Skip to main content
SpringerLink
Log in

Mechanisms of Pharmacologic Immune Suppression

  • Chapter
Immunology and Infectious Disease

Part of the book series: Molecular and Cellular Biology of Critical Care Medicine ((MCCM,volume 3))

  • 179 Accesses

Abstract

As our understanding of the cellular and molecular mechanisms that mediate allograft rejection has advanced, so has the development of immunosuppressive agents. Each phase in the historical development of immunosuppressive therapies for organ transplantation reviewed herein shows distinctive molecular mechanisms, clinical effects, and toxicities. The matrix of actions of available immunosuppressive agents used in maintenance therapy is shown in Figure 1.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

  1. Fessier BJ, Paliogianni F, Hama N, Balow JE, Boumpas DT. Glucocorticoids modulate CD28 mediated pathways for interleukin 2 production in human T cells: evidence for posttranscriptional regulation. Transplantation 1996; 62: 1113.

    Google Scholar 

  2. Bischof F, Melms A. Glucocorticoids inhibit CD40 ligand expression of peripheral CD4+ lymphocytes. Cell Immunol 1998; 187: 38.

    PubMed  CAS  Google Scholar 

  3. Kahan BD, Podbielski J, Napoli KL, Katz SM, Meier-Kriesche H-U, Van Buren CT. Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation. Transplantation 1998; 66: 1040.

    PubMed  CAS  Google Scholar 

  4. Matsunami C, Hilton AF, Dyer JA, Rumbach OW, Hardie IR. Ocular complications in renal transplant patients. Aust N Z J Ophthalmol 1994; 22: 53.

    PubMed  CAS  Google Scholar 

  5. Hricik DE, Bartucci MR, Moir EJ, Mayes JT, Schulak JA. Effects of steroid withdrawal on posttransplant diabetes mellitus in cyclosporine-treated renal transplant recipients. Transplantation 1991; 51: 374.

    PubMed  CAS  Google Scholar 

  6. Solez K, Axelsen RA, Benediktsson H, et al. International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology. Kidney Int 1993; 44: 411.

    PubMed  CAS  Google Scholar 

  7. Schwartz RS, Dameshek W. Drug-induced immunological tolerance. Nature 1959; 183: 1682.

    PubMed  CAS  Google Scholar 

  8. Calne RY, Alexandre GP, Murray JE. A study of the effects of drugs in prolonged survival of homologous renal transplantation in dogs. Ann NY Acad Sci 1962; 99: 743.

    PubMed  CAS  Google Scholar 

  9. Fox M. Suppression of tissue immunity by cyclophosphamide. Transplantation 1964; 2: 465.

    Google Scholar 

  10. Starzl TE, Halgrimson CG, Penn I, et al. Cyclophosphamide and human organ transplantation. Lancet 1971; 2: 70.

    PubMed  CAS  Google Scholar 

  11. Murphy MM, Morris RE. Brequinar sodium is a highly potent antimetabolite immunosuppressant that suppresses heart allograft rejection. Med Sci Res 1991; 19: 835.

    CAS  Google Scholar 

  12. Winkelstein A. The effect of azathioprine and 6-MP on immunity. J Immunopharmacol 1979; 1: 429.

    PubMed  CAS  Google Scholar 

  13. Bertino JR. Chemical action and pharmacology of methotrexate, azathioprine, and cyclophosphamide in man. Arthritis Rheum 1973; 16: 79.

    PubMed  CAS  Google Scholar 

  14. Lennard L, Maddocks JL. Assay of 6-thioguanine nucleotide, a major metabolite of azathioprine, 6-mercaptopurine and 6-thioguanine in human red blood cells. J Pharmacol 1983; 35: 15.

    CAS  Google Scholar 

  15. Chan GL, Canafax DM, Johnson CA. The therapeutic use of azathioprine in renal transplantation. Pharmacotherapy 1987; 7: 165.

    PubMed  CAS  Google Scholar 

  16. Tidd DM, Paterson ARP. Distinction between inhibition of purine nucleotide synthesis and the delayed cytotoxic reaction of 6-mercaptopurine. Cancer Res 1974; 34: 733.

    PubMed  CAS  Google Scholar 

  17. Vathsala A, Chou TC, Kahan BD. Analysis of the interactions of immunosuppressive drugs with cyclosporine in inhibiting DNA proliferation. Transplantation 1990; 49: 463.

