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 assays 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 heterogeneity (HLA-Bw4) had profound inhibitory effects in a variety of in vitro assays of human T lymphocyte function. Furthermore, a 2-wk course of human HLA sequences and cyclosporine therapy induced enduring immunologic 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 intracellular calcium flux and interrupting normal signal transduction pathways. Furthermore, these peptides bind to members of the heat-shock protein 70 family, implicating these ubiquitous proteins in the immunomodulatory pathway. Such peptides may be normal physiologic mediators. In any case, they represent potential new immunotherapeutics for a variety of immune-mediated diseases.
D000595:Amino Acid Sequence; D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use; D006085:Graft Survival; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D016027:Heart Transplantation; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D011919:Rats, Inbred Strains; D013601:T-Lymphocytes / Q000276:immunology
D018840:HSP70 Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D010455:Peptides; D016572:Cyclosporine