NOD MOUSE DIABETES - THE UBIQUITOUS MOUSE HSP60 IS A BETA-CELL TARGETANTIGEN OF AUTOIMMUNE T-CELLS

In the NOD mouse, the onset of beta-cell destruction is associated wit h spontaneous development of T-lymphocytes reactive to members of the 60 kDa heat shock protein (hsp60) family, including the Mycobacterial (MT) and the human (H) hsp60 molecules. Diabetes in the NOD mouse is a spontaneous tissue-specific autoimmune disease occurring without prio r immunization. Therefore, it has been suggested that the anti-hsp60 T cells involved in the autoimmune diabetes of NOD mice might reflect m olecular mimicry between MT-hsp60 and a beta-cell tissue specific mole cule sharing similar T cell epitopes, the p277 peptide of hsp60 in par ticular. We cloned and expressed the mouse hsp60 cDNA from a beta-cell tumour. This mouse beta-cell hsp60 cDNA was found to be identical in sequence to the hsp60 of mouse fibroblasts. We further report that NOD spleen cells and an NOD diabetogenic T cell clone C9 responded to the recombinant mouse hsp60 and to its peptide M-p277 to the same extent as to H-hsp60 and H-p277. Splenocytes of mice of other strains did not respond to p277. Moreover, treatment of 3 month old NOD mice with the non-modified self M-p277 peptide was as efficient as H-p277, from whi ch it differs in one amino acid, in halting progression of the disease . Thus, anti-H-p277 T cells modulating diabetes in the NOD mouse are a utoreactive, and are targeted at the mouse beta-cell hsp60, which is n ot tissue specific. These findings raise the question of how a non-tis sue specific molecule may be a target of a tissue-specific autoimmune disease. (C) 1996 Academic Press Limited