RDP1258, a new rationally designed immunosuppressive peptide, prolongs allograft survival in rats: analysis of its mechanism of action

• Published in: Molecular medicine (Cambridge, Mass.) Mass.), 1999-12, Vol.5 (12), p.820-832
• Main Authors: Cuturi, M C, Christoph, F, Woo, J, Iyer, S, Brouard, S, Heslan, J M, Pignon, P, Soulillou, J P, Buelow, R
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - chemical synthesis; Adjuvants, Immunologic - pharmacology; Animals; Cell Movement - drug effects; Cell Movement - immunology; Cytotoxicity, Immunologic - drug effects; Enzyme Inhibitors - immunology; Enzyme Inhibitors - pharmacology; Graft Survival - drug effects; Heart Transplantation - immunology; Heart Transplantation - pathology; Heme Oxygenase (Decyclizing) - antagonists & inhibitors; Heme Oxygenase (Decyclizing) - metabolism; Immunosuppressive Agents - chemical synthesis; Immunosuppressive Agents - pharmacology; Isoantibodies - biosynthesis; Male; Oligopeptides - chemical synthesis; Oligopeptides - pharmacology; Protoporphyrins - immunology; Protoporphyrins - pharmacology; Rats; Rats, Inbred Lew; RNA, Messenger - biosynthesis
• ISSN: 1076-1551; 1528-3658
• DOI: 10.1007/bf03401995

Peptides derived from the HLA class I heavy chain (a.a. 75-84) have been shown to modulate immune responses in vitro and in vivo in a non-allele-restricted fashion. In vivo studies in rodents have demonstrated prolonged allograft survival following peptide therapy. The immunomodulatory effect of these peptides has been correlated with peptide-mediated modulation of heme oxygenase 1 activity (HO-1). Recently, we used a rational approach for designing novel peptides with enhanced immunosuppressant activity. These peptides were also more potent inhibitors of HO-1 activity in vitro. Here we evaluated one of these peptides, RDP1258, for its ability to prolong heterotopic heart graft survival in rats. The peptide mediated effect on HO-1 was analyzed in vitro and in vivo. Peptide RDP1258 was shown to inhibit rat HO-1 in vitro in a dose-dependent fashion. However, RDP1258, like other HO-inhibitors, when administered to rats, secondarily resulted in an up-regulation of splenic HO-1 activity. Up-regulation of HO-1 was associated with prolonged heart allograft survival (6.6 +/- 0.6 vs. 2/14 > 100 days and 12/14 16.2 +/- 1.7 days; p < 0.001). The analysis of graft infiltrating cells on day 5 after transplantation showed a significant decrease in the number of graft infiltrating cells in RDP1258-treated recipients compared to untreated ones (14.8 vs. 32.7%; p < 0.01). In addition, grafts from peptide-treated animals showed significantly decreased expression of TNF-alpha mRNA and increased levels of iNOS mRNA. Our results are consistent with the recent observation that up-regulation of HO-1 results in the inhibition of several immune effector functions. Modulation of HO-1 activity may enable the development of novel immunomodulatory strategies in humans.