in vivo

RCAI research retreat program. Previously, outside participants were
excluded from the retreat because much of the data presented there
was preliminary and unpublished. However, this year we invited senior
editors from Nature Immunology, Nature Medicine and Immunity to
participate. I appreciate their involvement in discussions and I also
appreciate the efforts of the organizers, Dr. Udono and Dr. Kaisho.
Primary immunodeficiency project
Primary immunodeficiency (PID) describes a collection of
diseases caused by mutations in genes required for the normal
development and function of the human immune system. The PIDs are
clinically heterogeneous, but typically are characterized by increased
susceptibility to infections and, in their most severe form, are fatal if
untreated. In the 2006 Annual Report I described the establishment
of the Human Immunodeficiency Network. At that time, RCAI, the
Clinical Study Group for PID, and the Kazusa DNA Research Institute
established a platform to combine genetic diagnosis and basic and
clinical research. The goal of this Network is to encourage synergistic
collaboration between clinical and basic researchers, to identify new
PID genes, and to develop better approaches for the early diagnosis
and treatment of PID. The basic goals remain the same, however the
Network has expanded considerably during the past year and is now
a collaboration between RCAI and 13 universities in Japan, Kazusa,
the Institute of Bioinformatics (IOB) in Bangalore, India, and the Jeffrey
Modell Foundation in the United States. Dr. Sujatha Mohan of the IOB,
an institute renowned for its expertise in bioinformatics, has become
an RCAI unit leader to spearhead the expansion of the PID database for
predicting the onset of PID pathology and defining optimal treatments.
In addition to serving as a repository for PID patient samples and the
analysis of their genetic defects, the Network has a strong research
component with a focus on recapitulating human PID in the humanized
mouse model, where immunophenotypic analyses can be readily
performed and therapeutic strategies can be evaluated. The activity
of RCAI in the area of PID came to the attention of the Jeffrey Modell
Foundation (JMF), an American non-profit organization founded by
Fred and Vicki Modell in memory of their son Jeffrey, who died at the
age of 15 from pneumonia resulting from a PID. Established in 1987,
the foundation is dedicated to early and precise diagnosis, meaningful
treatments, and ultimately cures of PID throughout the world. RCAI and
JMF have agreed to a joint project, the RIKEN Jeffrey Modell Diagnostic
and Research Center for Primary Immunodeficiencies. The Center will
contribute to the study of basic human immunology and will also play
a major role in speeding up the diagnosis of PID and the selection of
optimal treatments. To open the new center, RCAI held an inaugural
dedication ceremony that was attended by JMF founders Mr. Fred and
Mrs. Vicki Modell, Peter Turner the President of CSL Behring, a major
financial backer of the JMF, Jan Bult the President of the Plasma Protein
Therapeutic Association (PPTA), and representatives of Tsubasa no Kai,
a Japanese advocacy group for PID patients and their families.
Publications by young investigators
Overall, RCAI investigators had an excellent year in that 25% of 126
publications from our institute were in high impact journals, i.e. those
with an impact factor greater than ten. As one of my goals is to develop the
potential of young RCAI investigators, it was rewarding to see significant
progress this year as measured by the number of young investigators
who published highly significant papers. Dr. Taniuchi studies cell fate
decisions using CD4/CD8 lineage commitment in the thymus as a
model. He has found that the Runx transcription factor complex actively
suppresses the expression of another transcription factor required for
CD4 T cell development, thus allowing for differentiation of cytotoxic
T cells (Science 2008). The transcription factor NF-κB is a central
regulator of host immune and inflammatory responses, and its activity
must be tightly regulated in order to prevent inflammatory diseases.
Dr. Kaisho identified a novel nuclear ubiquitin ligase that terminates
NF-κB activation through intranuclear sequestration and subsequent
degradation (Nature Immunology 2007). Dr. Sato has identified a new
type of dendritic cell, DCreg, and found that these regulatory dendritic
cells protect against cutaneous chronic graft-versus-host disease by
generating regulatory T cells (Blood 2007). Dr. Ishikawa has used his
humanized mouse model to identify and characterize the leukemic
stem cells in acute myelogenous leukemia. He found that quiescence
of human LS cells may be a mechanism underlying resistance to
cell cycle-dependent cytotoxic therapy, and validated the humanized
mouse as potentially useful model for development of novel therapeutic
strategies (Nature Biotechnology. 2007). Dr. Kawamoto has previously
proposed a model for fetal heamtopoiesis in which developing cells
maintain myeloid potential even after segregation toward B and T cell
lineages. He now has convincing data demonstrating that the “myeloid
based” model holds true for adult heamtopoiesis as well (Nature 2008).
Dr. Watarai discovered a novel TREM family receptor expressed only
on TLR activated plasmacytoid dendritic cells, which plays a crucial
role in Type I interferon production after TLR activation. His studies
provide new insights into the early events after pathogen infection
(PNAS 2008). Injection of apoptotic cells can induce suppression of
immune responses to cell-associated antigens. Dr. Tanaka has shown
that intravenous injection of apoptotic cells expressing a fragment
of myelin oligodendrocyte glycoprotein prevented the development
of EAE, a mouse model for human multiple sclerosis. Marginal zone
macrophages are a critical cell type for this immunosuppressive effect
(J. Clin. Invest. 2007). Dr. Tokunga has developed a highly inclined thin
illumination system that enables clear single-molecule imaging in cells.
This method will permit researchers to visualize and quantify molecular
dynamics, interactions and kinetics in cells for molecular systems
biology (Nature Methods 2008). Dr. Fujii found that cross-presentation
of glycolipid from tumor cells loaded with alpha-galactosylceramide
could induce T cell mediated immunity via dendritic cells. This novel
experimental therapeutic approach led to highly protective and longlived
adaptive immunity directed toward tumor antigens (J. Exp. Med.
2007).
Senior investigators have also published milestone papers. Dr.
Koseki studies epigenetic inheritance and has indentified a protein,
Np95, that is essential in vivo to maintain global and local DNA
methylation and to repress transcription of retrotransposons and
imprinted genes (Nature 2007). Calcium is a well know intracellular
second messenger in cell signaling but Dr. Hirano has found that zinc is
as well. He was able to visualize a zinc wave following cross-linking of
the FcεR1 on mast cells (J. Cell Biology 2007). Dr. Saito found that the
Bcl-10 adaptor–binding partner CARD9 is a critical common adaptor
protein in myeloid cells for signaling through both ITAM-associated
receptors and Toll-like receptors (Nature Immunology 2007). Dr.
Kurosaki discovered that the calcium-binding endoplasmic reticulum
protein STIM1 is critical to mast cell function. STIM1 critically regulates
FceRI Ca influx, activation of the NF-κB and NFAT transcription factors,
degranulation, and in vivo anaphylaxis responses (Nature Immunology
2007).
Masaru Taniguchi
March, 2008
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