Abstract
T cells play a key role in orchestrating the immune response to an allograft. The discovery of a potent and immunologically specific inhibitor of T cell activation, ciclosporin, dramatically improved the results of renal transplantation and transformed other types of organ transplantation from experimental to standard therapy. The discovery of a second drug, tacrolimus, that was structurally unrelated to ciclosporin but which had an identical mechanism of action, facilitated research which clarified the mechanisms underlying T cell activation. Although these drugs are powerful immunosuppressants, their clinical use is limited by their nephrotoxicity. In transplantation, this has led to their use in lower doses in combination with other immunosuppressive drugs. However long-term nephrotoxicity remains a significant problem, and this has curtailed the use of calcineurin-inhibitors for indications outside the field of transplantation. Ciclosporin and tacrolimus are metabolised by cytochrome P450 3A and are substrates for the P-glycoprotein transporter system. This results in complex pharmacokinetics with large variations in bioavailability and metabolism between individuals as well as a great number of clinically significant drug interactions. Therapeutic drug monitoring has been used to address these issues. For the foreseeable future, these powerful immunosuppressive agents are likely to continue to play a role in organ transplantation. However, newer immunosuppressants that are not nephrotoxic may begin to replace calcineurin-inhibitors for long-term maintenance therapy after transplantation.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Abe M, Sawada T, et al (2003) C4d deposition in peritubular capillary and alloantibody in the allografted kidney suffering severe acute rejection. Clin Transplant 17Suppl 10:14–9
Actis GC, Volpes R, et al (1999) Oral microemulsion cyclosporin to reduce steroids rapidly in chronic active ulcerative colitis. Eur J Gastroenterol Hepatol 11:905–8
Adams DO, Hamilton TA (1984) The cell biology of macrophage activation. Annu Rev Immunol 2:283–318
Amenabar JJ, Gomez-Ullate P, et al (1998) A randomized trial comparing cyclosporine and steroids with cyclosporine, azathioprine, and steroids in cadaveric renal transplantation. Transplantation 65:653–61
Andoh TF, Bennett WM (1998) Chronic cyclosporine nephrotoxicity. Curr Opin Nephrol Hypertens 7:265–70
Andoh TF, Lindsley J, et al (1996) Synergistic effects of cyclosporine and rapamycin in a chronic nephrotoxicity model. Transplantation 62:311–6
Andoh TF, Gardner MP, et al (1997) Protective effects of dietary L-arginine supplementation on chronic cyclosporine nephrotoxicity. Transplantation 64:1236–40
Andoh TF, Johnson RJ, et al (2001) Subclinical renal injury induced by transient cyclosporine exposure is associated with salt-sensitive hypertension. Am J Transplant 1:222–7
Arranz R, Conde E, et al (2002) CsA-based post-graft immunosuppression: the main factor for improving outcome of allografted patients with acquired aplastic anemia. A retrospective survey by the Spanish Group of Hematopoietic Transplantation. Bone Marrow Transplant 29:205–11
Assan R, Fredj G, et al (1994) FK 506/fluconazole interaction enhances FK 506 nephrotoxicity. Diabete Metab 20:49–52
Assis SM, Monteiro JL, et al (1997) L-Arginine and allopurinol protect against cyclosporine nephrotoxicity. Transplantation 63:1070–3
Austin HA, Palestine AG 3rd, et al (1989) Evolution of ciclosporin nephrotoxicity in patients treated for autoimmune uveitis. Am J Nephrol 9:392–402
Azimzadeh A, C Schroeder, et al (2003) Xenotransplantation. In: Banner NR, Polak JM, Yacoub MH (eds) Lung transplantation. Cambridge University Press, Cambridge, pp 374–385
Ballantyne CM (2000) Statins after cardiac transplantation: which statin, what dose, and how low should we go? J Heart Lung Transplant 19:515–7
Ballantyne CM, Podet EJ, et al (1989) Effects of cyclosporine therapy on plasma lipoprotein levels. Jama 262:53–6
Banerjee R, Leaver N, et al (2001) Coadministration of itraconazole and tacrolimus after thoracic organ transplantation. Transplant Proc 33:1600–2
Banner NR (2003) Cytomegalovirus infection. In: Banner NR, Polak JM, Yacoub MH (eds) Lung transplantation. Cambridge University Press, Cambridge, pp 261–273
Banner NR, Lyster H (2003) Pharmacological immunosuppression. In: Banner NR, Polak JM, Yacoub MH (eds) Lung transplantation. Cambridge University Press, Cambridge, pp 205–42
Bargman JM (1999) Management of minimal lesion glomerulonephritis: evidence-based recommendations. Kidney Int Suppl 70:S3–16
Barone GW, Gurley BJ, et al (2000) Drug interaction between St. John’s wort and cyclosporine. Ann Pharmacother 34:1013–6
