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Immunobiology and immunopharmacology of organ allograft rejection

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Abstract

Much has been learned regarding immunobiological mechanisms responsible for the rejection of histoincompatible allografts. There has also been considerable progress in our understanding of mechanisms responsible for tolerance. The new knowledge gained regarding graft destructive alloimmunity process and the mechanisms of action of immunosuppressants have resulted in solid organ graft survival rates that are in excess of 80% at one year posttransplantation. The principles of tolerance mechanisms are yet to be successfully applied in the clinic. In this review, molecular and cellular mechanisms of action of clinically useful immunosuppressive drugs are reviewed from the perspective of regulation of the anti-allograft repertory.

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References

  1. Unanue ER, Cerottoni J-C: Antigen presentation. FASEB 3:2496–2502, 1989

    Google Scholar 

  2. Germain RN: MHC-dependent antigen processing and peptide presentation: Providing ligands for T lymphocyte activation. Cell 76:287–299, 1994

    PubMed  Google Scholar 

  3. Shoskes DA, Wood KJ: Indirect presentation of MHC antigens in transplantation. Immunol Today 15:32–38, 1994

    PubMed  Google Scholar 

  4. Weiss A, Littman DR: Signal transduction by lymphocyte antigen receptors. Cell 76:263–264, 1994

    PubMed  Google Scholar 

  5. Clevers H, Alarcon B, Wileman T, Terhorst C: The T-cell receptor/CD3 complex: A dynamic protein ensemble. Annu Rev Immunol 6:629–662, 1988

    PubMed  Google Scholar 

  6. Miceli MC, Parnes JR: The role of CD4 and CD8 in T-cell activation. Semin Immunol 3:133–141, 1991

    PubMed  Google Scholar 

  7. Suthanthiran M: A novel model for antigen-dependent activation of normal human T-cells. Transmembrane signaling by crosslink-age of the CD3/T cell receptor-α/β complex with the cluster determinant 2 antigen. J Exp Med 171:1965–1979, 1990

    PubMed  Google Scholar 

  8. Brown MH, Cantrell DA, Brattsand G, Crumpton MJ, Gullberg M: The CD2 antigen associates with the T-cell antigen receptor/CD3/antigen complex on the surface of human T lymphocytes. Nature 339:551–553, 1989

    PubMed  Google Scholar 

  9. Beyers AD, Spruyt LL, Williams AF: Molecular associations between the T-lymphocyte antigen receptor complex and the surface antigens CD2, CD4, or CD8 and CD5. Proc Natl Acad Sci USA 89:2945–2949, 1992

    PubMed  Google Scholar 

  10. Klausner RD, Samelson LE: T-cell antigen receptor activation pathways: The tyrosine kinase connection. Cell 64:875–878, 1991

    PubMed  Google Scholar 

  11. Nishizuka Y: Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258:607–614, 1992

    PubMed  Google Scholar 

  12. O'Keefe SJ, Tamura J, Kincaid RL, Tocci MJ, O'Neill EA: FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin. Nature 357:692–694, 1992

    PubMed  Google Scholar 

  13. Clipstone NA, Crabtree GR: Identification of calcineurin as a key signaling enzyme in T-lymphocyte activation. Nature 357:695–697, 1992

    PubMed  Google Scholar 

  14. Liu J, Farmer JDJr, Lane WS, Friedman J, Weissman I, Schreiber SL: Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66:807–815, 1991

    PubMed  Google Scholar 

  15. Fruman DA, Klee CB, Bierer BE, Burakoff SJ: Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. Proc Natl Acad Sci USA 89:3686–3690, 1992

    PubMed  Google Scholar 

  16. Schwartz RH: T-cell anergy. Sci Am 269:62–71, 1993

    PubMed  Google Scholar 

  17. Suthanthiran M: Signaling features of T-cells: Implications for the regulation of the anti-allograft response. Kidney Int 44:S-3–S-11, 1993

    Google Scholar 

  18. Williams JM, DeLoria D, Hansen JA, Dinarello CA, Loertscher R, Shapiro HM, Strom TB: The events of primary T-cell activation can be staged by use of sepharose-bound anti-T3 [64.1] monoclonal antibody and purified interleukin-1. J Immunol 135:2249–2255, 1985

    PubMed  Google Scholar 

  19. June CH, Ledbetter JA, Linsley PS, Thompson CB: Role of the CD28 receptor in T-cell activation. Immunol Today 11:211–216, 1990

