SPLENIC MACROPHAGES FROM THE NOD MOUSE ARE DEFECTIVE IN THE ABILITY TO PRESENT ANTIGEN

IDDM results from the destruction of pancreatic beta-cells by autoreac tive T-cells that appear to avoid deletion early in development, possi bly due to improper interaction with antigen-presenting cells (APCs) r esident in the thymus or periphery. In the nonobese diabetic (NOD) mou se, there exists a defect in APC function characterized by its failure to fully mature upon stimulation. The NOD mouse thus provides an exce llent model for the investigation of APC dysfunction and development a nd how these relate to the incidence of autoimmune diabetes. We initia ted studies of APC function in the NOD mouse with respect to antigen p rocessing and presentation, using a well-characterized antigen hen egg lysozyme (HEL) and comparing it with the closely related, major histo compatibility complex (MHC) (I-A(g7)) identical, diabetes-resistant mo use strain NOR. Proliferation assays comparing NOD and NOR HEL-specifi c T-cells demonstrated that the T-cell proliferation response of the N OD mouse to both native and denatured forms of the antigen is lower th an that of NOR. When crisscross proliferation experiments were conduct ed using purified T-cells and irradiated spleen cells as APCs from bot h strains, the results demonstrated that the defect in proliferation r esided in the APC compartment of activation. The levels of intracellul ar glutathione (GSH) mere compared in splenic macrophages from NOD and NOR mice; it was found that on antigenic stimulation, NOR macrophages produced significantly more intracellular GSH than did NOD macrophage s, even under hyperglycemic (50 mmol/l glucose) conditions. The lower amount of GSH seen in the NOD may result in less efficient processing of antigen, and subsequently, lower levels of T-cell activation.