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Abstract

Grant Number:	5R01CA031798-23
Project Title:	LYMPHOCYTE FUNCTION ASSOCIATED ANTIGENS

PI Information:	Name	Email	Title
	SPRINGER, TIMOTHY A.	springer_lab@idi.harvard.edu	PROFESSOR

Abstract: DESCRIPTION (Adapted from Investigator's Abstract): Lymphocyte function-associated (LFA) molecules and intercellular adhesion molecules (ICAMs) are important both in antigen-specific interactions in immune responses and in interactions with endothelial cells during leukocyte localization in inflammation. LFA-1 is an alpha/beta heterodimer and a member of the integrin family. It binds to 3 ICAMs, (ICAM-1, ICAM-2, and ICAM-3) that are members of the Ig superfamily (IgSF) and are closely related (35-55%) to one another. ICAM-4 and ICAM-5 are further homologues that bind more weakly to LFA-1. The physiologic importance of these molecules is demonstrated by effect of deficiency of LFA-1 in an inherited disease, LAD; effect of ICAM-1 deficiency in mice; and effect of mAb to these molecules in inhibiting antigen-specific T lymphocyte responses, graft rejection, and animal models of disease. Studies of the function of these molecules in health and disease, the regulation of adhesiveness through them, and the structure of their interaction sites is of great importance, and may lead to the development of novel anti- inflammatory agents. We will determine the structure of domains 3, 4, and 5 in ICAMs, reconstruct the architecture of dimeric ICAM-1 on the cell surface, and determine the function of dimerization in binding to LFA-1. The hypothesis that the LFA-1 I domain exists in high and low affinity states will be examined with mutations that stabilize these states, determining the binding sites and inhibitory mechanisms of antibodies, and determining the structure of the LFA-1 I domain complexed with 1 or 2 domain fragments of ICAM-1. A low-resolution structure of LFA-1 will include information on domain associations and their alteration in activation. The crystal structure will be determined for LFA-1 or its fragments.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
chemical binding, chemical structure function, integrin, leukocyte adhesion molecule
T lymphocyte, antibody, binding site, gene mutation, protein folding
X ray crystallography, laboratory mouse

Institution:	IMMUNE DISEASE INSTITUTE, INC.
	3 Blackfan Circle
	BOSTON, MA 02115
Fiscal Year:	2003
Department:
Project Start:	01-JUL-1981
Project End:	29-FEB-2004
ICD:	NATIONAL CANCER INSTITUTE
IRG:	ALY

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