Abstract
| Grant Number: |
5R01DK051362-06 |
| PI Name: |
BLUMBERG, RICHARD S. |
| PI Email: |
mailto:rblumberg@partners.org |
| PI Title: |
ASSOCIATE PROFESSOR OF MEDICINE |
| Project Title: |
Regulation of Mucosal Lymphocytes |
Abstract: The gut associated lymphoid tissue must manage a tedious
balance between "physiologic" and "tissue destructive" inflammation associated
acutely with exposure to pathogens and other exogenous assaults and
chronically in the setting of the idiopathic types of inflammation associated
with inflammatory bowel disease. Central to understanding and thus being to be
able to intervene into these types of inflammations is the need to gain a
deeper understanding into the mechanisms by which T cells are regulated by
professional and nonprofessional antigen presenting cells in the gut. Many
immune-mediated diseases of the intestine are directly dependent upon the
activation of Y cells and their cytokine products. As such, understanding the
molecular mechanisms by which the functional levels of T cells are managed is
increasingly relevant to the pathogenesis of gut- associated diseases. T cells
are primarily activated by signals delivered to the antigen specific receptor,
the T cell receptor (TCR)/CD3 complex, which is modified by secondary signals
that are either stimulatory or inhibitory. The responsiveness of a T cell is
thus tunable through specific affinities of its TCR/CD3 complex for antigen in
the context of a major histocompatibility complex (MHC) molecule and the
compilation of concomitant positive and negative secondary signals. The major
secondary stimulatory and inhibitory signals for the majority of T cells are
those delivered by either CD28 or CTLA-4, respectively. It has, however,
become increasingly evident that many T cells, including those in the
intestine, do not express these molecules and, as a corollary, other molecules
may provide such functions. This grant application proposes to investigate the
novel hypothesis that CEACAM1 functions to negatively regulate the activities
of mucosal T cells initiated by antigen/MHC mediated signals. We, therefore,
propose the following specific aims: (1) to examine the expression and
function of CEACAM1 by human and mouse mucosal T cells including a
determination of whether CEACAM1 regulates T helper 1 (Th1) and Th2 cytokine
production; (2) to determine whether homophilic-CEACAM1 interactions are
involved in regulating mucosal T cell functions by testing whether wild-type
CEACAM1-Fc fusion proteins, but not fusion proteins mutant in the homophilic
binding sites, inhibit mucosal T cell function in vitro; (3) determining
whether the phosphorylation state of the CEACAM1 cytoplasmic tail regulates
the cellular distribution and inhibitory functions of CEACAM1, and; (4) to
determine whether CEACAM1 specific antibodies and CEACAM1-Fc fusion proteins,
but not CEACAM1-Fc fusion proteins mutated in the homophilic binding site, can
inhibit Th1-mediated inflammation in vivo.
Thesaurus Terms:
CD antigen, T lymphocyte, cell adhesion
molecule, gut associated lymphoid tissue, immunoregulation, inflammation
T
cell receptor, antigen presenting cell, carcinoembryonal antigen, cytokine,
helper T lymphocyte, leukocyte activation /transformation, major
histocompatibility complex, mucosal immunity, phosphorylation, protein
tyrosine phosphatase
chimeric protein, human tissue, laboratory mouse
| Institution: |
BRIGHAM AND WOMEN'S HOSPITAL |
|
75 FRANCIS ST |
|
BOSTON, MA 02115 |
| Fiscal Year: |
2002 |
| Department: |
|
| Project Start: |
01-APR-1997 |
| Project End: |
31-MAR-2006 |
| ICD: |
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY
DISEASES |
| IRG: |
GMA |
  
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