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RDP1258, a New Rationally Designed Immunosuppressive Peptide, Prolongs Allograft Survival in Rats: Analysis of Its Mechanism of Action

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Abstract

Peptides derived from the HLA dass I heavy chain (a.a. 75–84) have been shown to modulate irnmune responses in vitro and in vivo in a non-allele-restricted fashion. In vivo studies in rodents have demonstrated prolonged allograft survival foUowing 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-α 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.

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References

  1. Parham P, Clayberger C, Zorn SL, Ludwig DS, Schoolnik GK, Krensky AM. (1987) Inhibition of alloreactive cytotoxic T lymphocytes by peptides from the alpha 2 domain of HLA-A2. Nature325: 625–628.

    Article  CAS  PubMed  Google Scholar 

  2. Olson CA, Williams LC, McLaughlin-Taylor E, McMillan M. (1989) Creation of H-2 class I epitopes using synthetic peptides: recognition by alloreactive cytotoxic T lymphocytes. Proc. Natl. Acad. Sci. U.S.A.86: 1031–1035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Clayberger C, Parham P, Rothbard J, Ludwig DS, Schoolnik GK, Krensky AM. (1987) HLA-A2 peptides can regulate cytolysis by human allogeneic T lymphocytes. Nature330: 763–765.

    Article  CAS  PubMed  Google Scholar 

  4. Clayberger C, Krensky AM. (1995) Immunosuppressive peptides corresponding to MHC class I sequences. Curr. Opin. Immunol.7: 644–648.

    Article  CAS  PubMed  Google Scholar 

  5. Clayberger C, Lyu SC, Pouletty P, Krensky AM. (1993) Peptides corresponding to T-cell receptor-HLA contact regions inhibit class I-restricted immune responses. Transplant. Proc.25: 477–478.

    PubMed  CAS  Google Scholar 

  6. Cuturi MC, Josien R, Douillard P, et al. (1995) Prolongation of allogeneic heart graft survival in rats by administration of a peptide (a.a. 75–84) from the alpha 1 helix of the first domain of HLA-B7 01. Transplantation59: 661–669.

    Article  CAS  PubMed  Google Scholar 

  7. Buelow R, Veyron P, Clayberger C, Pouletty P, Touraine JL. (1995) Prolongation of skin allograft survival in mice following administration of AL-LOTRAP. Transplantation59: 455–460.

    Article  CAS  PubMed  Google Scholar 

  8. Buelow R, Burlingham WJ, Clayberger C. (1995) Immunomodulation by soluble HLA class I. Transplantation59: 649–654.

    Article  CAS  PubMed  Google Scholar 

  9. Nisco S, Vriens P, Hoyt G, et al. (1994) Induction of allograft tolerance in rats by an HLA class I-derived peptide and cyclosporine A. J. Immunol.152: 3786–3792.

    PubMed  CAS  Google Scholar 

  10. Iyer S, Woo J, Cornejo MC, et al. (1998) Characterization and biological significance of immunosuppressive peptide D2702.75-84(E → V) binding protein. Isolation of heme oxygenase-1. J. Biol. Chem.273: 2692–2697.

    Article  CAS  PubMed  Google Scholar 

  11. Grassy G, Calas B, Yasri A, et al. (1998) In silico screening applied to the rational design of novel immunosuppressive compounds. Nat. Biotechnol.16: 748–752.

    Article  CAS  PubMed  Google Scholar 

  12. Kutty RK, Maines MD. (1981) Purification and characterization of biliverdin reductase from rat liver. J. Biol. Chem.256: 3956.

    PubMed  CAS  Google Scholar 

  13. Ono K, Lyndsey ES. (1969) Improved technique of heart transplantation in rats. J. Thorac. Cardiovasc. Surg.57: 225–229.

    PubMed  CAS  Google Scholar 

  14. Josien R, Pannetier C, Douillard P, et al. (1995) Graft infiltrating T helper cells, CD45RC phenotype, and Thl/Th2-related cytokines in donor specific transfusion-induced tolerance in adult rats. Transplantation60: 1131–1139.

    Article  CAS  PubMed  Google Scholar 

  15. Chirgwin JJ, Przbyla AE, MacDonald RJ, Rutter WJ. (1979) Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry18: 5294–5297.

    Article  CAS  PubMed  Google Scholar 

  16. Cuturi MC, Josien R, Douillard P, Giral M, Soulillou JP. (1996) Synthetic peptides derived from human MHC class I sequences delay allograft rejection in rodents and inhibit cell-mediated cytotoxicity in vivo and in vitro. Immunol. Rev.154: 5–20.

    Article  CAS  PubMed  Google Scholar 

  17. Rosenberg DW, Drummond DS, Kappas A. (1982) The influence of organometals on heme metabolism. In vitro and in vivo studies with organotins. Mol. Pharmacol.21: 150–158.

