Immunosuppression in Experimental Heart Transplantation

  • M. T. Menard
  • J. C. Madsen

Abstract

Advances in immunosuppression have had a significant impact on the field of whole-organ transplantation. New chemical agents utilizing novel mechanisms have been developed, resulting in prolonged survival times in both the experimental and clinical arenas. Despite the improved efficacy of these new nonspecific immunosuppressive agents, host susceptibility to infection and malignancy and organ-specific toxicities are still serious constraints. Thus, more specific “biologic” immunosuppression has been developed in the form of monoclonal antibodies which target specific populations of alloreactive T cells. These reagents theoretically spare the overall defense capabilities of the host by targeting only those lymphocytes which interact with donor antigen. This chapter reviews the important chemical and biologic immunosuppressive agents that have been evaluated in rodent models of heart transplantation.

Keywords

Arthritis Tyrosine Cyclosporine Tacrolimus Arena 

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References

  1. 1.
    Sollinger H, Przepiorka D (eds) (1994) Recent developments in transplantation medicine, vol 1. New immunosuppressive drugs. Physicians and Scientists, Glenview, Ill, pp 1–208Google Scholar
  2. 2.
    Brazelton TR, Morris RE (1996) Molecular mechanisms of action of new xenobiotic immunosuppressive drugs: tacrolimus (FK506), sirolimus (rapamycin), mycophenolate mofetil and leflunomide. Curr Opin Immunol 8:710–720PubMedCrossRefGoogle Scholar
  3. 3.
    Markus PM, Van den Brink MR, Luchs BA, Fung JJ, Starzl TE, Hiserodt JC (1991) Effects of in vivo treatment with FK506 on natural killer cells in rats. Transplantation 51:913–915PubMedCrossRefGoogle Scholar
  4. 4.
    Nishinaka H, Nakafusa Y, Hirano T, Takeda K, Kawano R, Nakano M, Arima T, Nakamura K, Kamei T, Tanaka M (1997) Graft persistence effectively induces and maintains donor-specific unresponsiveness. J Surg Res 68:145–152PubMedCrossRefGoogle Scholar
  5. 5.
    Ochiai T, Nakajima K, Nagata M, Hori S, Asano T, Isono K (1987) Studies of the induction and maintenance of long-term graft acceptance by treatment with FK506 in heterotopic cardiac allotransplantation in rats. Transplantation 44:734–738PubMedCrossRefGoogle Scholar
  6. 6.
    Murase N, Kim DG, Todo S, Cramer DV, Fung J, Starzl TE (1990) FK506 suppression of heart and liver allograft rejection. II: The induction of graft acceptance in rats. Transplantation 50:739–744PubMedCrossRefGoogle Scholar
  7. 7.
    Murase N, Kim DG, Todo S, Cramer DV, Fung JJ, Starzl TE (1990) Suppression of allograft rejection with FK506.I. Prolonged cardiac and liver survival in rats following short-course therapy. Transplantation 50:186–189PubMedCrossRefGoogle Scholar
  8. 8.
    Jiang H, Takahara S, Takano Y, Li D, Kyo M, Valdivia LA, Kokado Y, Ishibashi M, Sonoda T (1991) Effect of FK 506 on heart allograft survival in highly sensitized recipient rats in comparison with cyclosporine. Transplant Proc 23:540–541PubMedGoogle Scholar
  9. 9.
    Miyagawa S, Stepkowski SM, Kahan BD (1991) Mechanism of unresponsiveness in rats induced by a short course of FK 506 or CyA. Transplant Proc 23:334–335PubMedGoogle Scholar
  10. 10.
