Immunosuppression in Liver Transplantation

Mark S. Cattral; Leslie B. Lilly; Gary A. Levy

doi:10.1055/s-2000-13160

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2000; 20(4): 523-532
DOI: 10.1055/s-2000-13160

Immunosuppression in Liver Transplantation

Mark S. Cattral¹ , Leslie B. Lilly² , Gary A. Levy²

¹Department of Surgery and the Multi Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada and
²Department of Medicine, and the Multi Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada

Abstract

ABSTRACT

Prevention of graft rejection while minimizing morbidity remains the single most important objective in liver transplantation. Advances in immunosuppression have provided excellent patient and graft survival with relatively low incidences of acute rejection. However, it is apparent that the toxicity of the present immunosuppressive drugs accounts for much of the morbidity after transplantation. Attention is now being focused on combination drug therapies to reduce morbidity while maintaining the excellent results achieved with present immunosuppressive agents.

KEYWORD

liver transplantation - immunosuppression - rejection

Full Text

References

REFERENCES

1 Dempster W. Kidney homotransplantation. Br J Surg . 1953; 40 447-465
2 Murray J, Merrill J, Harrison H. Prolonged survival of human-kidney homografts by immunosuppressive drug therapy. N Engl J Med . 1963; 268 1315-1323
3 Goodwin W, Kaufmann J, Mims M. Human renal transplantation. I. Clinical experiences with six cases of renal homotransplantation. . 1963; 89 13-24
4 Starzl T, Marchioro T, Waddell W. The reversal of rejection in human renal homografts with subsequent development of homograft tolerance. Surg Gynecol Obstet . 1963; 117 385-395
5 Hume D, Magee J, Kauffman H. Renal transplantation in man with modified recipients. Ann Surg . 1963; 158 608-644
6 Stegall M D, Wachs M E, Everson G. Prednisone withdrawal 14 days after liver transplantation with mycophenolate: a prospective trial of cyclosporine and tacrolimus. Transplantation . 1997; 64 1755-1760
7 Abbasoglu O, Levy M F, Brkic B B. Ten years of liver transplantation: an evolving understanding of late graft loss. Transplantation . 1997; 64 1801-1807
8 Magy N, Cribier B, Schmitt C. Effects of corticosteroids on HCV infection. Int J Immunopharmacol . 1999; 21 253-261
9 Everson G, Trouillot T, Wachs M. Early steroid withdrawal in liver transplantation is safe and beneficial. Liver Transpl Surg . 1999; 5 S48-S57
10 Sollinger H W. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation . 1995; 60 225-232
11 The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation [see comments]. Transplantation . 1996; 61 1029-1037
12 Kobashigawa J, Miller L, Renlund D. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Mycophenolate Mofetil Investigators [see comments]. Transplantation . 1998; 66 507-515
13 Azuma H, Binder J, Heemann U. Effects of RS61443 on functional and morphological changes in chronically rejecting rat kidney allografts. Transplantation . 1995; 59 460-466
14 Schmid C, Heemann U, Azuma H, Tilney N L. Rapamycin inhibits transplant vasculopathy in long-surviving rat heart allografts. Transplantation . 1995; 60 729-733
15 Eckhoff D E, McGuire B M, Frenette L R. Tacrolimus (FK506) and mycophenolate mofetil combination therapy versus tacrolimus in adult liver transplantation. Transplantation . 1998; 65 180-187
16 Fisher R A, Ham J M, Marcos A. A prospective randomized trial of mycophenolate mofetil with neoral or tacrolimus after orthotopic liver transplantation. Transplantation . 1998; 66 1616-1621
17 Mamelok R, Klintmalm G, Langnas A. A randomized, double-blind comparitive study of mycophenolate mofetil (MMF) and azathioprine (AZA), in combination with cyclosporine and cortcosteroids in liver transplant recipients. Hepatology . 1999; 30 222A
18 Hebert M F, Ascher N L, Lake J R. Four-year follow-up of mycophenolate mofetil for graft rescue in liver allograft recipients. Transplantation . 1999; 67 707-712