Bekersky I, Dressler D, et al (2001) Comparative tacrolimus pharmacokinetics: normal versus mildly hepatically impaired subjects. J Clin Pharmacol 41:628–35
Bell WR, Braine HG, et al (1991) Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med 325:398–403
Bennett WM, DeMattos A, et al (1996) Chronic cyclosporine nephropathy: the Achilles’heel of immunosuppressive therapy. Kidney Int 50:1089–100
Berg KJ, Forre O, et al (1986) Side effects of cyclosporin A treatment in patients with rheumatoid arthritis. Kidney Int 29:1180–7
Bertani T, Ferrazzi P, et al (1991) Nature and extent of glomerular injury induced by cyclosporine in heart transplant patients. Kidney Int 40:243–50
Bierer BE, Mattila PS, et al (1990) Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. Proc Natl Acad Sci U S A 87:9231–5
Bittner HB, Dunitz J, et al (2001) Hyperacute rejection in single lung transplantation—case report of successful management by means of plasmapheresis and antithymocyte globulin treatment. Transplantation 71:649–51
Bohmig GA, Regele H, et al (2001) C4d-positive acute humoral renal allograft rejection: effective treatment by immunoadsorption. J Am Soc Nephrol 12:2482–9
Borel JF, Feurer C, et al (1976) Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions 6:468–75
Bossaller C, Forstermann U, et al (1989) Ciclosporin A inhibits endothelium-dependent vasodilatation and vascular prostacyclin production. Eur J Pharmacol 165:165–9
Boubenider S, Vincent I, et al (2000) Interaction between theophylline and tacrolimus in a renal transplant patient. Nephrol Dial Transplant 15:1066–8
Calne RY, White DJ, et al (1978) Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 2:1323–7
Canadian-European Randomized Control Trial Group (1988) Cyclosporin-induced remission of IDDM after early intervention. Association of 1 yr of cyclosporin treatment with enhanced insulin secretion. The Canadian-European Randomized Control Trial Group. Diabetes 37:1574–82
Canadian Multicenter Transplant Study Group (1983) A randomized clinical trial of cyclosporine in cadaveric renal transplantation. N Engl J Med 309:809–15
Canadian Multicentre Transplant Study Group (1986) A randomized clinical trial of cyclosporine in cadaveric renal transplantation. Analysis at three years. N Engl J Med 314:1219–25
Carstensen H, Jacobsen N, et al (1986) Interaction between cyclosporin A and phenobarbitone. Br J Clin Pharmacol 21:550–1
Cattran DC, Appel GB, et al (1999) A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group. Kidney Int 56:2220–6
Chaudhary PM, Mechetner EB, et al (1992) Expression and activity of the multidrug resistance P-glycoprotein in human peripheral blood lymphocytes. Blood 80:2735–9
Cherry R, Nielsen H, et al (1992) Vascular (humoral) rejection in human cardiac allograft biopsies: relation to circulating anti-HLA antibodies. J Heart Lung Transplant 11:24–9; discussion 30
Choi JK, Kearns J, et al (1999) Hyperacute rejection of a pulmonary allograft. Immediate clinical and pathologic findings. Am J Respir Crit Care Med 160:1015–8
Christians U, Sewing KF (1993) Cyclosporin metabolism in transplant patients. Pharmacol Ther 57:291–345
Christians U, Jacobsen W, et al (2002) Mechanisms of clinically relevant drug interactions associated with tacrolimus. Clin Pharmacokinet 41:813–51
Cohen JI (2000) Epstein-Barr virus infection. N Engl J Med 343:481–92
Coley SC, Porter DA, et al (1999) Quantitative MR diffusion mapping and cyclosporine-induced neurotoxicity. AJNR Am J Neuroradiol 20:1507–10
Cooney GF, Mochon M, et al (1995) Effects of carbamazepine on cyclosporine metabolism in pediatric renal transplant recipients. Pharmacotherapy 15:353–6
Crabtree GR (1989) Contingent genetic regulatory events in T lymphocyte activation. Science 243:355–61
Crowe A, Bruelisauer A, et al (1999) Absorption and intestinal metabolism of SDZ-RAD and rapamycin in rats. Drug Metab Dispos 27:627–32
de Groen PC (1988) Cyclosporine, low-density lipoprotein, and cholesterol. Mayo Clin Proc 63:1012–21
de Groen PC, Aksamit AJ, et al (1987) Central nervous system toxicity after liver transplantation. The role of cyclosporine and cholesterol. N Engl J Med 317:861–6
Deeg HJ, Storb R, et al (1985) Cyclosporine as prophylaxis for graft-versus-host disease: a randomized study in patients undergoing marrow transplantation for acute nonlymphoblastic leukemia. Blood 65:1325–34
Derici U, Arinsoy T, et al (2001) Cyclosporine-A induced neurotoxicity after renal transplantation. Acta Neurol Belg 101:124–7
Doody DP, Stenger KS, et al (1994) Immunologically nonspecific mechanisms of tissue destruction in the rejection of skin grafts. J Exp Med 179:1645–52