    PubMed  CAS  Google Scholar 

  18. Maines M. (1984) New developments in the regulation of heme metabolism and their implications. CRC Cut. Rev. Toxicol.12: 241–314.

    Article  CAS  Google Scholar 

  19. Maines M. (1997) The heme oxygenase system: a regulator of second messenger gases. Annu. Rev. Pharmacol. Toxicol.37: 517–554.

    Article  CAS  PubMed  Google Scholar 

  20. Seki T, Naruse M, Naruse K, et al. (1997) Roles of heme oxygenase/carbon monoxide system in genetically hypertensive rats. Biochem. Biophys. Res. Commun.241: 574–578.

    Article  CAS  PubMed  Google Scholar 

  21. Ye J, Laychock SG. (1998) A protective role for heme oxygenase expression in pancreatic islets exposed to interleukin-lbeta. Endocrinology139: 4155–4163.

    Article  CAS  PubMed  Google Scholar 

  22. Rodgers PA, Seidman DS, Wei PL, Dennery PA, Stevenson DK. (1996) Duration of action and tissue distribution of zinc protoporphyrin in neonatal rats. Pediatr. Res.39: 1041–1049.

    Article  CAS  PubMed  Google Scholar 

  23. Ny L, Aim P, Ekstrom P, Larsson B, Grundemar L, Andersson KE. (1996) Localization and activity of haem oxygenase and functional effects of carbon monoxide in the feline lower oesophageal sphincter. Br. J. Pharmacol.118: 392–399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Woo J, Iyer S, Cornejo M, et al. (1998) Stress protein induced immunosuppression: inhibition of cellular immune effector functions following overexpression of heme oxygenase (HSP32). Transplant. Immunol6: 84–93.

    Article  CAS  Google Scholar 

  25. Woo J, Gao L, Cornejo MC, Buelow R. (1995) A synthetic dimeric HLA class I peptide inhibits T cell activity in vitro and prolongs allogeneic heart graft survival in a mouse model. Transplantation60: 1156–1163.

    Article  CAS  PubMed  Google Scholar 

  26. Gao L, Woo J, Buelow R. (1996) Both l- and d-isomers of allotrap 2702 prolong cardiac allograft survival in mice. J. Heart Lung Transplant.15: 78–87.

    PubMed  CAS  Google Scholar 

  27. Murphy B, Kim KS, Buelow R, Sayegh MH, Hancock WW. (1997) Synthetic MHC class I peptide prolongs cardiac survival and attenuates transplant arteriosclerosis in the Lewis→ Fischer 344 model of chronic allograft rejection. Transplantation64: 14–19.

    Article  CAS  PubMed  Google Scholar 

  28. Hanaway MJ, Geissler EK, Wang J, Fechner JH, Jr, Buelow R, Knechtle S J. (1996) Immunosuppressive effects of an HLA class I-derived peptide in a rat cardiac allograft model. Transplantation61: 1222–1228.

    Article  CAS  PubMed  Google Scholar 

  29. Agarwal A, Younki K, Matas A, Alam J, Nath K. (1996) Gas generating systems in acute renal allograft rejection in the rat. Transplantation61: 93–98.

    Article  CAS  PubMed  Google Scholar 

  30. Durante W, Kroll M, Christodoulides N, Peyton K, Schäfer A. (1997) Nitric oxide induces heme oxygenase-1 gene expression and carbon monoxide production in vascular smooth muscle cells. Circ. Res.80: 557–564.

    Article  CAS  PubMed  Google Scholar 

  31. Kurata S, Matsumoto M, Ymashita U. (1996) Concomitant transcriptional activation of nictric oxide synthase and heme oxygenase genes during nitric oxide-mediated macrophage cytostasis. J. Biochem.120: 49–52.

    Article  CAS  PubMed  Google Scholar 

  32. Takahashi K, Hara E, Ogawa K, Kimura D, Fujita H, Shibahara S. (1997) Possible implications of the induction of human heme oxygenase-1 by nitric oxide donors. J. Biochem.121: 1161–1168.

    Article  Google Scholar 

  33. Alexander J, Valente J, Greenberg N, et al. (1998) Dietary omega-3 and omega-9 fatty acids uniquely enhance allograft survival in cyclosporine-treated and donor-specific transfusion-treated rats. Transplantation65: 1304–1309.

    Article  CAS  PubMed  Google Scholar 

  34. Shears L, Kawaharada N, Tzeng E, et al. (1997) Inducible nitric oxide synthase suppresses the development of allograft arteriosclerosis. J. Clin. Invest.100: 2035–2042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Willis D, Moore AR, Frederick R, Willoughby DA. (1996) Heme oxygenase: a novel target for the modulation of the inflammatory response. Nat. Med.2: 87.

