HSP60 PEPTIDE THERAPY OF NOD MOUSE DIABETES INDUCES A TH2 CYTOKINE BURST AND DOWN-REGULATES AUTOIMMUNITY TO VARIOUS BETA-CELL ANTIGENS

A peptide of the human BO-kDa heat-shock protein (hsp60), designated p 277, was found to be useful as a therapeutic agent to arrest the autoi mmune process responsible for diabetes in nonobese diabetic (NOD) mice . The effectiveness of peptide treatment was associated with the induc tion of peptide-specific antibodies of the IgG1 but not of the IgG2a i sotype, suggesting the possibility that a Th2-type response may have b een induced. We now report that the effectiveness of p277 treatment is associated with the transient activation of anti-p277 splenic T-cells that produce the Th2 cytokines interleukin-4 (IL-4) and IL-10. The Th 2 response to p277 was associated with reduced Th1-type autoimmunity t o hsp60 and to two other target antigens associated with diabetes: GAD and insulin. The Th2 shift appeared to be relatively specific; sponta neous T-cell reactivity to a bacterial antigen peptide remained in the Th1 mode in the p277-treated mice. Moreover, treatment with the bacte rial peptide did not induce a change in cytokine profile, and it did n ot affect progression of the disease. Thus, effective peptide treatmen t of the diabetogenic process associated with the induction of antibod ies may be explained by selective and transient activation of Th2 auto immune reactivity.