    PubMed  CAS  Google Scholar 

  18. Murray JE, Merrill JP, Harrison JH. Prolonged survival of human kidney homografts by immunosuppressive drug therapy. N Engl J Med 1963; 268: 1315.

    PubMed  CAS  Google Scholar 

  19. Goodwin WE, Kaufman JJ, Mims MM, et al. Human renal transplantation. I clinical experiences with 6 cases of renal homotransplantation. J Urol 1963; 89: 13.

    PubMed  CAS  Google Scholar 

  20. Starzl TE, Marchioro TL, Huntley RT, et al. Experimental and clinical homotransplantation of the liver. Ann N Y Acad Sci 1964; 120: 739.

    PubMed  CAS  Google Scholar 

  21. Allison AC, Eugui EM. Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil. Immunol Rev 1993; 136: 5.

    PubMed  CAS  Google Scholar 

  22. Mitsui A, Suzuki S. Immunosuppressive effect of mycophenolic acid. J Antibiot (Tokyo) 1969; 22: 358.

    CAS  Google Scholar 

  23. Morris RE, Wang J, Blum JR, et al. Immunosuppressive effects of the morpholinoethyl ester of mycophenolic acid (RS-61443) in rat and nonhuman primate recipients of heart allografts. Transplant Proc 1991; 23: 19.

    PubMed  Google Scholar 

  24. Sollinger HW for the U.S. Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995; 60: 225.

    Google Scholar 

  25. Platz KP, Sollinger HW, Hullett DA, Eckhoff DE, Eugui EM, Allison AC. RS-61443--a new, potent immunosuppressive agent. Transplantation 1991; 51: 27.

    PubMed  CAS  Google Scholar 

  26. Allison AC, Eugui EM. Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF). Clin Transplant 1996; 10: 77.

    PubMed  CAS  Google Scholar 

  27. Lowe JK, Brox L, Henderson JF. Consequences of inhibition of guanine nucleoside synthesis by mycophenolic acid and virazole. Cancer Res 1977; 37: 736.

    PubMed  CAS  Google Scholar 

  28. Fleming MA, Chambers SP, Connelly PR, et al. Inhibition of IMPDH by mycophenolic acid: dissection of forward and reverse pathways using capillary electrophoresis. Biochemistry 1996; 35: 6990.

    PubMed  CAS  Google Scholar 

  29. Makara GM, Keseru GM, Katjar-Peredy M, Anderson WK. Nuclear magnetic resonance and molecular modeling study on mycophenolic acid: implications for binding to inosine monophosphate dehydrogenase. J Med Chem 1996; 30: 1236.

    Google Scholar 

  30. Natsumeda Y, Carr SF. Human type I and II IMP dehydrogenase as targets. Ann NY Acad Sci 1993; 696: 88.

    PubMed  Google Scholar 

  31. Mathew T. A blinded, long-term, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation. Transplantation 1998; 65: 1450.

    PubMed  CAS  Google Scholar 

  32. Wiesel M, Carl S. A placebo controlled study of mycophenolate mofetil used in combination with cyclosporine and corticosteroids for the prevention of acute rejection in renal allograft recipients: 1 year results. The Journal of Urology 1998; 159: 28.

    PubMed  CAS  Google Scholar 

  33. Neylan JF for the U.S. Renal Transplant Mycophenolate Mofetil Study Group. Immunosuppressive therapy in high-risk transplant patients. Transplantation 1997; 64: 1277.

    Google Scholar 

  34. Kaplan B, Meier-Kriesche HU, Vaghela M, Friedman G, Mulgaonkar S, Jacobs M. Withdrawal of mycophenolate mofetil in stable renal transplant recipients. Transplantation 2000; 69: 1726.

    PubMed  CAS  Google Scholar 

  35. The Mycophenolate Mofetil Acute Renal Rejection Study Group. Mycophenolate mofetil for treatment of first acute renal rejection. Transplantation 1998; 65: 235.

    Google Scholar 

  36. Klupp J, Bechstein WO, Platz KP, et al. Mycophenolate mofetil added to immunosuppression after liver transplantation--first results. Transpl Int 1997; 10: 223.

