MOLECULAR BASIS OF HUMAN T-CELL HOMING TO INFLAMED SKIN

Project: Research project

Project Details

Description

The participation of lymphocytes in local immune or inflammatory responses
depends in part on their ability to recognize and extravasate through
specialized venules within lymphoid tissues and sites of chronic
inflammation. Recent functional and molecular studies have demonstrated
the existence of two independent lymphocyte-endothelial cell recognition
systems mediating lymphocyte extravasation in peripheral lymph node and
mucosal lymphoid tissues, systems thought to be critically important in the
maintenance of mucosal immune specialization. Independent tissue-selective
homing mechanisms have also been proposed for lymphocyte trafficking to
extra-lymphoid sites of chronic inflammation, but, to date, definitive
molecular proof of these putative homing specificities has not been
published. This proposal is directed at identifying and characterizing such tissue-
selective homing mechanisms in the setting of chronic inflammation, and the
determination of the functional consequences of these mechanisms to the
human inflammatory response. I have elected to focus on T-cell migration
to inflamed skin because my preliminary work suggests that this tissue is
likely a third lymphocyte homing specificity and site of tissue-specific
immune specialization. These data indicate that skin-associated memory T-
cells, both at cutaneous sites of chronic inflammation and circulating, can
be specifically identified by their expression of a novel cell surface
determinant, the Cutaneous Lymphocyte Associated antigen (CLA Ag), and that
this T-cell subset may specifically extravasate at cutaneous inflammatory
sites through an Endothelial-Leukocyte Adhesion Molecule-1 (ELAM-1)-
dependent mechanism. To further characterize this proposed skin-selective
homing specificity, my laboratory will initially focus on the structural
and functional analysis of the CLA Ag, particularly the determination of
whether this Ag represents the T-cell ELAM-1 ligand. If the CLA Ag proves
to be the T-cell ELAM-1 ligand, we will use monoclonal antibodies to this
molecule, to ELAM-1, and to other relevant adhesion molecule pairs (LFA-
1/ICAM-1, VLA-4/VCAM-1, LECCAM-1/PNAd) to determine the relative
participation of these adhesion systems in T-cell binding to venules at
cutaneous inflammatory sites. In parallel studies, we will 1) investigate
the regulation of the CLA Ag and ELAM-1 binding ability in T-cell
populations, particularly in regard to the characterization of skin-derived
factors responsible for this regulation, 2) characterize the mechanisms
responsible for preferential ELAM-1 expression on cutaneous venules in the
setting of chronic inflammation, 3) functionally analyze the CLA Ag+ T-cell
subset with the goal of identifying unique physiologic characteristics
indicative of functional adaptation to the cutaneous microenvironment, and
assess the involvement of skin-selective homing mechanisms in the
pathogenesis of the skin-associated T-cell lymphoma mycosis fungoides. An
understanding of the molecular basis and regulation of tissue-specific
homing mechanisms will be critical in the understanding of inflammatory
disease pathogenesis and lymphoma metastasis, and may lead to the
development of highly selective modalities for the treatment of these
disorders.
StatusFinished
Effective start/end date7/1/915/31/00

Funding

  • National Institutes of Health: $116,369.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $97,007.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)

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