T-CELLS IN AUTOIMMUNITY AND ALLOGRAFT-REJECTION

Since T lymphocytes are important regulators and effecters of the immu ne response, a basic understanding of T lymphocyte activation and diff erentiation may lay the basis for novel immunotherapies of immune medi ated diseases. Potential sites at which to interrupt T lymphocyte medi ated diseases include: (1) HLA-peptide interactions, (2)T cell recepto r (TCR) recognition of peptides in the context of HLA, (3) biochemical signals mediated via the TCR, (4) numerous other cellular adhesion an d signaling pathways, (5) second messengers, (6) transcription factors , and (7) various effector molecules, including granzymes and perforin . We have investigated the effects of peptides corresponding to linear sequences of HLA class I molecules. Previously, we showed that peptid es corresponding to regions of the polymorphic alpha(1) and alpha(2) d omains could inhibit lysis by cytotoxic T lymphocytes (CTL) specific f or those regions. We now show that peptides corresponding to certain c onserved regions of the HLA class I molecule can profoundly inhibit CT L. Furthermore, peptides corresponding to a particular conserved regio n of the HLA class I alpha(1) alpha helix are able to significantly pr olong rat heterotopic heart transplants when given in conjunction with a sub-therapeutic course of cyclosporin A. These observations raise t he possibility that soluble HLA molecules are natural immunoregulatory factors in vivo and that synthetic peptides may prove useful as novel immunosuppressive drugs.