    Murase N, Starzl TE, Demetris AJ, Valdivia L, Tanabe M, Cramer D, Makowka L (1993) Hamster-to-rat heart and liver xenotransplantation with FK506 plus antiproliferative drugs. Transplantation 55:701–707; discussion 707–708PubMedCrossRefGoogle Scholar
  11. 11.
    Meiser BM, Wang J, Morris RE (1989) Rapamycin: a new and highly active immunosuppessive macrolide with an efficacy superior to cyclosporine. In: Albert ED, von Boehmer H, Dierich MP (eds) Progress in immunology, proceedings of the 7th international congress of immunology. Springer, Berlin Heidelberg New York, pp 1195–1198Google Scholar
  12. 12.
    Morris RE, Meiser BM (1997) Identification of a new pharmacologic action for an old compound. Med Sci Res 17:877–878Google Scholar
  13. 13.
    Calne RY, Collier DSJ, Lim S, Pollard SG, Samaan A, White DJG, Thiru S (1989) Rapamycin for immunosuppression in organ allografting. Lancet 2:227PubMedCrossRefGoogle Scholar
  14. 14.
    Stepkowski SM, Chen H, Daloze P, Kahan BD (1991) Rapamycin, a potent immunosuppressive drug for vascularized heart, kidney, and small bowel transplantation in the rat. Transplantation 51:22–26PubMedCrossRefGoogle Scholar
  15. 15.
    Morris RE (1993) Prevention and treatment of allograft rejection in vivo by rapamycin: molecular and cellular mechanisms of action. Ann NY Acad Sci 685:68–72PubMedCrossRefGoogle Scholar
  16. 16.
    Wang J, Morris RE (1991) Effect of splenectomy and mono- or combination therapy with rapamycin, the morpholinoethyl ester of mycophenolic acid and deoxyspergualin on cardiac xenograft survival. Transplant Proc 23:699–702PubMedGoogle Scholar
  17. 17.
    Isobe M, Suzuki J, Yagita H, Okumura K, Sekiguchi M (1994) Effect of anti-VCAM-land anti-VLA-4 monoclonal antibodies on cardiac allograft survival and response to soluble antigens in mice. Transplant Proc 26:867–868PubMedGoogle Scholar
  18. 18.
    Meiser BM, Billingham ME, Morris RE (1991) Effects of cyclosporine, FK506, and rapamycin on graft-vessel disease. Lancet 338:1297–1298PubMedCrossRefGoogle Scholar
  19. 19.
    Gregory CR, Morris RE, Pratt R, Billingham MB, Shorthouse R (1992) The use of new antiproliferative immunosuppressants is a novel and highly effective strategy for the prevention of vascular occlusive disease. J Heart Lung Transplant 11:197Google Scholar
  20. 20.
    Kahan BD, Gibbons S, Tejpal N, Stepkowski SM, Chou TC (1991) Synergistic interactions of cyclosporine and rapamycin to inhibit immune performances of normal human peripheral blood lymphocytes in vitro. Transplantation 51:232–239PubMedCrossRefGoogle Scholar
  21. 21.
    Kahan BD, Tejpal N, Gibbons-Stubbers S, Tu Y, Wang M, Stepkowski S, Chou TC (1993) The synergistic interactions in vitro and in vivo of brequinar sodium with cyclosporine or rapamycin alone and in triple combination. Transplantation 55:894–900PubMedCrossRefGoogle Scholar
  22. 22.
    Kahan BD (1991) Synergism, how assessed and how achieved. Clin Transplant 5:534–539Google Scholar
  23. 23.
    Morris RE, Hoyt EG, Murphy MP, Eugui EM, Allison AC (1990) Mycophenolic acid morpholinoethylester (RS-61443) is a new immunosuppressant that prevents and halts heart allograft rejection by selective inhibition of T- and B-cell purine synthesis. Transplant Proc 22:1659–1662PubMedGoogle Scholar
  24. 24.
    Morris RE, Wang J, Blum JR, Flavin T, Murphy MP, Almquist SJ, Chu N, Tarn YL, Kaloos-tian M, Allison AC (1991) Immunosuppressive effects of the morpholinoethyl ester of mycophenolic acid (RS-61443) in rat and nonhuman primate recipients of heart allografts. Transplant Proc 23(2) [Suppl 2]:19–25PubMedGoogle Scholar
  25. 25.
    Knechtle SJ, Wang J, Burlingham WJ, Beeskau M, Subramanian R, Sollinger HW (1992) The influence of RS-61443 on antibody-mediated rejection. Transplantation 53:699–701PubMedCrossRefGoogle Scholar
  26. 26.
    Williams JW, Xiao F, Foster P, Clardy C, McChesney L, Sankary H, Chong AS (1994) Leflunomide in experimental transplantation. Control of rejection and alloantibody production, reversal of acute rejection, and interaction with cyclosporine. Transplantation 57:1223–1231PubMedCrossRefGoogle Scholar
  27. 27.
    Xiao F, Chong A, Foster P, Sankary H, McChesney L, Williams JM, Frieders D, Williams JW (1994) Effect of leflunomide in control of acute rejection in hamster-to-rat cardiac xenografts. Transplant Proc 26:1263–1265PubMedGoogle Scholar
  28. 28.
    Madsen JC, Morris PJ, Wood KJ (1997) Immunogenetics of heart transplantation in rodents. Transplant Rev 11:141–150CrossRefGoogle Scholar
  29. 29.
    Guttman RD, Forbes RDC, Fuks A (1985) Rejection and prolongation of rat cardiac allografts across intra-major histocompatibility complex (MHC) and non-MHC differences using congenic lines: evidence for decreased class I immunogenicity. Transplant Proc 17:1911–1913Google Scholar
  30. 30.
    Lim SML, White DJG, Calne RY (1987) Minor and class I MHC incompatibilities do not cause rejection of heart grafts but influence the rejection of skin grafts. Transplant Proc 19:4229–4230PubMedGoogle Scholar
  31. 31.
    Campos L, Naji A, Deli C, Kern JH, Kim JI, Barker CF, Markmann JF (1995) Survival of MHC-deficient mouse heterotopic cardiac allografts. Transplantation 59:187–191PubMedGoogle Scholar
  32. 32.
    Madsen JC, Peugh WN, Wood KJ, Morris PJ (1987) The effect of anti-L3T4 monoclonal antibody treatment on first-set rejection of murine cardiac allografts. Transplantation 44:849–852PubMedCrossRefGoogle Scholar
  33. 33.
    Mottram PL, Wheelahan J, McKenzie IFC, Clunie GJA (1987) Murine cardiac allograft survival following treatment of recipients with monoclonal anti-L3T4 or LY-2 antibodies. Transplant Proc 19:2898PubMedGoogle Scholar
  34. 34.
    Madsen JC (1991) An immunogenetic analysis of immunological unresponsiveness using recipient cells transfected with donor MHC genes (PhD thesis). Oxford University, Oxford, pp 1–398Google Scholar
  35. 35.
    Madsen JC, Wood KJ, Morris PJ (1989) Effects of anti-L3T4 and anti-Lyt 2 monoclonal antibody therapy on cardiac allograft survival in presensitized recipients. Transplant Proc 21:1022–1023PubMedGoogle Scholar
  36. 36.
    Mottram PL, Han WR, Purcell LJ, McKenzie IF, Hancock WW (1995) Increased expression of IL-4 and IL-10 and decreased expression of IL-2 and interferon-γ in long-surviving mouse heart allografts after brief CD4-monoclonal antibody therapy. Transplantation 59:559–565PubMedGoogle Scholar
  37. 37.
    Han WR, Mottram PL, Purcell LJ, Plenter RJ, McKenzie IF (1995) Infiltrating cells in mouse cardiac allografts after anti-CD4 monoclonal antibody treatment. Transplant Proc 27:2163PubMedGoogle Scholar
  38. 38.
    Darby CR, Bushell A, Morris PJ, Wood KJ (1994) Nondepleting anti-CD4 antibodies in transplantation. Evidence that modulation is far less effective than prolonged CD4 blockade. Transplantation 57:1419–1426PubMedGoogle Scholar
  39. 39.
    Darby CR, Morris PJ, Wood KJ (1992) Evidence that long-term cardiac allograft survival induced by anti-CD4 monoclonal antibody does not require depletion of CD4+ T cells. Transplantation 54:483–490PubMedCrossRefGoogle Scholar
  40. 40.
    Flavin T, Shizuru J, Seydel K, Wu A, Fujimoto N, Hoyt EG, Ivens K, Billingham M, Fathman CG, Starnes VA (1990) Selective T-cell depletion with Ox-38 anti-CD4 monoclonal antibody prevents cardiac allograft rejection in rats. J Heart Transplant 9:482–488PubMedGoogle Scholar
  41. 41.
    Waldmann H, Cobbold C (1993) The use of monoclonal antibodies to achieve immunological tolerance. Immunol Today 14:247–251PubMedCrossRefGoogle Scholar
  42. 42.
    Qin SX, Cobbold Sp, Pope H, Elliot J, Kioussis D, Davies J, Waldmann H (1993) “Infectious” transplantation tolerance. [Font:ZapfDingbats]zzz[ZapfDingbatsEnde]259:974–977Google Scholar
  43. 43.
    Qin SX, Wise M, Cobbold SP, Leong L, Kong YC, Parnes JR, Waldmann H (1990) Induction of tolerance in peripheral T cells with monoclonal antibodies. Eur J Immunol 20:2737–2745PubMedCrossRefGoogle Scholar
  44. 44.
    Russell PS, Chase CM, Winn HJ, Colvin RB (1994) Coronary atherosclerosis in transplanted mouse hearts. I. Time course and immunogenetic and immunopathological considerations. Am J Pathol 144:260–274PubMedGoogle Scholar
  45. 45.
    Orosz CG, Bergese SD, Huang EH, Vanbuskirk AM (1995) Immunologic characterization of murine cardiac allograft recipients with long-term graft survival due to anti-VCAM-1 or anti-CD4 monoclonal antibody therapy. Transplant Proc 27:387–388PubMedGoogle Scholar
  46. 46.
    Rehman A, Tu Y, Flye MW (1996) Combined CTLA4Ig and anti-CD4/CD8 monoclonal antibody treatment prolongs survival of rat-to-mouse heterotopic cardiac xenografts. Transplant Proc 28:660–661PubMedGoogle Scholar
  47. 47.
    Yang L, Mottram PL, Han WR, Smart YC (1995) Effect of anti-CD4, anti-NC, and anti-NK monoclonal antibody on the survival of cardiac xenografts and allografts in mice. Transplant Proc 27:2185–2186PubMedGoogle Scholar
  48. 48.
    Chen Z, Cobbold S, Metcalfe S, Waldmann H (1992) Tolerance in the mouse to major histocompatibility complex-mismatched heart allografts, and to rat heart xenografts, using monoclonal antibodies to CD4 and CD8. Eur J Immunol 22:805–810PubMedCrossRefGoogle Scholar
  49. 49.
    Pearson TC, Madsen JC, Larsen CP, Morris PJ, Wood KJ (1992) Induction of transplantation tolerance in the adult using donor and antigen anti-CD4 monoclonal antibody. Transplantation 54:475–483PubMedCrossRefGoogle Scholar
  50. 50.
    Bushell A, Pearson TC, Morris PJ, Wood KJ (1995) Donor-recipient microchimerism is not required for tolerance induction following recipient pretreatment with donor-specific transfusion and anti-CD4 antibody. Transplantation 59:1367–1371PubMedCrossRefGoogle Scholar
  51. 51.
    Saitovitch D, Bushell A, Mabbs DW, Morris PJ, Wood KJ (1996) Kinetics of induction of transplantation tolerance with a nondepleting anti-CD4 monoclonal antibody and donor-specific transfusion before transplantation. A critical period of time is required for development of immunological unresponsiveness. Transplantation 61:1642–1647PubMedCrossRefGoogle Scholar
  52. 52.
    Bushell A, Morris PJ, Wood KJ (1995) Transplantation tolerance induced by antigen pretreatment and depleting anti-CD4 antibody depends on CD4+ T cell regulation during the induction phase of the response. Eur J Immunol 25:2643–2649PubMedCrossRefGoogle Scholar
  53. 53.
    Pearson TC, Alexander DZ, Hendrix R, Elwood ET, Linsley PS, Winn KJ, Larsen CP (1996) CTLA4-Ig plus bone marrow induces long-term allograft survival and donor specific unresponsiveness in the murine model. Evidence for hematopoietic chimerism. Transplantation 61:997–1004PubMedCrossRefGoogle Scholar
  54. 54.
    Larsen CP, Elwood ET, Alexander DZ, Ritchie SC, Hendrix R, Tucker-Burden C, Cho HR, Aruffo A, Hollenbaugh D, Linsley PS, Winn KJ, Pearson TC (1996) Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 381:434–438PubMedCrossRefGoogle Scholar
  55. 55.
    Larsen CP, Alexander DZ, Hollenbaugh D, Elwood ET, Ritchie SC, Aruffo A, Hendrix R, Pearson TC (1996) CD40-gp39 interactions play a critical role during allograft rejection. Suppression of allograft rejection by blockade of the CD40-gp39 pathway. Transplantation 61:4–9PubMedCrossRefGoogle Scholar
  56. 56.
    Lakkis FG, Konieczny BT, Saleem S, Baddoura FK, Linsley PS, Alexander DZ, Lowry RP, Pearson TC, Larsen CP (1997) Blocking the CD28-B7 T cell costimulation pathway induces long-term cardiac allograft acceptance in the absence of IL-4. J Immunol 158:2443–2448PubMedGoogle Scholar
  57. 57.
    Bashuda H, Seino K, Kano M, Sato K, Azuma M, Yagita H, Okumura K (1996) Specific acceptance of cardiac allografts after treatment with antibodies to CD80 and CD86 in mice. Transplant Proc 28:1039–1041PubMedGoogle Scholar
  58. 58.
    Akimoto H, McDonald TO, Weyhrich JT, Thomas R, Rothnie CL, Allen MD (1996) Antibody to CD18 reduces neutrophil and T lymphocyte infiltration and vascular cell adhesion molecule-1 expression in cardiac rejection. Transplantation 61:1610–1617PubMedCrossRefGoogle Scholar
  59. 59.
    Isobe M, Yagita H, Okumura K, Ihara A (1992) Specific acceptance of cardiac allograft after treatment with antibodies to ICAM-1 and LFA-1. Science 255:1125–1127PubMedCrossRefGoogle Scholar
  60. 60.
    Russell PS, Chase CM, Colvin RB (1995) Coronary atherosclerosis in transplanted mouse hearts. IV. Effects of treatment with monoclonal antibodies to intercellular adhesion molecule-1 and leukocyte function-associated antigen-1. Transplantation 60:724–729PubMedCrossRefGoogle Scholar
  61. 61.
    Kupiec-Weglinski JW, Padberg W, Uhteg LC, Ma L, Lord RH, Araneda D, Strom TB, Diamantstein T, Tilney NL (1987) Selective immunosuppression with anti-interleukin 2 receptor-targeted therapy: helper and suppressor cell activity in rat recipients of cardiac allografts. Eur J Immunol 17:313–319PubMedCrossRefGoogle Scholar
  62. 62.
    Chavin KD, Qin L, Lin J, Kaplan AJ, Bromberg JS (1993) Anti-CD2 and anti-CD3 monoclonal antibodies synergize to prolong allograft survival with decreased side effects. Transplantation 55:901–908PubMedCrossRefGoogle Scholar
  63. 63.
    Zhang Z, Zhong R, Jiang J, Wang J, Garcia B, Le Feuvre C, White M, Stiller C, Lazarovits A (1997) Prevention of heart allograft and kidney xenograft rejection by monoclonal antibody to CD45RB. Transplant Proc 29:1253PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • M. T. Menard
  • J. C. Madsen

There are no affiliations available

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