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PROJECT
SUMMARY
Dendritic
cells (DCs) function as sentinels of the immune system and
have a remarkable ability to interpret environmental information
and then "decide" the most appropriate response.
Consequently, they are important for directing the immune
response towards reactivity or tolerance depending on the
context and balance of environmental signals. As DCs play
such vital roles in all aspects of immunity, understanding
their complex regulation, particularly in respect to endogenous
stimuli, is of significant importance to deepening understanding
of immunity, and consequently of immune-mediated diseases.
Galectin-1 is an endogenous
galactoside-binding lectin that has a broad range of immunomodulatory
abilities on various innate and adaptive immune cells. For
example, our lab previously showed that galectin-1 uniquely
activates human monocyte-derived dendritic cells to mature
while enhancing migration through extracellular matrix. However,
galectin-1 can have different effects on the same cell depending
on the concentration of the lectin and the activation state
of the cell. Interestingly, DCs are a dynamically changing
population consisting of functionally distinct subsets in
varying stages of differentiation and activation. This project
focuses on understanding the role of galectin-1 in the immunomodulatory
functions of DCs.
The goals of our research
are to identify the signaling mediators of galectin-1 induced
maturation, and to determine the functions of DCs exposed
to galectin-1 at various stages of differentiation. Using
biological inhibitors and knock-out mouse models, we will
identify the key signaling molecules and receptors that mediate
galectin-1 activity. We will also use in vitro and in vivo
models to co-culture galectin-1 treated DCs with naïve
T cells to functionally assess their ability to regulate immune
responses. Since the eventual goal of our studies is to provide
a basis for novel therapeutic approaches to immune-based diseases,
we will also study the effects of these galectin-1 treated
DCs in an autoimmune disease model.
Galectin-1 has well-documented
effects on both central and peripheral immune tolerance. Additionally,
treatment with galectin-1 has ameliorated disease in graft-versus
host disease as well as many autoimmune models including arthritis,
hepatitis, nephritis, diabetes and multiple sclerosis. While
some of this anti-inflammatory effect is likely due to the
apoptotic activity of galectin-1 on T cells, we speculate
that regulation of DC function may also contribute to the
maintenance of tolerance and avoidance of autoimmunity in
these studies. We will use a murine lupus model to address
the ability of galectin-1 treated DCs to regulate autoimmune
inflammatory conditions. Ultimately, our studies may be useful
for optimizing therapeutic vaccines based upon ex vivo-matured
DCs for autoimmune inflammatory diseases.
If interested, please take a look at our most recent publication
on this work:
Fulcher JA, Hashimi ST, Levroney EL, Pang M, Gurney KB, Baum
LG, Lee B. Galectin-1-Matured Human Monocyte-Derived Dendritic
Cells Have Enhanced Migration through Extracellular Matrix.
J Immunol. 2006 Jul 1;177(1):216-26.
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