title: Prevention of autoimmune diabetes by treatment with anti-LFA-1 and anti-ICAM-1 monoclonal antibodies.
abstract: Insulin-dependent diabetes mellitus (IDDM) in humans and mouse models is caused by a T cell-mediated destruction of the beta cells in the islets of Langerhans. The interaction between T cells and their antigens or targets is assisted by adhesion molecules on the surfaces of lymphocytes and counterreceptors on antigen-presenting or other cells. One such pair of molecules thought to be of importance in IDDM is lymphocyte function-related antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) because culture of islet cells with cytokines results in the expression of ICAM-1 on islet cells in vitro. To understand the importance of this interaction in the development of autoimmune diabetes, we have studied the ability of monoclonal antibodies (mAbs) against LFA-1 and/or ICAM-1 to prevent disease in multidose streptozotocin-induced diabetes mellitus (MDSDM). Treatment with both anti-LFA-1 and anti-ICAM-1 mAbs reduced the development of hyperglycemia and insulitis in this model. Treatment with the anti-LFA-1 and anti-ICAM-1 mAbs caused modulation of LFA-1 and ICAM-1 expression on splenocytes, respectively. In mice that were undergoing streptozotocin-induced diabetes, ICAM-1 was found on capillary endothelial cells and on cells surrounding the islets but was not expressed at detectable levels on islet endocrine cells. Thus, interaction between ICAM-1 and LFA-1 is involved in the development of autoimmune diabetes in MDSDM. It is unlikely that ICAM-1 molecules mediate adherence between T cells and islet cells themselves. Our results suggest that treatment with anti-ICAM-1 and anti-LFA-1 mAbs prevents localization of T cells to the islets rather than causing functional impairments of the lymphocytes. The actual sites of interaction between the T cells involved in MDSDM and ICAM-1 are unknown, but may occur on cells that normally express ICAM-1 in the islet or may occur outside the islet itself.
authors.affiliation: Department of Medicine, University of Chicago, Illinois 60637.
authors.forename: K C
authors.initials: KC
authors.lastname: Herold
authors.forename: V
authors.initials: V
authors.lastname: Vezys
authors.forename: A
authors.initials: A
authors.lastname: Gage
authors.forename: A G
authors.initials: AG
authors.lastname: Montag
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D016525:Antigenic Modulation; D015815:Cell Adhesion Molecules / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D006943:Hyperglycemia / Q000517:prevention & control; D007158:Immunologic Techniques; D018799:Intercellular Adhesion Molecule-1; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology; D013311:Streptozocin; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1; D013311:Streptozocin