19 Papatheodoridis G V, O'Beirne J, Mistry P. Mycophenolate mofetil monotherapy in stable liver transplant patients with cyclosporine-induced renal impairment: a preliminary report. Transplantation . 1999; 68 155-157
20 Liu J, Farmer Jr D J, Lane W S. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell . 1991; 66 807-815
21 Borel J F, Feurer C, Gubler H U, Stahelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions . 1976; 6 468-475
22 Borel J F, Kis Z L. The discovery and development of cyclosporine (Sandimmune). Transplant Proc . 1991; 23 1867-1874
23 Calne R Y, Rolles K, White D J. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet . 1979; 2 1033-1036
24 Merion R M, White D J, Thiru S. Cyclosporine: five years' experience in cadaveric renal transplantation. N Engl J Med . 1984; 310 148-154
25 Starzl T E, Klintmalm G B, Porter K A. Liver transplantation with use of cyclosporin A and prednisone. N Engl J Med . 1981; 305 266-269
26 Cantarovich M, Barkun J S, Tchervenkov J I. Comparison of neoral dose monitoring with cyclosporine through levels versus 2-hr postdose levels in stable liver transplant patients. Transplantation . 1998; 66 1621-1627
27 Hemming A W, Greig P D, Cattral M S. A microemulsion of cyclosporine without intravenous cyclosporine in liver transplantation. Transplantation . 1996; 62 1798-1802
28 Pinson C W, Chapman W C, Wright J K. Experience with neoral versus sandimmune in primary liver transplant recipients. Transpl Int . 1998; 11(Suppl 1) 278-283
29 Levy G A, Rasmussen A, Mayer A D. Neoral in de novo liver transplantation: adequate immunosuppression without intravenous cyclosporine. Liver Transpl Surg . 1997; 3 571-577
30 Graziadei I W, Wiesner R H, Marotta P J. Neoral compared to Sandimmune is associated with a decrease in histologic severity of rejection in patients undergoing primary liver transplantation. Transplantation . 1997; 64 726-731
31 Grant D, Kneteman N, Tchervenkov J. Peak cyclosporine levels (Cmax) correlate with freedom from liver graft rejection: results of a prospective, randomized comparison of neoral and sandimmune for liver transplantation (NOF-8). Transplantation . 1999; 67 1133-1137
32 Levy G, Lake J, Beauregard-Zollinger L, Prestele H. Improved clinical outcomes for liver transplant recipients using cyclosporine blood level monitoring based on two-hour post-dose levels. Transplantation (in press). 2000;
33 Kino T, Hatanaka H, Miyata S. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) . 1987; 40 1256-1265
34 Kino T, Hatanaka H, Hashimoto M. FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo) . 1987; 40 1249-1255
35 Starzl T E, Todo S, Fung J. FK 506 for liver, kidney, and pancreas transplantation. Lancet . 1989; 2 1000-1004
36 Todo S, Fung J J, Starzl T E. Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression. Ann Surg. 1994; 220 297-308 308 discussion-309 discussion
37 The U.S. Multicenter FK506 Liver Study Group. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med . 1994; 331 1110-1115
38 European FK506 Multicentre Liver Study Group. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. Lancet . 1994; 344 423-428
39 Rolles K, Davidson B R, Burroughs A K. A pilot study of immunosuppressive monotherapy in liver transplantation: tacrolimus versus microemulsified cyclosporin. Transplantation . 1999; 68 1195-1198
40 Sehgal S N. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem . 1998; 31 335-340
41 Li Y, Li X C, Zheng X X. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nat Med . 1999; 5 1298-1302
42 Wells A D, Li X C, Li Y. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance. Nat Med . 1999; 5 1303-1307
43 Luo H, Chen H, Daloze P. Inhibition of in vitro immunoglobulin production by rapamycin. Transplantation . 1992; 53 1071-1076
44 Poon M, Marx S O, Gallo R. Rapamycin inhibits vascular smooth muscle cell migration. J Clin Invest . 1996; 98 2277-2283
45 Poston R S, Billingham M, Hoyt E G. Rapamycin reverses chronic graft vascular disease in a novel cardiac allograft model. Circulation . 1999; 100 67-74
