Peptides corresponding to linear sequences of HLA molecules have been synthesized and tested for immunomodulatory activity inin vitroassays 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 ofin vitroassays 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.