374 The synthetic MHC class I peptide HLA-B27 (residues 75-84) has been shown to have immunoinhibitory effects in animal and human transplant studies. There is evidence that these effects may be mediated by binding to intracellular heat shock proteins, in particular heme oxygenase-1 (HO-1). Immunosuppressive activities, physico-chemical properties and molecular dynamic studies of peptide 2702.75-84 and derivatives thereof were used for the rational design of a new agent, RDP 1258 (bc-1-n1). In vitro, this peptide was shown to be 50 times more potent in inhibiting HO-1. In vivo, administration of RDP 1258 resulted in systemic upregulation of HO-1 activity, a property consistent with observations made with other in vitro inhibitors of HO-1. RDP 1258 also inhibited the rat, mouse and human MLR in a dose dependent manner. This was associated with dose dependent inhibition of INF-γ production(Figure 1). Mitogen responses were not inhibited. The effects of RDP 1258 in an acute rat renal allograft rejection model were then tested. Bilateral nephrectomized LEW rats were transplanted with full MHC mismatched WF kidneys. Rejection was defined as death (seeFigure 2). Control (n=6) animals received no treatment and survived for a median of 13.0 days. Treatment with peptide alone (1 mg i.p. on days -1, 0 and then twice weekly up to day 30; n=6) or low dose CsA alone (1 mg s.c on days 0-5; n=19) did not significantly prolong survival compared to controls: median survival 13.0 and 11.5 days, respectively. The combination of RDP 1258 + CsA (n=10), using the above regimens, significantly prolonged survival compared to all other groups (p<0.02, log rank test), to a median of 32.0 days.Fig. 1: Mean inhibition of proliferation and INF-γ production in rat MLRFig. 2: Kaplan-Meier survival plotIn conclusion, RDP 1258, a novel synthetic peptide, inhibited alloreactive responses in vitro and modified the course of acute renal allograft rejection. These effects may be related to in vivo upregulation of the immunomodulatory heat shock protein, HO-1.