    Article  CAS  PubMed  Google Scholar 

  36. Otterbein L, Sylvester S, Choi A. (1995) Hemoglobin provides protection against lethal endotoxemia in rats: the role of heme oxygenase-1. Cell. Mol. Biol.13: 595–601.

    CAS  Google Scholar 

  37. Vogt B, Shanley T, Croatt A, Alam J, Johnsons K, Nath K. (1996) Glomerular inflammation induces resistance to tubular injury in the rat. J. Clin. Invest.98: 2139–2145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Schwarzman M, Abraham N, Conners M, Dunn M, Levere R, Kappas A. (1997) Heme oxygenase induction with attenuation of experimentally induced corneal inflammation. Biochem. Pharmacol.53: 1069–1075.

    Article  Google Scholar 

  39. Novogrodsky A, Suthanthiran M, Stenzel K. (1989) Immune stimulatory properties of metalloporphyrins. J. Immunol.143: 3981–3987.

    PubMed  CAS  Google Scholar 

  40. Ignarro L, Ballot B, Wood K. (1984) Regulation of soluble guanylate cyclase activity by porphyrins and metalloporphyrins. J. Biol. Chem.209: 6201–6207.

    Google Scholar 

  41. Wolff D, Naddelman R, Lubeskie A, Saks D. (1996) Inhibition of nitric oxide synthase isoforms by porphyrins. Arch. Biochem. Biophys.333: 27–34.

    Article  CAS  PubMed  Google Scholar 

  42. Nakagami T, Toyomura K, Kinoshita T, Morisawa S. (1993) A beneficial role of bile pigments as an endogenous tissue protector: anti-complement effects of biliverdin and conjugated bilirubin. Biochem. Biophys. Acta1158: 189–193.

    Article  CAS  PubMed  Google Scholar 

  43. Haga Y, Tempero A, Kay D, Zetterman R. (1996) Intracellular accumulation of unconjugated bilirubin inhibits phytohemagglutinin-induced proliferation and interleukin-2 production of human lymphocytes. Digest. Dis. Sci.41: 1468–1474.

    Article  CAS  PubMed  Google Scholar 

  44. Haga Y, Tempero M, Zetterman R. (1996) Unconjugated bilirubin inhibits in vitro major histocompatibility complex-unrestricted cytotoxicity in human lymphocytes. Biochem. Biophys. Acta1316: 29–34.

    PubMed  Google Scholar 

  45. Verma A, Hirsch D, Glatt C, Ronnett G, Synder S. (1993) Carbon monoxide: a putative neural messenger. Science259: 381–384.

    Article  CAS  PubMed  Google Scholar 

  46. Brüne B, Ulrich V. (1987) Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase. Mol. Pharmacol.32: 497–504.

    PubMed  Google Scholar 

  47. Diaz J, Vara E, Garcia C, Villa N, Balibrea J. (1995) Evidence for a cyclic guanosine monophosphate-dependent, carbon monoxide-mediated, signaling system in the regulation of TNF-α production by human pulmonary macrophages. Arch. Surg.130: 1287–1293.

    Article  Google Scholar 

  48. Vaandrager A, de Jonge H. (1996) Signalling by cGMP-dependent protein kinases. Mol. Cell. Biochem.157: 23–30.

    Article  CAS  PubMed  Google Scholar 

  49. Lincoln T, Komalavilas P, Boerth N, MacMillan-Crow L, Cornwell T. (1995) cGMP signalling through cAMP- and cGMP-dependent protein kinases. Adv. Pharmacol.34: 305–322.

    Article  CAS  PubMed  Google Scholar 

  50. Finn J, Grunwald M, Yau K. (1996) Cyclic nucleotide-gated ion channels: an extended family with diverse functions. Annu. Rev. Physiol.58: 395–426.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Helga Smit, Valia Proust, and Claire Usai for their excellent work in heart allograft peptide therapy and animal care.

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Authors and Affiliations

  1. ITERT/INSERM U437, Centre Hospitalier, Universitaire de Nantes, Hotel-Dieu, 30 boulevard Jean Monnet, 44093, Nantes Cedex 1, France

    Maria Cristina Cuturi, Frank Christoph, Sophie Brouard, Jean Marie Heslan & Jean-Paul Soulillou

  2. SangStat Medical Corporation, Fremont, California, USA

    Jacky Woo, Suhasini Iyer & Roland Buelow

  3. SangStat Atlantique, CHU de Nantes, Nantes, France

    Pascale Pignon

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  1. Maria Cristina Cuturi
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Correspondence to Maria Cristina Cuturi.

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Cuturi, M.C., Christoph, F., Woo, J. et al. RDP1258, a New Rationally Designed Immunosuppressive Peptide, Prolongs Allograft Survival in Rats: Analysis of Its Mechanism of Action. Mol Med 5, 820–832 (1999). https://doi.org/10.1007/BF03401995

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