    PubMed  Google Scholar 

  20. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA: CTLA-4 is a second receptor for the B-cell activa-tion antigen B7. J Exp Med 1974:561–569, 1991

    Google Scholar 

  21. Thompson CB, Lindsten T, Ledbetter JA, Kunkel SL, Young HA, Emerson SG, Leiden JM, June CH: CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines. Proc Natl Acad Sci USA 86:1333–1337, 1989

    PubMed  Google Scholar 

  22. Sigal NH, Lin CS, Siekierka JJ: Inhibition of human T-cell activation by FK506, rapamycin and cyclosporine A. Transplant Proc 23(2):1–5, 1991

    Google Scholar 

  23. Isobe M, Yagita H, Okumura K, Ihara A: Specific acceptance of cardiac allograft after treatment with antibodies to ICAM-1 and LFA-1. Science 255:1125–1127, 1992

    PubMed  Google Scholar 

  24. Linsley PS, Wallace PM, Johnson J, Gibson MG, Greene JL, Ledbetter JA, Singh C, Tepper MA: Immunosuppressionin vivo by a soluble form of the CTLA-4 T-cell activation molecule. Science 257:792–795, 1992

    PubMed  Google Scholar 

  25. Bretcher P, Cohen M: A theory of self-nonself discrimination: Paralysis and induction involve the recognition of one and two determinants on an antigen, respectively. Science 169:1042–1049, 1970

    PubMed  Google Scholar 

  26. Clark EA, Ledbetter JA: How B and T-cells talk to each other. Nature 367:425–428, 1994

    PubMed  Google Scholar 

  27. Smith CA: Interleukin-2: Inception, impact, and implications. Science 240:1169–1176, 1988

    PubMed  Google Scholar 

  28. Waldmann TA: The interleukin-2 receptor. J Biol Chem 266:2681–2684, 1991

    PubMed  Google Scholar 

  29. Takeshita T, Asao H, Ohtani K, Ishii N, Kunaki S, Tanaka N, Munakata H, Nakamura M, Sugamura K: Cloning of theγ chain of the human IL-2 receptor. Science 257:379–382, 1992

    PubMed  Google Scholar 

  30. Hatakeyama M, Kono T, Kobayashi N, Kawahara A, Levin SD, Perlmutter RM, Taniguchi T: Interaction of the IL-2 receptor with the src-family kinase p56lck: Identification of novel intermolecular association. Science 52:523–528, 1991

    Google Scholar 

  31. Fung MR, Scearce RM, Hoffman JA, Peffer NJ, Hammes SR, Hosking JB, Schmandt R, Kuziel NA, Haynes BF, Mills GB: A tyrosine kinase physically associates with theβ-subunit of the human IL-2 receptor. J Immunol 147:1253–1260, 1991

    PubMed  Google Scholar 

  32. Remillard B, Petrillo R, Maslinski W, Tsudo M, Strom TB, Cantley L, Varticovski L: Interleukin-2 receptor regulattes activation of phosphatidylinositol 3-kinase. J Biol Chem 266:14167–14170, 1991

    PubMed  Google Scholar 

  33. Maslinski W, Remillard B, Tsudo M, Strom TB: Interleukin-2 induces tyrosine kinase dependent translocation of active raf-1 from the IL-2 receptor into the cytosol. J Biol Chem 267:15281–15284, 1992

    PubMed  Google Scholar 

  34. Shibuya H, Yoneyama M, Ninomiya-Tsuji J, Matsumoto K, Taniguchi T: IL-2 and EGF receptors stimulate the hematopoietic cell cycle via different signaling pathways: Demonstration of a novel role for c-myc. Cell 70:57–67, 1992

    PubMed  Google Scholar 

  35. Suthanthiran M, Strom TB: Renal Transplantation. N Engl J Med 331:365–376, 1994

    PubMed  Google Scholar 

  36. Strom TB, Tilney NL, Carpenter CB, Busch GJ: Identity and cytotoxic capacity of cells infiltrating renal allografts. N Engl J Med 292:1257–1263, 1975

    PubMed  Google Scholar 

  37. Suthanthiran M, Garovoy MR: Immunologic monitoring of the renal allograft recipient. Urol Clin North Am 10:315–325, 1983

    PubMed  Google Scholar 

  38. Lipman ML, Stevens AC, Bleackley RC, Helderman JH, McCune TR, Harmon WE, Shapiro ME, Rosen S, Strom TB: The strong correlation of cytotoxic T lymphocyte specific serine protease gene transcripts with renal allograft rejection. Transplantation 53:73–79, 1992