Dougados M, Awada H, et al (1988) Cyclosporin in rheumatoid arthritis: a double blind, placebo controlled study in 52 patients. Ann Rheum Dis 47:127–33
Dumont FJ, Staruch MJ, et al (1990) Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin. J Immunol 144:251–8
Durand DB, Shaw JP, et al (1988) Characterization of antigen receptor response elements within the interleukin-2 enhancer. Mol Cell Biol 8:1715–24
Edwards DJ, Fitzsimmons ME, et al (1999) 6′,7′-Dihydroxybergamottin in grapefruit juice and Seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin Pharmacol Ther 65:237–44
Eisen HJ, Hobbs RE, et al (2001) Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine—results at 24 months after transplantation. Transplantation 71:70–8
Eisen HJ, Tuzcu EM, et al (2003) Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 349:847–58
Ellis CN, Gorsulowsky DC, et al (1986) Cyclosporine improves psoriasis in a double-blind study. Jama 256:3110–6
Elzinga LW, Rosen S, et al (1993) Dissociation of glomerular filtration rate from tubulointerstitial fibrosis in experimental chronic cyclosporine nephropathy: role of sodium intake. J Am Soc Nephrol 4:214–21
Emery RW, Cork R, et al (1986) Cardiac transplant patient at one year. Cyclosporine vs conventional immunosuppression. Chest 90:29–33
Esterl RM Jr, Gupta N, et al (1996) Permanent blindness after cyclosporine neurotoxicity in a kidney-pancreas transplant recipient. Clin Neuropharmacol 19:259–66
European FK506 Multicentre Liver Study Group (1994) Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. Lancet 344:423–8
European multicentre trial group (1983) Cyclosporin in cadaveric renal transplantation: one-year follow-up of a multicentre trial. Lancet 2:986–9
European Mycophenolate Mofetil Cooperative Study Group (1995) Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. European Mycophenolate Mofetil Cooperative Study Group. Lancet 345:1321–5
Euvrard S, Kanitakis J, et al (2003) Skin cancers after organ transplantation. N Engl J Med 348:1681–91
Falkenhain ME, Cosio FG, et al (1996) Progressive histologic injury in kidneys from heart and liver transplant recipients receiving cyclosporine. Transplantation 62:364–70
Feucht HE (2003) Complement C4d in graft capillaries—the missing link in the recognition of humoral alloreactivity. Am J Transplant 3:646–52
Fierro L, Lund PE, et al (2000) Comparison of the activation of the Ca2+ release-activated Ca2+ current ICRAC to InsP3 in Jurkat T-lymphocytes, pulmonary artery endothelia and RBL-1 cells. Pflugers Arch 440:580–7
Fishman JA, Rubin RH (1998) Infection in organ-transplant recipients. N Engl J Med 338:1741–51
Floren LC, Bekersky I, et al (1997) Tacrolimus oral bioavailability doubles with coadministration of ketoconazole. Clin Pharmacol Ther 62:41–9
Forre O (1994) Radiologic evidence of disease modification in rheumatoid arthritis patients treated with cyclosporine. Results of a 48-week multicenter study comparing low-dose cyclosporine with placebo. Norwegian Arthritis Study Group. Arthritis Rheum 37:1506–12
Forre O, Bjerkhoel F, et al (1987) An open, controlled, randomized comparison of cyclosporine and azathioprine in the treatment of rheumatoid arthritis: a preliminary report. Arthritis Rheum 30:88–92
Fruman DA, Klee CB, et al (1992) Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. Proc Natl Acad Sci U S A 89:3686–90
Furlan V, Perello L, et al (1995) Interactions between FK506 and rifampicin or erythromycin in pediatric liver recipients. Transplantation 59:1217–8
Furst DE, Saag K, et al (2002) Efficacy of tacrolimus in rheumatoid arthritis patients who have been treated unsuccessfully with methotrexate: a six-month, double-blind, randomized, dose-ranging study. Arthritis Rheum 46:2020–8
Garrett HE Jr, Groshart K, et al (2002) Treatment of humoral rejection with rituximab. Ann Thorac Surg 74:1240–2
Grandtnerova B, Javorsky P, et al (1995) Treatment of acute humoral rejection in kidney transplantation with plasmapheresis. Transplant Proc 27:934–5
Guella A, Daoud M, et al (1998) Uneventful re-treatment with cyclosporin in two cases of cyclosporin-induced haemolytic uraemic syndrome. Nephrol Dial Transplant 13:1864–5
Hall BM, Dorsch S, et al (1978) The cellular basis of allograft rejection in vivo. I. The cellular requirements for first-set rejection of heart grafts. J Exp Med 148:878–89
Handschumacher RE, Harding MW, et al (1984) Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science 226:544–7
Hartmann A, Andereassen AK, et al (1996) Five years’ follow-up of renal glomerular and tubular functions in heart transplant recipients. J Heart Lung Transplant 15:972–9
Hebert MF, Lam AY (1999) Diltiazem increases tacrolimus concentrations. Ann Pharmacother 33:680–2
