IL-4 PREVENTS INSULITIS AND INSULIN-DEPENDENT DIABETES-MELLITUS IN NONOBESE DIABETIC MICE BY POTENTIATION OF REGULATORY T-HELPER-2 CELL-FUNCTION

Beginning at the time of insulitis, nonobese diabetic (NOD) mice demon strate a thymocyte and peripheral T cell proliferative hyporesponsiven ess induced by TCR cross-linking, which is associated with reduced IL- 2 and IL-4 secretion, We previously reported that NOD CD4(+) T cell hy poresponsiveness is reversed completely in vitro by exogenous IL-4, an d that administration of IL-4 to NOD mice prevents the onset of insuli n-dependent diabetes mellitus (IDDM), This result suggested that T cel l-mediated destruction of pancreatic islet beta cells may result from a hyporesponsiveness in regulatory Th2 cells favoring a Th1 cell-media ted environment in the pancreas, In the present study, we tested this possibility by analysis of the mechanisms of protection from IDDM affo rded by IL-4 treatment in NOD mice, We show that IL-4 protects NOD mic e from insulitis and IDDM when administered i.p. three times a week fo r 10 wk beginning at 2 wk of age, This occurs by the modulation of the homing of autoreactive cells to inflammatory sites and the stabilizat ion of a protective Th2-mediated environment in the thymus, spleen, an d pancreatic islets. Thus, IL-4 treatment favors the expansion of regu latory CD4(+) Th2 cells in vivo and prevents the onset of insulitis an d IDDM mediated by autoreactive Th1 cells.