RDP1258, a new rationally designed immunosuppressive peptide, prolongs allograft survival in rats: analysis of its mechanism of action.
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.
Cuturi
M C
MC
ITERT/INSERM U437, Nantes, France. ccuturi@nantes.inserm.fr
Christoph
F
F
Woo
J
J
Iyer
S
S
Brouard
S
S
Heslan
J M
JM
Pignon
P
P
Soulillou
J P
JP
Buelow
R
R
D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000276:immunology / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D007518:Isoantibodies / Q000096:biosynthesis; D008297:Male; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011524:Protoporphyrins / Q000276:immunology / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew
D000276:Adjuvants, Immunologic; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D009842:Oligopeptides; D011524:Protoporphyrins; C122045:RDP 1258; D012333:RNA, Messenger; C007095:cobaltiprotoporphyrin; D006419:Heme Oxygenase (Decyclizing)