Roland Tisch

The Role of Cell Adhesion Molecules in the Development of IDDM: Implications for Pathogenesis and Therapy

IDDM is a chronic inflammatory disease in which there is autoimmune-mediated organ-specific destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans. The migration of autoreactive lymphocytes and other leukocytes from the bloodstream into the target organ is of clear importance in the etiology of many organ-specific autoimmune/inflammatory disorders, including IDDM. In IDDM, this migration results in lymphocytic invasion of the islets (formation of insulitis) and subsequent destruction of β-cells. Migration of lymphocytes from the bloodstream into tissues is a complex process involving sequential adhesion and activation events. This migration is controlled in part by selective expression and functional regulation of cell adhesion molecules (CAMs) on the surface of lymphocytes and vascular endothelial cells or in the extracellular matrix. Understanding the mechanisms that regulate lymphocyte migration to the pancreatic islets will lead to further understanding of the pathogenesis of IDDM. In this article, we summarize the recent advances regarding the function of CAMs in the development of IDDM in animal models and in humans and discuss the potential for developing CAM-based therapies for IDDM.

Isolation of Nonobese Diabetic Mouse T-Cells That Recognize Novel Autoantigens Involved in the Early Events of Diabetes

Insulin-dependent diabetes mellitus (IDDM) is thought to result from chronic, cell-mediated, autoimmune islet damage. Our aim was to identify the earliest T-cell autoantigen in IDDM, reasoning that this antigen could be causally involved in the initiation of the disease. Identification of the earliest β-cell-specific autoantigen is extremely important in allowing advances in prevention and treatment of initial events in the development of inflammatory insulitis that precedes β-cell destruction and overt diabetes. Therefore, we analyzed the proliferative responses of peripheral β-cells from young, female nonobese diabetic (NOD) mice to extracts of pancreatic β-cell lines. We were able to demonstrate that T-cells responsive to β-cell antigens exist in the peripheral lymphoid tissue of these mice in the absence of deliberate priming before the manifestation of histologically detectable insulitis. T-cell lines and clones isolated from the peripheral lymphatic tissues of young, unimmunized, female NOD mice were also shown to react with extracts of β-cells. Fractionation of the β-cell extracts showed that these T-cell clones recognized multiple β-cell-specific autoantigens but none of the previously reported putative autoantigens (glutamic acid decarboxylase [GAD]65, GAD67, Hsp65, insulin, ICA 69, car boxy peptidase-H, and peripherin). Thus, we can conclude that these responses are specific for novel β-cell autoantigens. Finally, NOD T-cell proliferative responses were also seen to an extract of human islets suggesting potential shared antigenic determinants between human and mouse β-cells. Our observation that human and murine β-cell-specific antigens are conserved offers the possibility that identification of these murine autoantigens may lead to the discovery of the human homologue. This will pave the way toward effective diagnosis and/or immunotherapy to prevent diabetes.