T cells in autoimmunity and allograft rejection

Since T lymphocytes are important regulators and effectors of the immune response, a basic understanding of T lymphocyte activation and differentiation may lay the basis for novel immunotherapies of immune mediated diseases. Potential sites at which to interrupt T lymphocyte mediated diseases include: (1) HLA-peptide interactions, (2) T cell receptor (TCR) recognition of peptides in the context of HLA, (3) biochemical signals mediated via the TCR, (4) numerous other cellular adhesion and 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 peptides corresponding to regions of the polymorphic alpha 1 and alpha 2 domains could inhibit lysis by cytotoxic T lymphocytes (CTL) specific for those regions. We now show that peptides corresponding to certain conserved regions of the HLA class I molecule can profoundly inhibit CTL. Furthermore, peptides corresponding to a particular conserved region of the HLA class I alpha 1 alpha helix are able to significantly prolong rat heterotopic heart transplants when given in conjunction with a sub-therapeutic course of cyclosporin A. These observations raise the possibility that soluble HLA molecules are natural immunoregulatory factors in vivo and that synthetic peptides may prove useful as novel immunosuppressive drugs.