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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA031798-23
Application #
6632890
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Gallahan, Daniel L
Project Start
1981-07-01
Project End
2004-02-29
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
23
Fiscal Year
2003
Total Cost
$565,521
Indirect Cost
Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
059709394
City
Boston
State
MA
Country
United States
Zip Code
02115
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