    PubMed  CAS  Google Scholar 

  37. Odorico JS, Pirsch JD, Knechtle SJ, D’Alessandro AM, Sollinger HW. A study comparing mycophenolate mofetil to azathioprine in simultaneous pancreas-kidney transplantation. Transplantation 1998; 66: 1751.

    PubMed  CAS  Google Scholar 

  38. Kobashigawa J, Miller L, Renlund D, et al. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Mycophenolate mofetil investigators. Transplantation 1998; 66: 507.

    PubMed  CAS  Google Scholar 

  39. Ross DJ, Waters PF, Levine M, Kramer M, Ruzevich S, Kass RM. Mycophenolate mofetil versus azathioprine immunosuppressive regimens after lung transplantation: preliminary experience. The Journal of Heart and Lung Transplantation 1998; 17: 768.

    PubMed  CAS  Google Scholar 

  40. Zuckermann A, Klepetko W, Birsan T, et al. Comparison between mycophenolate mofetil- and azathioprine-based immunosuppressions in clinical lung transplantation. J Heart Lung Transplant 1999; 18: 432.

    PubMed  CAS  Google Scholar 

  41. Bullingham R, Monroe S, Nicholls A, Hale M. Pharmacokinetics and bioavailability of mycophenolate mofetil in healthy subjects after single-dose oral and intravenous administration. J Clin Pharmacol 1996; 36: 315.

    PubMed  CAS  Google Scholar 

  42. Schmouder R, Arns W, Merkel F, et al. Pharmacokinetics of ERL080A: a new enteric coated formulation of mycophenolic acid-sodium (Abstract 787). 18th Annual Meeting of the American Society of Transplantation. Transplantation 1999; 67: S203.

    Google Scholar 

  43. Calne RY, White DJ, Thiru S, et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 1978; 2: 1323.

    PubMed  CAS  Google Scholar 

  44. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 2000; 342: 605.

    PubMed  CAS  Google Scholar 

  45. Niese D, Keown P. Safety and efficacy of microemulsion versus conventional cyclosporine in de novo renal allograft recipients. Kidney Int 1998; 54: 938.

    PubMed  Google Scholar 

  46. Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet 1989; 2: 1000.

    PubMed  CAS  Google Scholar 

  47. Johansson A, Moller E. Evidence that the immunosuppressive effects of FK506 and cyclosporine are identical. Transplantation 1990; 50: 1001.

    PubMed  CAS  Google Scholar 

  48. Hutchinson IV. The mode of action of Prograf (tacrolimus) and its significance for long-term graft survival. New Horizons in Kidney Transplantation 1997; 1: 22.

    Google Scholar 

  49. Kahan BD, Welsh M, Urbauer DL, et al. Low intra-individual variability of cyclosporine exposure reduces chronic rejection incidence and health care costs. J Am Soc Nephrol 2000; 11: 1122.

    PubMed  CAS  Google Scholar 

  50. Lindholm A, Welsh M, Alton C, Kahan BD. Demographic factors influencing cyclosporine pharmacokinetic parameters in patients with uremia: racial differences in bioavailability. Clin Pharmacol Ther 1992; 54: 359.

    Google Scholar 

  51. Kahan BD, Wideman CA, Ried M, et al. The value of serial serum trough cyclosporine levels in human renal transplantation. Transplant Proc 1984; 16: 1195.

    PubMed  CAS  Google Scholar 

  52. Levy G. Relationship of pharmacokinetics to clinical outcomes. Transplant Proc 1999; 31: 16541658.

    Google Scholar 

  53. Belitsky P, Dunn S, Johnston A, Levy G. Impact of absorption profiling on efficacy and safety of cyclosporin therapy in transplant recipients. Clin Pharmacokinet 2000; 39: 117.

    PubMed  CAS  Google Scholar 

  54. Lindholm A, Kahan BD. Influence of cyclosporine pharmacokinetics, trough concentrations, and AUC monitoring on outcome after kidney transplantation. Clin Pharmacol Ther 1993; 54: 205.

    PubMed  CAS  Google Scholar 

  55. Kahan BD. Established immunosuppressive drugs: clinical and toxic effects. In: Kahan BD, Ponticelli C (eds) Principles and Practice of Renal Transplantation. London: Dunitz; 2000.

