Brief overview of our projects:
We are working on various projects right from addressing issues of basic immunology to the development of clinical tools. Some of our projects are highlighted below.Basophils as regulators of immune responses and fibrosis
We have
identified
the
previously obscure
antigen-capturing cells
as
basophils. In
pre-immunized mice only two cell
populations are able to bind
(capture) significant amounts of
antigen on their cell surface.
These are antigen-specific B cells
that capture the antigen by their
specific B cell receptor; and
basophils that capture antigens by
antigen-specific IgE bound to the
high affinity FceRI-receptor.
Binding of antigens activates
basophils to immediately release
IL-4 and IL-6 (in mice). During a
secondary (memory) immune response
basophils are responsible for the
immediate production of IL-4
following injection of the antigen.
This leads to an enhancement of
humoral memory immune responses.
Also in primary immune responses
basophils constitute an important
source of IL-4 as basophils can
also be activated by various
cytokines and other molecules like
proteases from parasites. Thus
basophils are an important source
for the initial IL-4 which is
required to induce a Th2
differentiation. By enhancement of
humoral and Th2 immune responses,
basophils play an important role in
diseases like rheumatoid arthritis
and lupus nephritis. Due to the
profibrotic properties of IL-4
basophils are also involved in
fibrogenesis, as shown in a model
of chronic transplant rejection.
We currently further
analyze the role of basophils in
autoimmunity and fibrosis.
Role of IL-3 for autoimmunity and inflammation
IL-3 belongs to
the family of hematopoietic
cytokines including GM-CSF and
IL-5. For many years IL-3 was
considered to be mainly involved in
hematopoiesis and defense against
parasites. We have identified IL-3
as an essential cytokine in
systemic lupus erythematodes (SLE),
rheumatoid arthritis and multiple
sclerosis and demonstrate that T
cells are the main source of IL-3
in murine models of inflammation.
Blockade of IL-3 with an antibody
or genetic deletion of IL-3
markedly improved disease activity
in mouse models for systemic lupus
(MRL-lpr), rheumatoid arthritis
(collagen-induced arthritis, CIA)
and multiple sclerosis
(experimental autoimmune
encephalitis, EAE). We and others
found that IL-3 is an essential
inductor cytokine for several
classical proinflammatory
cytokines, like IL-6, TNF-alpha and
IL-1. In addition, IL-3 is
essential for mobilization of
innate immune cells from the bone
marrow during inflammation. Thus,
blockade of IL-3 interferes with
multiple proinflammatory mechanisms
explaining the superior efficacy of
inhibitory IL-3 antibodies.
Blockade or deficiency of IL-3 is
very well tolerated in mice. In
contrast, injection of recombinant
IL-3 significantly increased
disease activity in mouse models
and induced polyarthritis in
healthy rhesus monkeys.
In humans, IL-3
activates plasmocytoid dendritic
cells (pDC), monocytes, basophils,
mast cells, B cells and endothelial
cells. Plasmacytoid dendritic cells
are the most important producers of
type I interferons that play a
central role in the pathogenesis of
systemic lupus. Also monocytes and B
cells importantly contribute to
autoimmune diseases in humans. In
endothelial cells IL-3 induces the
upregulation of E- and P-selectins
and thus enables the transendothelial
migration of leukocytes. We have
generated multiple monoclonal
antibodies against human IL-3 and
currently analyze the expression of
IL-3 in patients with autoimmune and
inflammatory diseases. We also
evaluate the potential of these
antibodies for treatment of patients.
Functional analysis of monocyte subsets
Mouse and human
monocytes can be divided into CCR2+
and CCR2- monocytes. The majority of
monocytes is CCR2+ and is frequently
found in inflamed tissue. Using a
variety of animal models and
antibodies to specifically deplete
these cells we and others have shown
that CCR2+ monocytes are critically
involved in inflammation and tissue
destruction. We currently develop new
tools to specifically deplete CCR2+
monocytes in patients with
inflammatory and autoimmune diseases.
Mechanisms of fibrogenesis with focus on kidney fibrosis
During recent
years we and others have established
that collagen-producing cells in the
kidney can be derived from various
cellular sources, including resident
mesenchymal fibroblasts, pericytes,
bone marrow-derived cells, tubular
epithelial cells and endothelial
cells. Collagen producing bone marrow
derived cells are frequently called
fibrocytes. We investigate to what
extent fibrocytes contribute to renal
fibrosis, how they migrate into the
kidney and how they are activated to
produce collagen. We also study the
functional relevance of cell-type specific collagen-production in
the kidney.
Blockade of IL-3 to treat autoimmune and infalmmatory diseases
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Depletion of CCR2+ proinflammatory monocytes
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Basophils in immune regulation and fibrosis
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