Hebert MF, Fisher RM, et al (1999) Effects of rifampin on tacrolimus pharmacokinetics in healthy volunteers. J Clin Pharmacol 39:91–6
Hickstein H, Korten G, et al (1998) Protein A immunoadsorption (i.a.) in renal transplantation patients with vascular rejection. Transfus Sci 19Suppl:53–7
Holt DW, Johnston A, et al (1994) Methodological and clinical aspects of cyclosporin monitoring: report of the Association of Clinical Biochemists task force. Ann Clin Biochem 31:420–46
Hornick P, Lechler R (1997) Direct and indirect pathways of alloantigen recognition: relevance to acute and chronic allograft rejection. Nephrol Dial Transplant 12:1806–10
Hows JM, Palmer S, et al (1982) Use of cyclosporin A in allogeneic bone marrow transplantation for severe aplastic anemia. Transplantation 33:382–6
Hubbard MJ, Klee CB (1989) Functional domain structure of calcineurin A: mapping by limited proteolysis. Biochemistry 28:1868–74
Ichihashi T, Naoe T, et al (1992) Haemolytic uraemic syndrome during FK506 therapy. Lancet 340:60–1
Jacobsen W, Kuhn B, et al (2000) Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin. Drug Metab Dispos 28:1369–78
Jacobsen W, Serkova N, et al (2001) Comparison of the in vitro metabolism of the macrolide immunosuppressants sirolimus and RAD. Transplant Proc 33:514–5
Jarosz JM, Howlett DC, et al (1997) Cyclosporine-related reversible posterior leukoencephalopathy: MRI. Neuroradiology 39:711–5
Jegasothy BV, Ackerman CD, et al (1992) Tacrolimus (FK 506)—a new therapeutic agent for severe recalcitrant psoriasis. Arch Dermatol 128:781–5
Jensik SC (1998) Tacrolimus (FK 506) in kidney transplantation: three-year survival results of the US multicenter, randomized, comparative trial. FK 506 Kidney Transplant Study Group. Transplant Proc 30:1216–8
Johnson RJ, Herrera J-Acosta, et al (2002) Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med 346:913–23
Joint National Committee (1997) The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 157:2413–46
June CH, Ledbetter JA, et al (1987) T cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Mol Cell Biol 7:4472–81
Jusko WJ, Piekoszewski W, et al (1995) Pharmacokinetics of tacrolimus in liver transplant patients. Clin Pharmacol Ther 57:281–90
Jusko WJ, Thomson AW, et al (1995) Consensus document: therapeutic monitoring of tacrolimus (FK-506). Ther Drug Monit 17:606–14
Kahan BD (1989) Cyclosporine. N Engl J Med 321:1725–38
Kahan BD (2000) Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The Rapamune US Study Group. Lancet 356:194–202
Kahan BD, Welsh M, et al (1996) Variable oral absorption of cyclosporine. A biopharmaceutical risk factor for chronic renal allograft rejection. Transplantation 62:599–606
Kaplan B, Meier-Kriesche HU, al et (1998) The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent. Clin Pharmacol Ther 63:48–53
Karanam BV, Vincent SH, et al (1994) FK 506 metabolism in human liver microsomes: investigation of the involvement of cytochrome P450 isozymes other than CYP3A4. Drug Metab Dispos 22:811–4
Kasiske BL, Tortorice KL, et al (1991) The adverse impact of cyclosporine on serum lipids in renal transplant recipients. Am J Kidney Dis 17:700–7
Kay JE (1989) Inhibitory effects of cyclosporin A on lymphocyte activation. In: Thomson AW (ed) Cyclosporin. Kluwer Academic, Dordrecht, pp 1–23
Kay JE, Benzie CR, et al (1983) Effect of cyclosporin A on lymphocyte activation by the calcium ionophore A23187. Immunology 50:441–6
Kennedy MS, Deeg HJ, et al (1983) Acute renal toxicity with combined use of amphotericin B and cyclosporine after marrow transplantation. Transplantation 35:211–5
Keogh A, Spratt P, et al (1995) Ketoconazole to reduce the need for cyclosporine after cardiac transplantation. N Engl J Med 333:628–33
Keown PA, Laupacis A, et al (1984) Interaction between phenytoin and cyclosporine following organ transplantation. Transplantation 38:304–6
Khanna A, Kapur S, et al (1997) In vivo hyperexpression of transforming growth factorbeta1 in mice: stimulation by cyclosporine. Transplantation 63:1037–9
Khanna A, Cairns V, et al (1999) Tacrolimus induces increased expression of transforming growth factor-beta1 in mammalian lymphoid as well as nonlymphoid cells. Transplantation 67:614–9
Kincaid RL, Martensen TM, et al (1986) Modulation of calcineurin phosphotyrosyl protein phosphatase activity by calmodulin and protease treatment. Biochem Biophys Res Commun 140:320–8
Kino T, Hatanaka H, et al (1987) FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 40:1256–65
Klee CB, Draetta GF, et al (1988) Calcineurin. Adv Enzymol Relat Areas Mol Biol 61:149–200
Klintmalm G, Sawe J (1984) High dose methylprednisolone increases plasma cyclosporin levels in renal transplant recipients. Lancet 1:731
Knoll GA, Bell RC (1999) Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: meta-analysis of randomised trials. Bmj 318:1104–7
Kon V, Hunley TE, et al (1995) Combined antagonism of endothelin A/B receptors links endothelin to vasoconstriction whereas angiotensin II effects fibrosis. Studies in chronic cyclosporine nephrotoxicity in rats. Transplantation 60:89–95
Kulzer P, Wanner C (1998) Thrombotic microangiopathy: a challenge with uncertain outcome. Nephrol Dial Transplant 13:2154–60
Kumagai N, Benedict SH, et al (1988) Cyclosporin A inhibits initiation but not progression of human T cell proliferation triggered by phorbol esters and calcium ionophores. J Immunol 141:3747–52
Kuo PC, Luikart H, et al (1995) Clinical outcome of interval cadaveric renal transplantation in cardiac allograft recipients. Clin Transplant 9:92–7
Lampen A, Christians U, et al (1995) Metabolism of the immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug interactions, and interindividual variability. Drug Metab Dispos 23:1315–24
Lampen A, Zhang Y, et al (1998) Metabolism and transport of the macrolide immunosuppressant sirolimus in the small intestine. J Pharmacol Exp Ther 285:1104–12
Levy GA (2001) C2 monitoring strategy for optimising cyclosporin immunosuppression from the Neoral formulation. BioDrugs 15:279–90
Lin CS, Boltz RC, et al (1991) FK-506 and cyclosporin A inhibit highly similar signal transduction pathways in human T lymphocytes. Cell Immunol 133:269–84
Lin JH, Chiba M, et al (1999) Is the role of the small intestine in first-pass metabolism overemphasized? Pharmacol Rev 51:135–58
Lindholm A, Kahan BD (1993) Influence of cyclosporine pharmacokinetics, trough concentrations, and AUC monitoring on outcome after kidney transplantation. Clin Pharmacol Ther 54:205–18
Liu J (1993) FK506 and cyclosporin, molecular probes for studying intracellular signal transduction. Immunol Today 14:290–5
Liu J, Farmer Jr JD, et al (1991) Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66:807–15
Loh C, Shaw KT, et al (1996) Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity. J Biol Chem 271:10884–91
Luo C, Shaw KT, et al (1996) Interaction of calcineurin with a domain of the transcription factor NFAT1 that controls nuclear import. Proc Natl Acad Sci U S A 93:8907–12
MacDonald AS (2001) 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 71:271–80
Mackenzie HS, Brenner BM (1998) Current strategies for retarding progression of renal disease. Am J Kidney Dis 31:161–70
Maghrabi K, Bohlega S (1998) Cyclosporine-induced migraine with severe vomiting causing loss of renal graft. Clin Neurol Neurosurg 100:224–7
Manez R, Martin M, et al (1994) Fluconazole therapy in transplant recipients receiving FK506. Transplantation 57:1521–3
Marsland AM, Griffiths CE (2002) The macrolide immunosuppressants in dermatology: mechanisms of action. Eur J Dermatol 12:618–22
Mayer AD, Dmitrewski J, et al (1997) Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. Transplantation 64:436–43
McCormack G, McCormick PA, et al (2002) Cyclosporin therapy in severe ulcerative colitis: is it worth the effort? Dis Colon Rectum 45:1200–5
Mentzer RM Jr, Jahania MS, et al (1998) Tacrolimus as a rescue immunosuppressant after heart and lung transplantation. The U.S. Multicenter FK506 Study Group. Transplantation 65:109–13
Mieles L, Venkataramanan R, et al (1991) Interaction between FK506 and clotrimazole in a liver transplant recipient. Transplantation 52:1086–7
Mohamed MA, Robertson H, et al (2000) TGF-beta expression in renal transplant biopsies: a comparative study between cyclosporin-A and tacrolimus. Transplantation 69:1002–5
Morales JM, Munoz MA, et al (1995) Reversible acute renal failure caused by the combined use of foscarnet and cyclosporin in organ transplanted patients. Nephrol Dial Transplant 10:882–3
Muirhead N (1999) Management of idiopathic membranous nephropathy: evidence-based recommendations. Kidney Int Suppl 70:S47–55
Myers BD, Newton L, et al (1988) Chronic injury of human renal microvessels with low-dose cyclosporine therapy. Transplantation 46:694–703
Myers BD, Sibley R, et al (1988) The long-term course of cyclosporine-associated chronic nephropathy. Kidney Int 33:590–600
Nagase K, Iwasaki K, et al (1994) Distribution and protein binding of FK506, a potent immunosuppressive macrolide lactone, in human blood and its uptake by erythrocytes. J Pharm Pharmacol 46:113–7
Nghiem P, Pearson G, et al (2002) Tacrolimus and pimecrolimus: from clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis. J Am Acad Dermatol 46:228–41
Niaudet P (1994) Treatment of childhood steroid-resistant idiopathic nephrosis with a combination of cyclosporine and prednisone. French Society of Pediatric Nephrology. J Pediatr 125:981–6
Norman DJ, Illingworth DR, et al (1988) Myolysis and acute renal failure in a heart-transplant recipient receiving lovastatin. N Engl J Med 318:46–7
Nussenblatt RB, Palestine AG, et al (1985) Cyclosporine therapy for uveitis: long-term followup. J Ocul Pharmacol 1:369–82
Oellerich M, Armstrong VW, et al (1995) Lake Louise Consensus Conference on cyclosporin monitoring in organ transplantation: report of the consensus panel. Ther Drug Monit 17:642–54
Oellerich M, Armstrong VW, et al (1998) Therapeutic drug monitoring of cyclosporine and tacrolimus. Update on Lake Louise Consensus Conference on cyclosporin and tacrolimus. Clin Biochem 31:309–16
Olbricht C, Wanner C, et al (1997) Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses. Clin Pharmacol Ther 62:311–21
Onundarson PT, Rowe JM, et al (1992) Response to plasma exchange and splenectomy in thrombotic thrombocytopenic purpura. A 10-year experience at a single institution. Arch Intern Med 152:791–6
Oyer PE, Stinson EB, et al (1983) Cyclosporine in cardiac transplantation: a 2 1/2 year follow up. Transplant Proc 15:2546–52
Palestine AG, Austin HA 3rd, et al (1986) Renal histopathologic alterations in patients treated with cyclosporine for uveitis. N Engl J Med 314:1293–8
Panayi GS, Tugwell P (1997) The use of cyclosporin A microemulsion in rheumatoid arthritis: conclusions of an international review. Br J Rheumatol 36:808–11
Parekh AB, Fleig A, et al (1997) The store-operated calcium current I(CRAC): nonlinear activation by InsP3 and dissociation from calcium release. Cell 89:973–80
Passfall J, Schuller I, et al (1994) Pharmacokinetics of cyclosporin during administration of danazol. Nephrol Dial Transplant 9:1807–8
Patel R, Terasaki PI (1969) Significance of the positive crossmatch test in kidney transplantation. N Engl J Med 280:735–9
Penn I (2000) Cancers in renal transplant recipients. Adv Ren Replace Ther 7:147–56
Pichette V, Leblond FA (2003) Drug metabolism in chronic renal failure. Curr Drug Metab 4:91–103
Pierson RN, Loyd JE 3rd, et al (2002) Successful management of an ABO-mismatched lung allograft using antigen-specific immunoadsorption, complement inhibition, and immunomodulatory therapy. Transplantation 74:79–84
Pirsch JD, Miller J, et al (1997) A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation 63:977–83
Plosker GL, Foster RH (2000) Tacrolimus: a further update of its pharmacology and therapeutic use in the management of organ transplantation. Drugs 59:323–89
Przepiorka D, Ippoliti C, et al (1996) Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after matched unrelated donor marrow transplantation. Blood 88:4383–9
Ptachcinski RJ, Carpenter BJ, et al (1985) Effect of erythromycin on cyclosporine levels. N Engl J Med 313:1416–7
Ptachcinski RJ, Venkataramanan R, et al (1985) Cyclosporine kinetics in renal transplantation. Clin Pharmacol Ther 38:296–300
Ptachcinski RJ, Venkataramanan R, et al (1986) Clinical pharmacokinetics of cyclosporin. Clin Pharmacokinet 11:107–32
Reitz BA, Wallwork JL, et al (1982) Heart-lung transplantation: successful therapy for patients with pulmonary vascular disease. N Engl J Med 306:557–64
Reynolds NJ, Al-Daraji WI (2002) Calcineurin inhibitors and sirolimus: mechanisms of action and applications in dermatology. Clin Exp Dermatol 27:555–61
Robson RA, Fraenkel M, et al (1988) Cyclosporin-verapamil interaction. Br J Clin Pharmacol 25:402–3
Rose ML, Hutchinson IV (2003) Immunological mechanisms of graft injury. In: Banner NR, Polak JM, Yacoub MH (eds) Lung transplantation. Cambridge University Press, Cambridge, pp 185–204
Rosenberg AS, Mizuochi T, et al (1987) Phenotype, specificity, and function of T cell subsets and T cell interactions involved in skin allograft rejection. J Exp Med 165:1296–315
Roth D, Milgrom M, et al (1989) Posttransplant hyperglycemia. Increased incidence in cyclosporine-treated renal allograft recipients. Transplantation 47:278–81
Ruggenenti P, Perico N, et al (1994) Following an initial decline, glomerular filtration rate stabilizes in heart transplant patients on chronic cyclosporine. Am J Kidney Dis 24:549–53
Russell JH, Ley TJ (2002) Lymphocyte-mediated cytotoxicity. Annu Rev Immunol 20:323–70
Ruzicka T (1996) Cyclosporin in less common immune-mediated skin diseases. Br J Dermatol 135:40–2
Sadaba B, Lopez de Ocariz A, et al (1998) Concurrent clarithromycin and cyclosporin A treatment. J Antimicrob Chemother 42:393–5
Sandborn WJ, Lawson GM, et al (1995) Early cellular rejection after orthotopic liver transplantation correlates with low concentrations of FK506 in hepatic tissue. Hepatology 21:70–6
Sawada S, Suzuki G, et al (1987) Novel immunosuppressive agent, FK506. In vitro effects on the cloned T cell activation. J Immunol 139:1797–803
Sayegh MH, Turka LA (1998) The role of T cell costimulatory activation pathways in transplant rejection. N Engl J Med 338:1813–21
Scherrer U, Vissing SF, et al (1990) Cyclosporine-induced sympathetic activation and hypertension after heart transplantation. N Engl J Med 323:693–9
Schinkel AH, Wagenaar E, et al (1995) Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 96:1698–705
Schreiber SL, Crabtree GR (1992) The mechanism of action of cyclosporin A and FK506. Immunol Today 13:136–42
Schulman SL, Shaw LM, et al (1998) Interaction between tacrolimus and chloramphenicol in a renal transplant recipient. Transplantation 65:1397–8
Schvarcz R, Rudbeck G, et al (2000) Interaction between nelfinavir and tacrolimus after orthoptic liver transplantation in a patient coinfected with HIV and hepatitis C virus (HCV). Transplantation 69:2194–5
Schwartz RB, Bravo SM, et al (1995) Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy: CT and MR findings in 16 cases. AJR Am J Roentgenol 165:627–31
Scornik JC, Zander DS, et al (1999) Susceptibility of lung transplants to preformed donor-specific HLA antibodies as detected by flow cytometry. Transplantation 68:1542–6
Serkova N, Hausen B, et al (2000) Tissue distribution and clinical monitoring of the novel macrolide immunosuppressant SDZ-RAD and its metabolites in monkey lung transplant recipients: interaction with cyclosporine. J Pharmacol Exp Ther 294:323–32
Shapiro R, Venkataramanan R, et al (1993) FK 506 interaction with danazol. Lancet 341:1344–5
Shaw AS, Dustin ML (1997) Making the T cell receptor go the distance: a topological view of T cell activation. Immunity 6:361–9
Shaw JP, Utz PJ, et al (1988) Identification of a putative regulator of early T cell activation genes. Science 241:202–5
Shaw KT, Ho AM, et al (1995) Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells. Proc Natl Acad Sci U S A 92:11205–9
Sheikh AM, Wolf DC, et al (1999) Concomitant human immunodeficiency virus protease inhibitor therapy markedly reduces tacrolimus metabolism and increases blood levels. Transplantation 68:307–9
Sheiner PA, Mor E, et al (1994) Acute renal failure associated with the use of ibuprofen in two liver transplant recipients on FK506. Transplantation 57:1132–3
Shihab FS, Andoh TF, et al (1996) Role of transforming growth factor-beta 1 in experimental chronic cyclosporine nephropathy. Kidney Int 49:1141–51
Shimada T, Yamazaki H, et al (1994) Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270:414–23
Siekierka JJ, Hung SH, et al (1989) A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature 341:755–7
Sigal NH, Dumont F, et al (1991) Is cyclophilin involved in the immunosuppressive and nephrotoxic mechanism of action of cyclosporin A? J Exp Med 173:619–28
Smak Gregoor PJ, van Gelder T, et al (1999) Mycophenolic acid plasma concentrations in kidney allograft recipients with or without cyclosporin: a cross-sectional study. Nephrol Dial Transplant 14:706–8
Smith JD, Danskine AJ, et al (1993) The effect of panel reactive antibodies and the donor specific crossmatch on graft survival after heart and heart-lung transplantation. Transpl Immunol 1:60–5
Sowden JM, Berth J-Jones, et al (1991) Double-blind, controlled, crossover study of cyclosporin in adults with severe refractory atopic dermatitis. Lancet 338:137–40
Starzl TE, Klintmalm GB, et al (1981) Liver transplantation with use of cyclosporin A and prednisone. N Engl J Med 305:266–9
Storb R, Deeg HJ, et al (1986) Marrow transplantation for severe aplastic anemia: methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graft-versus-host disease. Blood 68:119–25
Storb R, Deeg HJ, et al (1988) Cyclosporine v methotrexate for graft-v-host disease prevention in patients given marrow grafts for leukemia: long-term follow-up of three controlled trials. Blood 71:293–8
Sugawara I, Hamada H, et al (1990) Specialized localization of P-glycoprotein recognized by MRK 16 monoclonal antibody in endothelial cells of the brain and the spinal cord. Jpn J Cancer Res 81:727–30
Taylor DO, Barr ML, et al (1999) A randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: decreased hyperlipidemia and hypertension with tacrolimus. J Heart Lung Transplant 18:336–45
Tejani A, Butt K, et al (1987) Cyclosporine-induced remission of relapsing nephrotic syndrome in children. J Pediatr 111:1056–62
Terasaki PI, Kreisler M, et al (1971) Presensitization and kidney transplant failures. Postgrad Med J 47:89–100
The European FK 506 Multicentre Psoriasis Study Group (1996) Systemic tacrolimus (FK 506) is effective for the treatment of psoriasis in a double-blind, placebo-controlled study. The European FK 506 Multicentre Psoriasis Study Group. Arch Dermatol 132:419–23
Tocci MJ, Matkovich DA, et al (1989) The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. J Immunol 143:718–26
Toronto Lung Transplant Group (1986) Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med 314:1140–5
Tufro-McReddie A, Gomez RA, et al (1993) Effect of CsA on the expression of renin and angiotensin type 1 receptor genes in the rat kidney. Kidney Int 43:615–22
Tugwell P, Pincus T, et al (1995) Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine Combination Study Group. N Engl J Med 333:137–41
U.S. Multicenter FK506 Liver Study (1994) A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. The U.S. Multicenter FK506 Liver Study Group. N Engl J Med 331:1110–5
Undre NA, Schafer A (1998) Factors affecting the pharmacokinetics of tacrolimus in the first year after renal transplantation. European Tacrolimus Multicentre Renal Study Group. Transplant Proc 30:1261–3
Valantine H, Keogh A, et al (1992) Cost containment: coadministration of diltiazem with cyclosporine after heart transplantation. J Heart Lung Transplant 11:1–7; discussion 7–8
van den Borne BE, Landewe RB, et al (1998) Combination therapy in recent onset rheumatoid arthritis: a randomized double blind trial of the addition of low dose cyclosporine to patients treated with low dose chloroquine. J Rheumatol 25:1493–8
Venkataramanan R, Swaminathan A, et al (1995) Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet 29:404–30
Verburgh CA, Vermeij CG, et al (1996) Haemolytic uraemic syndrome following bone marrow transplantation. Case report and review of the literature. Nephrol Dial Transplant 11:1332–7
Vincenti F, Laskow DA, et al (1996) One-year follow-up of an open-label trial of FK506 for primary kidney transplantation. A report of the U.S. Multicenter FK506 Kidney Transplant Group. Transplantation 61:1576–81
Walton RC, Nussenblatt RB, et al (1998) Cyclosporine therapy for severe sight-threatening uveitis in children and adolescents. Ophthalmology 105:2028–34
Weise WJ, Possidente CJ (2000) Fatal rhabdomyolysis associated with simvastatin in a renal transplant patient. Am J Med 108:351–2
Wiederrecht G, Brizuela L, et al (1991) FKB1 encodes a nonessential FK 506-binding protein in Saccharomyces cerevisiae and contains regions suggesting homology to the cyclophilins. Proc Natl Acad Sci U S A 88:1029–33
Wiederrecht G, Lam E, et al (1993) The mechanism of action of FK-506 and cyclosporin A. Ann N YAcad Sci 696:9–19
Wilkinson AH, Cohen DJ (1999) Renal failure in the recipients of nonrenal solid organ transplants. J Am Soc Nephrol 10:1136–44
Williams GM, Hume DM, et al (1968) Hyperacute renal-homograft rejection in man. N Engl J Med 279:611–8
Wolter K, Wagner K, et al (1994) Interaction between FK 506 and clarithromycin in a renal transplant patient. Eur J Clin Pharmacol 47:207–8
Woodle ES, Thistlethwaite JR, et al (1996) A multicenter trial of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection. A report of the Tacrolimus Kidney Transplantation Rescue Study Group. Transplantation 62:594–9
Wu A, Buhler LH, et al (2003) ABO-incompatible organ and bone marrow transplantation: current status. Transpl Int 16:291–9
Young BA, Marsh CL, et al (1996) Cyclosporine-associated thrombotic microangiopathy/hemolytic uremic syndrome following kidney and kidney-pancreas transplantation. Am J Kidney Dis 28:561–71
Zaltzman JS, Pei Y, et al (1992) Cyclosporine nephrotoxicity in lung transplant recipients. Transplantation 54:875–8
Zietse R, Balk AH, et al (1994) Time course of the decline in renal function in cyclosporine-treated heart transplant recipients. Am J Nephrol 14:1–5
Zonneveld IM, Rubins A, et al (1998) Topical tacrolimus is not effective in chronic plaque psoriasis. A pilot study. Arch Dermatol 134:1101–2
Zucker K, Rosen A, et al (1997) Augmentation of mycophenolate mofetil pharmacokinetics in renal transplant patients receiving Prograf and CellCept in combination therapy. Transplant Proc 29:334–6
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2005 Springer-Verlag
About this chapter
Cite this chapter
Banner, N.R., Lyster, H., Yacoub, M.H. (2005). Clinical Immunosuppression using the Calcineurin-Inhibitors Ciclosporin and Tacrolimus. In: Pinna, L.A., Cohen, P.T. (eds) Inhibitors of Protein Kinases and Protein Phosphates. Handbook of Experimental Pharmacology, vol 167. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-26670-4_12
Download citation
DOI: https://doi.org/10.1007/3-540-26670-4_12
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-21242-3
Online ISBN: 978-3-540-26670-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)