    Google Scholar 

  56. Laskow DA, Vincenti F, Neylan JF, et al. An open-label, concentration-ranging trial of FK506 in primary kidney transplantation. Transplantation 1996; 62: 900.

    PubMed  CAS  Google Scholar 

  57. Mayer AD, Dmitrewski J, Squifflet JP, et al. Multicenter randomized trial comparing tacrolimus and cyclosporine in the prevention of renal allograft rejection. Transplantation 1997; 64: 436.

    PubMed  CAS  Google Scholar 

  58. Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus and cyclosporine for immunosuppression after cadaveric renal transplantation. Transplantation 1997; 63: 977.

    PubMed  CAS  Google Scholar 

  59. Shapiro R, Jordan ML, Scantlebury VP, et al. A prospective, randomized trial of tacrolimus/prednisone versus tacrolimus/prednisone/mycophenolate mofetil in renal transplant recipients. Transplantation 1999; 67: 411.

    PubMed  CAS  Google Scholar 

  60. Gruessner RWG, Burke GW, Stratta R, et al. A multicenter analysis of the first experience with FK506 for induction and rescue therapy after pancreas transplantation. Transplantation 1996; 61: 261.

    PubMed  CAS  Google Scholar 

  61. Pham SM, Kormos RL, Hatter BG, et al. A prospective trial of tacrolimus (FK506) in clinical heart transplantation: intermediate-term results. J Thorac Cardiovasc Surg 1996; 111: 764.

    PubMed  CAS  Google Scholar 

  62. Reichart B, Meiser B, Vigano M, et al. European Multicenter Tacrolimus (FK506) heart pilot study: one-year results—European Tacrolimus Mutlicenter Heart Study Group. J Heart Lung Transplant 1998; 17: 775.

    PubMed  CAS  Google Scholar 

  63. Tsamandas AC, Pham SM, Seaberg EC, et al. Adult heart transplantation under tacrolimus (FK506) immunosuppression: histopathologic observations and comparison to a cyclosporine-based regimen with lympholytic (ATG) induction. J Heart Lung Transplant 1997; 16: 723.

    PubMed  CAS  Google Scholar 

  64. Keenan RJ, Konishi H, Kawai A, et al. Clinical trial of tacrolimus versus cyclosporine in lung transplantation. Ann Thorac Surg 1995; 60: 580.

    PubMed  CAS  Google Scholar 

  65. MacDonald AS for the Rapamune Global Study Group. A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 2001; 71: 271.

    Google Scholar 

  66. Jordan ML, Naraghi R, Shapiro R, et al. Tacrolimus rescue therapy for renal allograft rejection: five years experience. Transplantation 1997; 63: 223.

    PubMed  CAS  Google Scholar 

  67. Yang HC, Holman MJ, Langhoff E, et al. Tacrolimus/“low-dose” mycophenolate mofetil versus microemulsion cyclosporine/“low-dose” mycophenolate mofetil after kidney transplantation- 1-year follow-up of a prospective, randomized clinical trial. Transplant Proc 1999; 31: 1121.

    PubMed  CAS  Google Scholar 

  68. Randhawa PS, Shapiro R, Jordan ML, Starzl TE, Demetris AJ. The histopathological changes associated with allograft rejection and drug toxicity in renal transplant recipients maintained on FK506. Am J Surg Pathol 1993; 17: 60.

    PubMed  CAS  Google Scholar 

  69. Gao B, Esnouf MP. Multiple interactive residues of recognition. J Immunol 1996; 157: 183.

    PubMed  CAS  Google Scholar 

  70. Bennett WM, DeMattos A, Meyer MM, Andoh T, Barry JM. Chronic cyclosporine nephropathy: the Achilles’ heel of immunosuppressive therapy. Kidney Int 1996; 50: 1089.

    PubMed  CAS  Google Scholar 

  71. Kahan BD, Van Buren CT, Flechner SM, et al. Clinical and experimental studies with cyclosporine in renal transplantation. Surgery 1985; 97: 125.

    PubMed  CAS  Google Scholar 

  72. Radermacher J, Meiners M, Bramlage C, et al. Pronounced renal vasoconstriction and systemic hypertension in renal transplant patients treated with cyclosporin A versus FK 506. Transpl Int 1998; 11: 3.

