Tolerance to Cardiac Grafts Following Intra-Graft Infusion of 16,16 Dimethyl PGE2

  • M. Wayne Flye
  • Takafumi Kamei
  • Samuel Yu
Part of the GWUMC Department of Biochemistry Annual Spring Symposia book series (GWUN)


Although prostaglandins of the E series (PGE) have been reported to down-regulate immune responses as indicated by inhibition of T cell proliferation,1 interference with the effector activity of cytotoxic T cells,2 reduction of IL-2 production,3,4 suppression of lymphocyte migration5 and decreased Ia expression by macrophages,6 attempts to demonstrate a beneficial effect of PGE on solid-organ allograft survival have been limited. Quagliata et al.7 increased mouse skin graft survival by 8 days when systemically administered PGE1 was combined with procarbazine, while PGE1 alone had no effect. Subcutaneous PGE1 given twice daily (1 mg/kg) also increased hamster to rat cardiac xenograft survival from 74 to 94 hours.8 The limited effectiveness of PGE is partly due to its very short half life in vivo.9 PGE is usually rapidly metabolized locally at injection site and almost totally inactivated during a single passage through the lung.9 In contrast, the more stable synthetic PGE2 analogues have half lives of several hours.10 Kort et al.11 found that although oral (15S)–15 methyl PGE1 alone did not increase rat heart allograft survival, when combined with prednisolone or azathioprine, survival was increased from 8 to 25.5 and 16.5 days respectively. Using 16, 16 dimethyl prostaglandin E2 methyl ester (di-M-PGE2), Anderson et al.12 reported prolongation of mean skin graft survival from 13.8 to 16.7 days in mice given di-M-PGE2 intraperitoneally.


Cardiac Allograft Allograft Survival Mixed Lymphocyte Culture Mean Survival Time Cardiac Graft 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Goodwin JA, Bankhurst AD, Messner RP: Suppression of human T cell mitogenesis by prostaglandins. J. Exp. Med. 1977; 146: 1719.PubMedCrossRefGoogle Scholar
  2. 2.
    Plaut M, Marone G, Gillespie: The role of cyclic AMP in modulating cytotoxic T lymphocytes. II. Sequential changes during culture in responsiveness of cytotoxic lymphocytes to cyclic AMP active agents. J. Immunol. 1983; 131: 2945.Google Scholar
  3. 3.
    Rappaport RS, Dodge GR: Prostaglandin E inhibits the production of human interleukin 2. J. Exp. Med. 1982; 155: 943.Google Scholar
  4. 4.
    Chouaib S, Fradelizi D: The mechanism of inhibition of human IL-2 production. J. Immunol. 1982; 129: 2463.Google Scholar
  5. 5.
    Jordan ML, Hoffman RA, Debe EF, West MA, Simmons RL: Prostaglandin E2 mediates subset-specific effects on the functional responses of allosensitized T lymphocyte clones. Transplantation 1987; 43: 117.PubMedCrossRefGoogle Scholar
  6. 6.
    Synder DS, Beller DI, Unanue ER: Prostaglandins modulate macrophage la expression. Nature 1982; 299: 163.CrossRefGoogle Scholar
  7. 7.
    Quagliata F, Lawrence VLW, Phillips-Quagliata JM: Prostaglandin E, as a regulator of lymphocyte function. Cell Immunol. 1973; 6: 457.PubMedCrossRefGoogle Scholar
  8. 8.
    Kakita A, Blanchard J, Fortner JG: Effectiveness of prostaglandin El and procarbazine hydrochloride in prolonging the survival of vascularized cardiac hamster-to-rat xenograft. Transplantation 1975; 20: 439.PubMedCrossRefGoogle Scholar
  9. 9.
    Piper PJ, Vane JR, Wyllie JH: Inactivation of prostaglandins by the lung. Nature 1970; 225: 600.PubMedCrossRefGoogle Scholar
  10. 10.
    Weeks JR, Ducharme DW, Magee WE, Miller WL: The biological activity of the (15S)-15-methyl analogues of prostaglandins E2 and F2a. J. Pharmacol. Exp. Ther. 1973; 186: 67.PubMedGoogle Scholar
  11. 11.
    Kort WJ, Bonta IL, Adolfs MJP, Westbroek DL: Synergism of (15S)15 methyl prostaglandin E, with either azathioprine or prednisolone on the survival of heart allografts in rats. Prostagland., Leukotrienes and Med. 1982; 8: 661.Google Scholar
  12. 12.
    Anderson CB, Jaffee BM, Graff RJ: Prolongation of murine skin allografts by prostaglandin E. Transplantation 1977; 23: 44.CrossRefGoogle Scholar
  13. 13.
    Strom TB, Tilney NL, Paradysz JM, Bancewicz PJ, Carpenter CB: Cellular components of allograft rejection: identity, specificity, and cytotoxic function of cells infiltrating acutely rejecting allografts. J. Immunol. 1977; 118: 2020.Google Scholar
  14. 14.
    Tilney NL, Ford WL: The migration of rat lymphoid cells into skin grafts. Some sensitized cells localize preferentially in specific allografts. Transplantation 1974; 17: 12.PubMedCrossRefGoogle Scholar
  15. 15.
    Ascher NL, Chen S, Hoffman RA, Simmons RL: Maturation of cytotoxic T cells within sponge matrix allografts. J. Immunol. 1983; 131: 617.PubMedGoogle Scholar
  16. 16.
    Grosz CG, Zinn NE, Sirinek L, Ferguson RM: In vivo mechanisms of alloreactivity. I. Frequency of donor-reactive cytotoxic T lymphocytes in sponge matrix allografts. Transplantation 1986; 41: 75.CrossRefGoogle Scholar
  17. 17.
    Gruber SA, Hrushesky WJM, Cipolle RJ et al: Local immunosuppression with reduced systemic toxicity in a canine renal allograft model. Transplantation 1989; 48: 936.PubMedCrossRefGoogle Scholar
  18. 18.
    Stepkowski SM, Coto S, Ito T, et al: Prolongation of heterotopic heart allograft survival by local delivery of continuous low-dose cyclosporine therapy. Transplantation 1989; 47: 17.PubMedCrossRefGoogle Scholar
  19. 19.
    Ruers TJM, Buurman WA, van Boxtel CJ, van der Linden CJ, Kootsra G: Immunohistological observation in rat kidney allografts after local steroid administration. J. Exp. Med. 1987; 166: 1205.PubMedCrossRefGoogle Scholar
  20. 20.
    Flye MW, Yu S: Inhibition of cell mediated cytotoxicity by 16,16 dimethyl PGE2. Transplant Proc. 21: 1156, 1989.PubMedGoogle Scholar
  21. 21.
    Ono K, Lindsey ES: Improved technique of heart transplantation in rats. J. Thorac. Cardiovasc. Surg. 1969; 52: 225.Google Scholar
  22. 22.
    Zoller M, Malzker S: Characterization of natural cytotoxicity in vitro in a spontaneous rat tumor model. J. Immunol 1980; 124: 1683.PubMedGoogle Scholar
  23. 23.
    Gillis S, Ferm MM, Du W, Smith KA: T cell growth factor: Parameters of production and a quantitative microassay for activity. J. Immunol. 1978; 120: 2027.Google Scholar
  24. 24.
    Pedersen NC, Morris B: The role of the lymphatic system in the rejection of homografts: A study of lymph from renal transplants. J. Exp. Med. 1970; 131: 936.PubMedCrossRefGoogle Scholar
  25. 25.
    Milton AD, Fabre JW: Massive induction of donor-type class I and II major histocompatibility complex antigens in rejecting cardiac allografts in the rats. J. Exp. Med. 1985; 161: 98.PubMedCrossRefGoogle Scholar
  26. 26.
    Foegh ML, Alijani MR, Helfrich GB, Ramwell PW: Eicosanoids and organ transplantation. Ann. Clin. Res. 1984; 16: 318.PubMedGoogle Scholar
  27. 27.
    Stephan RN, Conrad PJ, Saizawa M, Dean RE, Chaudry I: Prostaglandin E2 depresses antigen-presenting cell function of peritoneal macrophages. J. Surg. Res. 1988; 44: 733.PubMedCrossRefGoogle Scholar
  28. 28.
    Faist E, Meives A, Baker CC: Prostaglandin E2 dependent suppression of interleukin 2 production in patients with major trauma. J. Trauma 1987; 28: 837.CrossRefGoogle Scholar
  29. 29.
    Gallery MP, Kamei T, Mangino, MJ, Flye, MW: Interleukin-6 production by endotoxin (LPS) stimulated Kupffer cells is regulated by Prostaglandin E 2. J. Surg. Res. 1990; 48: 523.CrossRefGoogle Scholar
  30. 30.
    Kunkel SL, Spengler M, May MA, Spengler R, Larrick J, Remick D: Prostaglandin-E2 regulates macrophage-derived tumor necrosis factor gene expression. J. Biol. Chem. 1988; 263: 5380.PubMedGoogle Scholar
  31. 31.
    Plaut M: The role of cyclic AMP in modulating cytotoxic T lymphocytes. I. In vivo generated cytotoxic lymphocytes, but not in vitro generated cytotoxic lymphocytes, are inhibited by cyclic AMP-active agents. J. Immunol. 1979; 123: 692.PubMedGoogle Scholar
  32. 32.
    Strom TB, Carpenter CB: Prostaglandin as an effective antirejection therapy in rat renal allograft recipients. Transplantation 1983; 35: 279.PubMedCrossRefGoogle Scholar
  33. 33.
    Knudsen PJ, Dinarello CA, Strom TB: Prostaglandins post-transcriptionally inhibit monocyte expression of interleukin 1 activity by increasing intracellular cyclic adenosine monophosphate. J. Immunol. 1986; 137: 3189.PubMedGoogle Scholar
  34. 34.
    Webb DR, Nowowiejski I: Control of suppressor cell activation via endogenous prostaglandin synthesis: the role of T cells and macrophages. Cell Immunol. 1986; 63: 321.CrossRefGoogle Scholar
  35. 35.
    Webb DR, Nowowiejski I: Nitrogen-induced changes in lymphocyte prostaglandin levels: a signal for the induction of suppressor cell activity. Cell Immunol. 1978; 41: 72.PubMedCrossRefGoogle Scholar
  36. 36.
    Penarrubia PG, Bankhurst AD, Koster FT: Prostaglandins from human T suppressor/cytotoxic cells modulate natural killer antibacterial activity. J. Exp. Med. 1989; 170: 601.CrossRefGoogle Scholar
  37. 37.
    Field M, Musch MW, Stoff JS: Role of prostaglandins in the regulation of intestinal electrolyte transport. Prostaglandins 1981; 21: 73.PubMedGoogle Scholar
  38. 38.
    Lechler RI, Batchelor JR: Restoration of immunogenicity to passenger cell-depleted kidney allografts by the addition of donor strain dendritic cells. J. Exp. Med. 1982; 155: 31.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • M. Wayne Flye
    • 1
  • Takafumi Kamei
    • 1
  • Samuel Yu
    • 1
  1. 1.Department of Surgery, Washington University School of MedicineOne Barnes Hospital PlazaSt. LouisUSA

Personalised recommendations