CD40 LIGAND-CD40 INTERACTIONS ARE NECESSARY FOR THE INITIATION OF INSULITIS AND DIABETES IN NONOBESE DIABETIC MICE

The nonobese diabetic (NOD) mouse spontaneously develops T cell-depend ent autoimmune diabetes, Here, we investigate the role of CD40 ligand (CD40L)-CD40 costimulation in the initiation and progression of this d isease, Anti-CD40L mAb treatment of 3- to 4-wk-old NOD females (the ag e at which insulitis typically begins) completely prevented the insuli tis and diabetes, in contrast, treatment of such mice with anti-CD40L at > 9 wk of age did not inhibit the disease process. These results su ggest that a costimulatory signal by CD40L is required early but not i n the effector phase of disease development, Anti-CD40L treatment affe cted the priming of islet Ag-specific T fell responses in vivo, Cytoki ne analysis revealed a dramatic decrease in IFN-gamma and IL-2 release without a concomitant increase in IL-4 production by T cells from ant i-CD40L-treated mice, Thus, anti-CD40L impaired the islet Ag-specific Th1 cell response in vivo, and the prevention of diabetes by anti-CD40 L was not associated with switching of the response from a Th1 to a Th 2 profile, Cotransfer of splenocytes from anti-CD40L-treated mice with splenocytes from diabetic NOD mice into NOD/scid mice did not inhibit the transfer of disease, indicating that anti-CD40L does not prevent the disease by inducing regulatory cells. Since anti-CD40L clearly pre vented the insulitis by inhibiting the development and further accumul ation of pathogenic Th1 cells to islets of Langerhans, we conclude tha t CD40L-CD40 costimulation is required for early events in the develop ment of spontaneous autoimmune diabetes.