    PubMed  Google Scholar 

  39. Wang JC, Xu G, Li B, Mouradian JK, Cheigh JS, Riggio RR, Stenzel KH, Suthanthiran M: Human renal graft rejection: Molecular characterization including quantification of intragraft gene expression. J Am Soc Nephrol 3(3):849, 1992 (abstract)

    Google Scholar 

  40. Suthanthiran M, Strom TB: Immunology and genetics of transplantation.In Textbook of Nephrology, 3rd ed., SG Massry, RJ Glassock (eds). Baltimore, Williams and Wilkins, 1994, pp 1629–1637

    Google Scholar 

  41. Nossal GJ: Immunological tolerance: Collaboration between antigen and lymphokines. Science 245:147–153, 1989

    PubMed  Google Scholar 

  42. Schreiber SC: Immunophilin-sensitive protein phosphatase activation in cell signaling pathways. Cell 70:365–368, 1992

    PubMed  Google Scholar 

  43. Roberts AB, Sporn MB: Physiological actions and clinical applications of transforming growth factor-β (TGF-β). Growth Factors 8:1–9, 1993

    PubMed  Google Scholar 

  44. Li B, Sehajpal PK, Khanna A, Vlassara H, Cerami A, Stenzel KH, Suthanthiran M: Differential regulation of transforming growth factor beta and interleukin-2 genes in human T-cells: Demonstration by usage of novel competitor DNA constructs in the quantitative polymerase chain reaction. J Exp Med 174:1259–1262, 1991

    PubMed  Google Scholar 

  45. Khanna A, Li B, Stenzel KH, Suthanthiran M: Regulation of new DNA synthesis in mammalian cells by cyclosporine. Demonstration of a transforming growth factorβ-dependent mechanism of inhibition of cell growth. Transplantation 57:577–582, 1994

    PubMed  Google Scholar 

  46. Knudsen PJ, Dinarello CA, Strom TB: Glucocorticoids inhibit transcription and posttranscriptional expression of interleukin-1. J Immunol 139:4129–4134, 1987

    PubMed  Google Scholar 

  47. Zanker B, Walz G, Wieder KJ, Strom TB: Evidence that glucocorticosteroids block expression of the human interleukin-6 gene by accessory cells. Transplantation 49:183–185, 1990

    PubMed  Google Scholar 

  48. Arya SK, Wong-Staal F, Gallo RC: Dexamethasone mediated inhibition of T-cell growth factor and gamma interferon messenger RNA. J Immunol 133:273–276, 1984

    PubMed  Google Scholar 

  49. Almawi WY, Lipman ML, Stevens AC, Zanker B, Hadro ET, Strom TB: Abrogation of glucocorticosteroid-mediated inhibition of T-cell proliferation by the synergistic action of IL-1, IL-6, and IFN. J Immunol 146:3523–3527, 1991

    PubMed  Google Scholar 

  50. Vacca A, Felli MP, Farina AR, Martinotti S, Maroder M, Screpanti I, Meco D, Petrangeli E, Frati L, Gulino A: Glucocorticoid receptor-mediated suppression of the interleukin-2 gene expression through impairment of the cooperativity between nuclear factor of activated T-cells and AP-1 enhancer elements. J Exp Med 175:637–646, 1992

    PubMed  Google Scholar 

  51. Elion GB: Biochemistry and pharmacology of purine analogues. Fed Proc 26:898–904, 1967

    PubMed  Google Scholar 

  52. Bach JF, Strom TB: The Mode of Action of Immunosuppressive Agents, 2nd rev. ed., vol 9, Research Monographs in Immunology, Amsterdam, Elsevier, 1986, pp 105–108

    Google Scholar 

  53. Morris RE: Rapamycins: Antifungal, antitumor, antiproliferative, and immunosuppressive macrolides. Transplant Rev 6:39–87, 1992

    Google Scholar 

  54. Chung J, Kuo CJ, Crabtree GR, Blenis J: Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell 69:1227–1236, 1992

    PubMed  Google Scholar 

  55. Sabatini DM, Erdjument Bromage H, Lui M, Tempst P, Snyder SH: Raf-1: A mammalian protein that binds to FKBP 12 in a rapamycin dependent fashion and is homologous to yeast TORS. Cell 78:35–43, 1994

    PubMed  Google Scholar 

  56. Morris RE, Wang J: Comparison of the immunosuppressive effects of mycophenolic acid and the morpholinethal ester of mycophenolic acid (RS-61443) in recipients of heart grafts. Transplant Proc 23:493–506, 1991