    PubMed  CAS  Google Scholar 

  73. Nakafusa Y, Goss JA, Monhanakumar T, lye MW. Induction of donor specific tolerance to cardiac but not skin or renal allografts by intrathymic injection of splenocyte antigen. Transplantation 1993; 55: 877.

    PubMed  CAS  Google Scholar 

  74. Katari SR, Magnone M, Shapiro R, et al. Clinical features of acute reversible tacrolimus (FK506) nephrotoxicity in kidney transplant recipients. Clin Transplant 1997; 11: 237.

    PubMed  CAS  Google Scholar 

  75. Weinstock PH, Bisgaier CL, Aalto-Setala K, et al. Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes. J Clin Invest 1995; 96: 2555.

    Google Scholar 

  76. DiMartini AF, Trzepacz PT, Pajer KA, Faett D, Fung J. Neuropsychiatric side effects of FK506 vs. cyclosporine A. First-week postoperative findings. Psychosomatics 1997; 38::565.

    PubMed  Google Scholar 

  77. Neylan JF. Racial differences in renal transplantation after immunosuppression with tacrolimus versus cyclosporine. Transplantation 1998; 65: 515.

    PubMed  CAS  Google Scholar 

  78. Sehgal SN, Baker H, Vezina C. Rapamycin (AY-22,989), a new antifungal antibiotic: II. Fermentation, isolation and characterization. J Antibiot (Tokyo) 1975; 28: 727.

    CAS  Google Scholar 

  79. Vezina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic: I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 1975; 28: 721.

    CAS  Google Scholar 

  80. Kahan BD, Dunn J, Fitts C, et al. Reduced inter- and intrasubject variability in cyclosporine pharmacokinetics in renal transplant recipients treated with a microemulsion formulation in conjunction with fasting, low-fat meals, or high-fat meals. Transplantation 1995; 59: 505.

    PubMed  CAS  Google Scholar 

  81. Kuo CJ, Chung J, Fiorentino DF, Flanagan WM, Blenis J, Crabtree GR. Rapamycin selectively inhibits interleukin-2 activation of p70 s6 kinase. Nature 1992; 358: 70.

    PubMed  CAS  Google Scholar 

  82. Brown EJ, Albers MW, Shin TB, et al. A mammalian protein targeted by G1-arresting-rapamycin-receptor complex. Nature 1994; 369: 756.

    PubMed  CAS  Google Scholar 

  83. Stepkowski SM, Chen H, Daloze P, Kahan BD. Rapamycin, a potent immunosuppressive drug for vascularized heart, kidney, and small bowel transplantation in the rat. Transplantation 1991; 51: 22.

    PubMed  CAS  Google Scholar 

  84. Kahan BD, Gibbons S, Tejpal N, Stepkowski SM, Chou T-C. Synergistic interactions of cyclosporine and rapamycin to inhibit immune performances of normal human peripheral blood lymphocytes in vitro. Transplantation 1991; 51: 232.

    PubMed  CAS  Google Scholar 

  85. Zimmerman J, Kahan BD. Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Pharmacol 1997; 37: 405.

    PubMed  CAS  Google Scholar 

  86. Napoli KL, Kahan BD. Routine clinical monitoring of sirolimus (rapamycin) whole-blood concentrations by HPLC with ultraviolet detection. Clin Chem 1996; 42: 1943.

    PubMed  CAS  Google Scholar 

  87. Groth CG, Backman L, Morales JM, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999; 67: 1036.

    PubMed  CAS  Google Scholar 

  88. Kahan BD, Julian BA, Pescovitz MD, Vanrenterghem Y, Neylan J, for the Rapamune Study Group. Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in Caucasian recipients of mismatched primary renal allografts: A phase II trial. Transplantation 1999; 68: 1526.

    PubMed  CAS  Google Scholar 

  89. Pescovitz MD, Kahan BD, Julian B, Neylan J, Chan G. Sirolimus (SRL) permits early steroid withdrawal from a triple therapy renal prophylaxis regimen (Abstract). XVI Annual Meeting of the American Society for Transplant Physicians 1997.

    Google Scholar 

  90. Kahan BD, for the Rapamune U.S. Study Group. Sirolimus (Rapamune, rapamycin) is more effective than azathioprine to reduce the incidence of acute renal allograft rejection episodes when used in combination with cyclosporine and prednisone: A phase III U.S. multicenter trial. Lancet 2000; 356: 194.

