GLUTAMATE DECARBOXYLASE-REACTIVE PERIPHERAL-BLOOD LYMPHOCYTES FROM PATIENTS WITH IDDM EXPRESS GUT-SPECIFIC HOMING RECEPTOR ALPHA(4)BETA(7)-INTEGRIN

Migration of lymphocytes to the pancreas is a prerequisite for insulit is in IDDM. Mucosal vascular addressin (MAdCAM-1), involved in the rec irculation of lymphocytes to the gut, has been found in the inflamed i slets in NOD mice. In humans, triggers of the gut immune system (e.g., early exposure to cow's milk proteins in infancy, exposure to enterov iral infections) have been associated with IDDM. To study the possible link between the gut immune system and IDDM, we tested the expression of the alpha(4) beta(7)-integrin, a homing receptor for MAdCAM-1, on GAD65-reactive lymphocytes. Using immunomagnetic cell sorting, we depl eted the lymphocytes with high expression of alpha(4) beta(7)-integrin in the peripheral blood mononuclear cell population from IDDM patient s and patients with autoimmune polyendocrine disease type 1 (APD-I). T he depletion led to a marked decrease (mean 70%) in the cellular respo nse against GAD65 in three of six IDDM patients and in one subject at high risk fdr IDDM. A decrease of 37% in the GAD response was observed after depletion in the case of one APD-I patient who also had IDDM. C ellular response to tetanus toroid increased in the majority of patien ts as well as in three control subjects studied. We demonstrated that a remarkable population of islet cell antigen-reactive lymphocytes exp ress the gut-specific homing receptor, which emphasizes the role of gu t immunity in IDDM. The manipulation of the gut immune system is there fore proposed as a tool for modulation of the autoimmunity against pan creatic beta-cells in IDDM.