    PubMed  Google Scholar 

  57. Sweeney MJ, Hoffman DH, Esterman MA: Metabolism and biochemistry of mycophenolic acid. Cancer Res 32:1803–1809, 1972

    PubMed  Google Scholar 

  58. Sollinger HW, Deierhoi MH, Belzer FO, Diethelm AG, Kauffman RS: RS-61443—A phase I clinical trial and pilot rescue study. Transplantation 53:428–432, 1992

    PubMed  Google Scholar 

  59. Turka LA, Dayton J, Sinclair G, Thompson CB, Mitchell BS: Guanine ribonucleotide depletion inhibits T-cell activation: Mechanism of action of the immunosuppressive drug mizoribine. J Clin Invest 87:940–948, 1991

    PubMed  Google Scholar 

  60. Kokado Y, Ishibahi M, Jiang H: Low dose cyclosporin, mizoribine and prednisone in renal transplantation: A new triple drug therapy. Clin Transplant 4:191–197, 1990

    Google Scholar 

  61. Takeuchi T, Iinuma H, Kunimoto S, Masuda T, Ishizuka M, Takeuchi M, Hamada M, Naganawa H, Kondo S, Umezawa H: A new antitumor antibiotic, spergualin: Isolation and antitumor activity. J Antibiot (Tokyo) 34:1619–1621, 1981

    Google Scholar 

  62. Umeda Y, Moriguchi M, Kuroda H, Nakamura T, Iinuma H, Takeuchi T, Umezawa H: Synthesis and antitumor activity of spergualin analogues. I. Chemical modification of 7-guanidino-3-hydroxyacyl moiety. J Antibiot (Tokyo) 38:886–898, 1985

    Google Scholar 

  63. Nadler SG, Tepper MA, Schacter B, Mazzucco CE: Interaction of the immunosuppressant deoxyspergualin with a member of the Hsp70 family of heat shock proteins. Science 258:484–485, 1992

    PubMed  Google Scholar 

  64. Makowka L, Sher LS, Cramer DV: The development of Brequinar as an immunosuppressive drug for transplantation. Immunol Rev 136:51–70, 1993

    PubMed  Google Scholar 

  65. Norman DJ: Antilymphocyte antibodies in the treatment of allograft rejection: Targets, mechanisms of action, monitoring, and efficacy. Semin Nephrol 12:315–324, 1992

    PubMed  Google Scholar 

  66. Cecka JM, Cho YW, Terasaki PI: Analysis of the UNOS scientific renal transplant registry at three years—early events affecting transplant success. Transplantation 53:59–64, 1992

    PubMed  Google Scholar 

  67. Ortho Multicenter Transplant Study Group: A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 313:337–342, 1985

    Google Scholar 

  68. Suthanthiran M, Fotino M, Riggio RR, Cheigh JS, Stenzel KH: OKT3-associated adverse reactions: Mechanistic basis and therapeutic options. Am J Kidney Dis 14:39–44, 1989

    Google Scholar 

  69. Vincenti FG, Vasconcelos M, Birnbaum HL, Tomlanovich SJ, Amend WJC Jr, Melzer JS, Snyder JP: Pentoxifylline reduces the first-dose reactions following OKT3. Transplant Proc 25:57–59, 1993

    Google Scholar 

  70. First MR, Schroeder TJ, Hariharan S, Weiskittel P: Reduction of the initial febrile response to OKT3 with indomethacin. Transplant Proc 25:52–54, 1993

    Google Scholar 

  71. Chatenoud L: OKT3-induced cytokine-release syndrome: Preventive effect of anti-tumor necrosis factor monoclonal antibody. Transplant Proc 25:47–51, 1993

    Google Scholar 

  72. Waid TH, Lucas BA, Thompson JS, Brown SA, Munch L, Prebeck RJ, Jezek D: Treatment of acute cellular rejection with T10B9.1A-31 or OKT3 in renal allograft recipients. Transplantation 53:80–86, 1992

    PubMed  Google Scholar 

  73. Yoshimura N, Takahashi K, Ishibashi M: Treatment of acute cellular rejection with BMA031 in renal transplant recipients—a multicentered trial in Japan. Abstracts from the meeting of the American Society of Transplant Surgeons, Chicago, Illinois, May 1992, p 63

  74. Soulillou J-P, Cantarovich D, Le Mauff B, Gival M, Robillard N, Hourmant M, Him M, Jacques Y: Randomized controlled trial of a monoclonal antibody against the interleukin-2 receptor (33B3.1) as compared with rabbit antithymocyte globulin for prophylaxis against rejection of renal allografts. N Engl J Med 322:1175–1182, 1990