    PubMed  CAS  Google Scholar 

  91. Hong JC, Kahan BD. Sirolimus rescue therapy for refractory rejection in renal transplantation. Transplantation (in press).

    Google Scholar 

  92. Murgia MG, Jordan S, Kahan BD. The side effect profile of sirolimus: A phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. Kidney Int 1996; 49: 209.

    PubMed  CAS  Google Scholar 

  93. Hong JC, Kahan BD. Sirolimus-induced thrombocytopenia and leukopenia in renal transplant recipients: risk factors, incidence, progression, and management. Transplantation 2000; 69: 2085.

    Google Scholar 

  94. DiJoseph JF, Sharma RN, Chang JY. The effect of rapamycin on kidney function in the Sprague-Dawley rat. Transplantation 1992; 53: 507.

    PubMed  CAS  Google Scholar 

  95. Andoh TF, Burdmann EA, Fransechini N, Houghton DC, Bennett WM. Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506. Kidney Int 1996; 50: 1110.

    PubMed  CAS  Google Scholar 

  96. Andoh TF, Bennett WM. The synergistic effects of cyclosporine and sirolimus (reply). Transplantation 1997; 63: 1703.

    PubMed  CAS  Google Scholar 

  97. Morales JM, Wramner H, Kreis D, et al. Sirolimus vs. cyclosporine: a comparison of renal function over two years. XVIII International Congress of the Transplantation Society 2000; Abstract 0428: 140.

    Google Scholar 

  98. Napoli KL, Wang ME, Stepkowski SM, Kahan BD. Relative tissue distributions of cyclosporine and sirolimus after concomitant peroral administration to the rat: evidence for pharmacokinetic interactions. Ther Drug Monit 1998; 20: 123.

    PubMed  CAS  Google Scholar 

  99. Keane WF. Lipids and progressive renal disease: the cardio-renal link. Am J Kidney Dis 1999; 34: xliii-xlvi.

    PubMed  CAS  Google Scholar 

  100. Levin B, Hoppe RT, Collins G, et al. Treatment of cadaveric renal transplant recipients with total lymphoid irradiation, antithymocyte globulin, and low-dose prednisone. Lancet 1985; 2: 1321.

    PubMed  CAS  Google Scholar 

  101. Frankson C, Bloomstrand R. Drainage of the thoracic lymph duct during homologous kidney transplantation in man. Scand J Urol Nephrol 1967; 1: 123.

    Google Scholar 

  102. Russell PS, Monaco AP. Heterologous antilymphocyte sera and some of their effects. Transplantation 1967; 5: 1086.

    PubMed  Google Scholar 

  103. Starzl TE, Marchioro TL, Porter KA, Iwasaki Y, Cerilli GJ. The use of heterologous antilymphoid agents in canine renal and liver homotransplantation and in human renal homotransplantation. Surg Gynecol Obstet 1967; 124: 301.

    PubMed  CAS  Google Scholar 

  104. Najarian JS, Simmons RL, Gewurz H, Moberg A, Merkel F, Moore GE. Antihuman lymphoblast globulin. Fed Proc 1970; 29: 197.

    PubMed  CAS  Google Scholar 

  105. Metchnikoff E. Etudes sur la resorption des cellules. Ann Inst Pasteur 1899; 13: 737.

    Google Scholar 

  106. Gaber AO, First MR, Tesi RJ, et al. Results of the double-blind, randomized, multicenter, phase III clinical trial of thymoglobulin versus ATGAM in the treatment of acute graft rejection episodes after renal transplantation. Transplantation 1998; 66: 29.

    PubMed  CAS  Google Scholar 

  107. Cosimi AB. Clinical development of orthoclone OKT3. Transplant Proc 1987; 14 (Suppl 1): 7.

    Google Scholar 

  108. Hayes JM. The immunobiology and clinical use of current immunosuppressive therapy for renal transplantation. J Urol 1993; 149: 437.

    PubMed  CAS  Google Scholar 

  109. Swinnen LJ, Costanzo-Nordin MR, Fisher SG, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med 1990; 323: 1723.

    PubMed  CAS  Google Scholar 

  110. Solomon H, Gonwa TA, Mor E, et al. OKT3 rescue for steroid-resistant rejection in adult liver transplantation. Transplantation 1993; 55: 87.

