HLA-DERIVED PEPTIDES AS NOVEL IMMUNOSUPPRESSIVES

Peptides corresponding to linear sequences of HLA molecules have been synthesized and tested for immunomodulatory activity in in vitro assay s using human T lymphocytes. Sequences from different parts of the HLA molecules have different effects. Peptides corresponding to residues 75-84 of an HLA class I supratypic specificity of limited heterogeneit y (HLA-Bw4) had profound inhibitory effects in a variety of in vitro a ssays of human T lymphocyte function. Furthermore, a 2-wk course of hu man HLA sequences and cyclosporine therapy induced enduring immunologi c tolerance in a rat model of heterotopic heart transplantation. These studies prompted clinical trials which are currently in progress. The peptides appear to induce T cell anergy by causing a prolonged intrac ellular calcium flux and interrupting normal signal transduction pathw ays. Furthermore, these peptides bind to members of the heat-shock pro tein 70 family, implicating these ubiquitous proteins in the immunomod ulatory pathway. Such peptides may be normal physiologic mediators. In any case, they represent potential new immunotherapeutics for a varie ty of immune-mediated diseases.