    PubMed  Google Scholar 

  75. Kirkman RL, Shapiro ME, Carpenter CB, McKay DR, Milford EL, Ramos EL, Tilney NL, Waldmann TA, Zimmerman CE, Strom TB: A randomized prospective trial of anti-Tac monoclonal antibody in human renal transplantation. Transplantation 51:107–113, 1991

    PubMed  Google Scholar 

  76. Goodman ER, Hardy MA: Transplantation 1992: The year in review.In Clinical Transplants 1992, PI Terasaki, JM Cecka (eds). Los Angeles, UCLA Tissue Typing Laboratory, 1993, pp 285–297

    Google Scholar 

  77. Queen C, Schneider WP, Selick HE, Payne PW, Landolfi NF, Duncan JF, Avdalovic NM, Levitt M, Junghans RP, Waldmann TA: A humanized antibody that binds to the interleukin 2 receptor. Proc Natl Acad Sci USA 86:10029–10033, 1989

    PubMed  Google Scholar 

  78. Meyers BD: Cyclosporine nephrotoxicity. Kidney Int 30:964–974, 1986

    PubMed  Google Scholar 

  79. Weir MR: Clinical benefits of calcium antagonists in renal transplant recipients.In Calcium Antagonists in Clinical Medicine, M Epstein (ed). Philadelphia, Hanley and Belfus, 1992, pp 391–412

    Google Scholar 

  80. Schrier RW, Arnold PE, Van Putten VJ, Burke TJ: Cellular calcium in ischemic acute renal failure; role of calcium entry blockers. Kidney Int 32:313–322, 1987

    PubMed  Google Scholar 

  81. Suthanthiran M, Haschemeyer RH, Riggio RR, Adubor C, Friedman GS, Cheigh JS, Wang JC, Fotino M, Stubenbord WT, Saal SD, Stenzel KH, Rubin AL: Excellent outcome with a calcium channel blocker supplemented immunosuppressive regimen in cadaveric renal transplantation: A potential strategy to avoid antibody induction protocols. Transplantation 55:1008–1013, 1993

    PubMed  Google Scholar 

  82. Neumayer H-H, Kunzendorf U, Schreiber M: Protective effects of calcium antagonists in human renal transplantation. Kidney Int 41:S87-S93, 1992

    Google Scholar 

  83. Kunzendorf U, Walz G, Brockmoeller J, Neumayer HH, Jochinsen F, Roots I, Offermann G, Strom TB: Effects of diltiazen upon metabolism and immunosuppressive action of cyclosporine in kidney graft recipients. Transplantation 52:280–284, 1991

    PubMed  Google Scholar 

  84. Dawidson I, Rooth P, Lu C, Sagalowsky A, Diller K, Palmer B, Peters P, Risser R, Sandor Z, Seney F: Verapamil improves the outcome after cadaver renal transplanatation. J Am Soc Nephrol 2:983–990, 1991

    PubMed  Google Scholar 

  85. Kelley VE, Kirkman RL, Bastos M, Barrett LV, Strom TB: Enhancement of immunosuppression by substitution of fish oil for olive oil as a vehicle for cyclosporine. Transplantation 48:98–102, 1989

    PubMed  Google Scholar 

  86. Rogers TS, Elzinga L, Bennett WM, Kelley VE: Selective enhancement of thromboxane in macrophages and kidneys in cyclosporine-induced nephrotoxicity. Dietary protection by fish oil. Transplantation 45:153–156, 1988

    PubMed  Google Scholar 

  87. Van Der Heide JJH, Bilo HJG, Donker JM, Wilmink JM, Tegzess AM: Effect of dietary fish oil on renal function and rejection in cyclosporine-treated recipients of renal transplants. N Engl J Med 329:769–773, 1993

    PubMed  Google Scholar 

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  1. Department of Transplantation and Extracorporeal Therapy, Division of Nephrology, Department of Medicine, The Rogosin Institute, The New York Hospital-Cornell Medical Center, New York, New York

    Manikkam Suthanthiran

  2. Division of Immunology, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts

    Terry B. Strom

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  1. Manikkam Suthanthiran
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Suthanthiran, M., Strom, T.B. Immunobiology and immunopharmacology of organ allograft rejection. J Clin Immunol 15, 161–171 (1995). https://doi.org/10.1007/BF01541085

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