    PubMed  CAS  Google Scholar 

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

    Google Scholar 

  112. Abramowicz D, Norman DJ, Vereerstraeten P, et al. OKT3 prophylaxis in renal grafts with prolonged cold ischemia times: association with improvement in long-term survival. Kidney Int 1996; 49: 768.

    PubMed  CAS  Google Scholar 

  113. Nashan B, Moore R, Amlot P, Schmidt A-G, Abeywickrama K, Soulillou J-P. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. Lancet 1997; 350: 1193.

    PubMed  CAS  Google Scholar 

  114. Vincenti F, Kirkman R, Light S, et al. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. N Engl J Med 1998; 338: 161.

    PubMed  CAS  Google Scholar 

  115. Hakimi J, Chizzonite R, Luke DR, et al. Reduced immunogenicity and improved pharmacokinetics of humanized anti-Tac in cynomolgus monkeys. J Immunol 1991; 147: 1352.

    PubMed  CAS  Google Scholar 

  116. Kahan BD, Rajagopalan PR, Hall ML, for the United States Simulect® Renal Study Group. Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin-2-receptor monoclonal antibody. Transplantation 1999; 67: 276.

    PubMed  CAS  Google Scholar 

  117. Kovarik JM, Kahan BD, Rajagopalan PR, et al. Population pharmacokinetics and exposure-response relationships for basiliximab in kidney transplantation. The U.S. Simulect Renal Transplant Study Group. Transplantation 1999; 68: 1288.

    PubMed  CAS  Google Scholar 

  118. Vincenti F, Nashan B, Light S. Daclizumab: Outcome of phase III trials and mechanism of actions. Transplant Proc 1998; 30: 2155.

    Google Scholar 

  119. Brinkmann I, Pinschewer I, Chiba I, Feng I. FTY720: a novel transplantation drug that modulates lymphocyte traffic rather than activation. Trends Pharmacol Sci 2000; 21: 49.

    PubMed  CAS  Google Scholar 

  120. Brinkmann V, Pinschewer D, Feng L. FTY720 suppresses immune responses by modulating G-protein coupled receptors on lymphocytes resulting in altered lymphocyte homing [Abstract 879]. XVIII Annual Meeting of the American Society of Transplantation 1999.

    Google Scholar 

  121. Wang ME, Tejpal N, Qu X, et al. Immunosuppressive effects of FTY720 alone or in combination with cyclosporine or sirolimus. Transplantation 1998; 65: 899.

    PubMed  CAS  Google Scholar 

  122. Troncoso P, Stepkowski SM, Wang ME, et al. Prophylaxis of acute renal allograft rejection using FTY720 in combination with subtherapeutic doses of cyclosporine. Transplantation 1999; 67: 145.

    PubMed  CAS  Google Scholar 

  123. Brunkhorst R, Neumayer H-H, Hiss M, et al. Human safety and pharmacology of FTY720 [Abstract 585]. XVIII Annual Meeting of the American Society of Transplantation 1999.

    Google Scholar 

  124. Tedesco H, Kahan BD. [Abstract]. AST 2001 (in preparation).

    Google Scholar 

  125. Kahan BD, Chodoff A, Leichtman J, et al. Safety and pharmacodynamics of multiple doses of FTY720 [Abstract]. Transplantation 2000.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Immunology and Organ Transplantation, The University of Texas Medical School at Houston, USA

    Barry D. Kahan Ph.D., M.D.

Authors
  1. Barry D. Kahan Ph.D., M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Pediatric Critical Care Medicine, Rhode Island Hospital, Providence, RI, USA

    Lesley A. Doughty M.D.

  2. Critical Care Medicine/Infectious Disease, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Peter Linden M.D.

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Springer Science+Business Media New York

About this chapter

Cite this chapter

Kahan, B.D. (2003). Mechanisms of Pharmacologic Immune Suppression. In: Doughty, L.A., Linden, P. (eds) Immunology and Infectious Disease. Molecular and Cellular Biology of Critical Care Medicine, vol 3. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0245-6_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-0245-6_4

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-4984-6

  • Online ISBN: 978-1-4615-0245-6

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation