A RATIONALLY DESIGNED IMMUNOMODULATORY PEPTIDE UPPREGULATES EXPRESSION OF HEMEOXYGENASE-1 AND ATTENUATES CHRONIC REJECTION IN A RAT RENAL ALLOGRAFT MODEL

Abstract

982 Upregulation of hemeoxygenase-1 (HO-1) has been shown to be associated with long term graft survival in various transplant models. In addition, modulation of HO-1 was shown to inhibit cell proliferation of several immune effector functions. Recently, a novel rationally designed immunomodulatory peptide (RDP1258) was shown to induce HO-1 expression in vivo. The present study was undertaken to determine whether peptide RDP1258 would attenuate the pathological changes seen in chronic renal allograft rejection. Orthotopic renal transplantations were performed using F344 (RT11v1) rats as donors and Lewis (RT11) rats as recipients. Recipients were treated briefly (10 days) with low dose cyclosporine (CsA, 0.75mg/kg sc) to reverse the initial acute rejection. Animals that survived > 140 days demonstrated histological evidence of chronic rejection characterized by vascular obliteration, tubular atrophy, glomerulosclerosis as well as interstitial and cortical fibrosis. Recipients were randomly allocated into one of four groups: 1) CsA alone (n=11); 2) CsA + RDP1258, day 0-20 (n=10); 3) CsA + RDP1258, day 50-70 (n=8); and 4) CsA + RDP1258 day 100-120 (n=9). Renal function was assessed by serum creatinine levels at day 140 and pathology was graded by two blinded pathologists. Survival rate > 140 days was 58.3%, 50%, 87.5% and 62.5% for groups 1-4 respectively. Mean serum creatinine levels were all within normal range (66.4-130.1 μmol/L). Grafts treated with CsA and RDP1258 from day 50-70 had a marked reduction in both intimal thickening and cortical scarring compared to grafts treated with CsA alone. (Table)TableLew-Lew controls had 100% survival rate and had no histological evidence of chronic rejection. We conclude that peptide RDP1258 can inhibit transplant vasculopathy in rat renal allografts. Although RDP1258 was shown to upregulate HO-1 expression and to decrease TNFα production, further studies will be necessary to elucidate the peptide's mechanism of action in this chronic rejection model.