Prolongation of heart xenograft survival in a hamster-to-rat model after therapy with a rationally designed immunosuppressive peptide

Background Modification of the aminoacid sequence of peptides derived hom t he HLA class I heavy chain in combination with computer rational design res ulted in the development of a peptide, RDP1258, with enhanced immunosuppres sive activity. Methods. We evaluated the activity of this peptide, analyzing infiltrate by immunohistology and cytokine transcripts by reverse transcriptase-polymera se chain reaction method, in a hamster-to-rat xenograft model where recipie nts were treated with cobra venom factor (CVF) and peptide. Results. Although CVF or peptide alone had no effect, a combination of CVF/ peptide RDP1258 resulted in a significant prolongation of graft survival (7 .9+/-1 vs. 4.5+/-0 and 3.5+/-0 days, P<0.001). This effect was associated w ith an increased expression, of heme oxygenase 1 (HO-1) in spleen, a signif icant reduced graft infiltrate, and a decrease of tumor necrosis factor-alp ha mRNA transcripts (P<0.05) compared with CVF-treated recipients (1.6+/-0. 07 vs. 3.3+/-0.3%, P=0.001) on day 3 after transplantation. Conclusion. These observations are consistent with the observation that up- regulation of HO-1 results in inhibition of immune effector functions and s uggest that the peptide acts, at least partially, through HO-1 regulation.