Computer-assisted rational design of immunosuppressive compounds.

We describe the rational design of immunosuppressive peptides without relying on information regarding their receptors or mechanisms of action. The design strategy uses a variety of topological and shape descriptors in combination with an analysis of molecular dynamics trajectories for the identification of potential drug candidates. This strategy was applied to the development of immunosuppressive peptides with enhanced potency. The lead compounds were peptides, derived from the heavy chain of HLA class I, that modulate immune responses in vitro and in vivo. In particular, a peptide derived from HLA-B2702, amino acids 75-84 (2702.75-84) prolonged skin and heart allograft survival in mice. The biological activity of the rationally designed peptides was tested in a heterotopic mouse heart allograft model. The molecule predicted to be most potent displayed an immunosuppressive activity approximately 100 times higher than the lead compound.

Decreased cytotoxic activity of natural killer cells in kidney allograft recipients treated with human HLA-derived peptide.

Peptides derived from a conserved region (aa 75-84) of HLA class I, overlapping the supertypic HLA-BW4/BW6 antigen region, have been shown to exhibit nonallele restricted immunosuppressive properties in rats and mice, prolonging survival of major histocompatibility complex-mismatched allografts. Furthermore, HLA-B7 peptides inhibit alloreactive cytotoxic cells, and both HLA-B7 and HLA-B2702 peptides inhibit natural killer (NK) cytotoxicity in vivo. In this article, we report on a randomized, controlled study of the safety and pharmacokinetics of HLA-B2702-derived peptide in human recipients of a first kidney allograft. Escalating doses of HLA-B2702 were compared with doses of placebo controls. No toxicity and no immunization against the peptide were noted. Although the study was not designed as an efficacy trial, patients who received the high-dose protocol (7 mg/kg) did experience more rejection episodes, but this was not statistically significant when compared with control patients. Interestingly, in human recipients, as previously observed in rodents, administration of the peptide was associated with a statistically significant decrease in the cytotoxicity of NK cells against K562 targets (P<0.001). As these peptides correspond to a region of the HLA class I molecule that interacts with the newly described NK receptors for class I, their mode of action through interaction with such receptors is discussed. As a peptide of the same sequence from HLA-B7 blocks both NK and alloreactive T cell cytotoxicity, it is possible that, in humans too, both types of cytotoxic cells are affected by this peptide. The biological significance of these observations should be confirmed in future controlled studies with a larger patient population.