DIVERSIFICATION OF T-CELL RESPONSES TO CARBOXY-TERMINAL DETERMINANTS WITHIN THE 65-KD HEAT-SHOCK-PROTEIN IS INVOLVED IN REGULATION OF AUTOIMMUNE ARTHRITIS

The T cell response to the 65-kD mycobacterial heat-shock protein (Bhs p65) has been implicated in the pathogenesis of autoimmune arthritis. Adjuvant arthritis (AA) induced in the Lewis rat (RT-1(1)) by injectio n of Mycobacterium tuberculosis serves as an experimental model for hu man rheumatoid arthritis (RA). However, the immunological basis of reg ulation of acute AA, or of susceptibility/resistance to AA is not know n. We have defined the specificity of the proliferative T cell respons es to Bhsp65 during the course of AA in the Lewis rat. During the earl y phase of the disease (6-9 d after onset of AA), Lewis rats raised T cell responses to many determinants within Bhsp65, spread throughout t he molecule. Importantly, in the late phase of the disease (8-10 wk af ter onset of AA), there was evidence for diversification of the T cell responses toward Bhsp65 carboxy-terminal determinants (BCTD) (namely, 417-431, 441-455, 465-479, 513-527, and 521-535). Moreover, arthritic rats in the late phase of AA also raised vigorous T cell responses to those carboxy-terminal determinants within self(rat) hsp65 (Rhsp65) t hat correspond in position to the above BCTD. These results suggest th at the observed diversification is possibly triggered in vivo by induc tion of self(Rhsp65)-reactive T cells. Interestingly, another strain o f rat, the Wistar Kyoto (WKY/NHsd) rat (RT-1(1)), with the same major histocompatibility complex class II molecules as the Lewis rat, was fo und to be resistant to AA. In WKY rats, vigorous responses to the BCTD , to which the Lewis rat responded only in the late phase of AA, were observed very early, 10 d after injection of M. tuberculosis, Striking ly, pretreatment with the peptides comprising the set of BCTD, but not its amino-terminal determinants, provided significant protection to n aive Lewis rats from subsequent induction of AA. Thus, T cell response s to the BCTD are involved in regulating inflammatory arthritis in the Lewis rat and in conferring resistance to AA in the WKY rat. These re sults have important implications in understanding the pathogenesis of RA and in devising new immunotherapeutic strategies for this disease.