TREATMENT OF AUTOIMMUNE DIABETES AND INSULITIS IN NOD MICE WITH HEAT-SHOCK-PROTEIN-60 PEPTIDE P277

We recently showed that a peptide of the M(r), 60,000 heat shock protein molecule, designated peptide p277, is a target of T-cells in autoimmune diabetes in NOD mice. Indeed, the p277 peptide could be used as a therapeutic agent to arrest the autoimmune process even after it was far advanced. The present study was done to document the effects of p277 therapy on inflammation of the islets and on T-cell responsiveness to p277. Groups of female NOD mice of various ages up to 17 weeks were treated with a single inoculation of p277 given before or after the onset of overt hyperglycemia, We now report that fragments of p277 can affect diabetes but that optimal therapy requires the whole peptide. The positive response to p277 was dependent on administration of a threshold dose of peptide. Therapy was accompanied by the regression of intra-islet inflammation and the reappearance of histologically normal islets. Successful peptide therapy was associated with downregulation of T-cell immunity to p277. Adoptive transfer experiments demonstrated that the spleen cells of p277-treated mice were no longer diabetogenic and also could suppress the diabetogenic potential of cotransferred spleen cells of untreated female NOD mice. These results indicate that specific treatment of diabetes with a defined peptide can reprogram the autoimmune response.