital-Rikshospitalet
Sognsvannsveien 20
Building A2/A3
N-0027 Oslo
Mailing address
Centre for Immune Regulation
OUS HF, Rikshospitalet
P.O.Box 4956 Nydalen
N-0424 OSLO
Norway
Phone (+47) 23 07 35 00
Fax (+47) 23 07 35 10
Email [email protected]
www.cir.uio.no

CIR ANNUAL REPORT 2014

Transcription

Similar documents

the oscarsborg opera

Broszura

The Expanding Frontiers of the Functionality Doctrine in Trademark

ú ú ú ú ú ú ú - City of Smyrna, GA

A Leading Think-tank in Central and Eastern Europe

press release

Citi Habitats - CIR/SEIU Healthcare

CIR Annual Report for 2009

(Microsoft PowerPoint

JfMUu? Jpiik Mt* Wvid 4 M{e. LOYALTY —TO YOURSELF? RESELL