46 Kimball P M, Kerman R H, Kahan B D. Production of synergistic but nonidentical mechanisms of immunosuppression by rapamycin and cyclosporine. Transplantation . 1991; 51 486-490
47 Groth C G, Backman L, Morales J M. 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 1036-1042
48 Brattstrom C, Wilczek H, Tyden G. Hyperlipidemia in renal transplant recipients treated with sirolimus (rapamycin). Transplantation . 1998; 65 1272-1274
49 Kahan B D, Julian B A, Pescovitz M D. Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group. Transplantation . 1999; 68 1526-1532
50 McAlister V C, Gao Z, Peltekian K. Sirolimus-tacrolimus combination immunosuppression [letter]. Lancet . 2000; 355 376-377
51 Wall W J, Ghent C N, Roy A. Use of OKT3 monoclonal antibody as induction therapy for control of rejection in liver transplantation. Dig Dis Sci . 1995; 40 52-57
52 Fung J, Starzl T. Prophylactic use of OKT3 in liver transplantation. A review. Dig Dis Sci . 1991; 36 1427-1430
53 McDiarmid S V, Busuttil R W, Levy P. The long-term outcome of OKT3 compared with cyclosporine prophylaxis after liver transplantation. Transplantation . 1991; 52 91-97
54 Portela D, Patel R, Larson-Keller J J. OKT3 treatment for allograft rejection is a risk factor for cytomegalovirus disease in liver transplantation. J Infect Dis . 1995; 171 1014-1018
55 Langrehr J M, Glanemann M, Guckelberger O. A randomized, placebo-controlled trial with anti-interleukin-2 receptor antibody for immunosuppressive induction therapy after liver transplantation. Clin Transplant . 1998; 12 303-312
56 Nashan B, Moore R, Amlot P. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group [published erratum appears in Lancet 1997;15:350(9089):1484]. Lancet . 1997; 350 1193-1198
57 Nashan B, Light S, Hardie I R. Reduction of acute renal allograft rejection by daclizumab. Daclizumab Double Therapy Study Group. Transplantation . 1999; 67 110-115
58 Vincenti F, Kirkman R, Light S. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. Daclizumab Triple Therapy Study Group. N Engl J Med . 1998; 338 161-165
59 Kneteman N, Roy A, Neuhaus P. Basiliximab (Simulect) effectively reduces the rate and severity of acute rejection episodes with no increase in side effects in adult liver transplant recipients. Transplantation (in press). 2000;
60 Hirose R, Roberts J P, Quan D. Experience with daclizumab in liver transplantation: renal transplant dosing without calcineurin inhibitors is insufficient to prevent acute rejection in liver transplantation. Transplantation . 2000; 69 307-311
61 Eckhoff D, McGuire B, Sellers M. The safety and efficacy of a two-dose daclizumab (zenapax) induction therapy in liver transplant patients. Transplantation . 1999; 67 S32
62 Emre S, Vanin A, Cervantes E. Use of daclizumab (zenapax) as initial immunosuppression in liver transplant recipients with kidney failure. Transplantation . 1999; 67 S600
63 Feray C, Samuel D, Thiers V. Reinfection of liver graft by hepatitis C virus after liver transplantation. J Clin Invest . 1992; 89 1361-1365
64 Gane E J, Portmann B C, Naoumov N V. Long-term outcome of hepatitis C infection after liver transplantation. N Engl J Med . 1996; 334 815-820
65 Prieto M, Berenguer M, Rayon J M. High incidence of allograft cirrhosis in hepatitis C virus genotype 1b infection following transplantation: relationship with rejection episodes. Hepatology . 1999; 29 250-256
66 Sheiner P A, Schwartz M E, Mor E. Severe or multiple rejection episodes are associated with early recurrence of hepatitis C after orthotopic liver transplantation. Hepatology . 1995; 21 30-34
67 Charlton M, Seaberg E. Impact of immunosuppression and acute rejection on recurrence of hepatitis C: results of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Liver Transpl Surg . 1999; 5(Suppl 1) 107-114
68 Charlton M, Seaberg E, Wiesner R. Predictors of patient and graft survival following liver transplantation for hepatitis C. Hepatology . 1998; 28 823-830
69 Zervos X A, Weppler D, Fragulidis G P. Comparison of tacrolimus with microemulsion cyclosporine as primary immunosuppression in hepatitis C patients after liver transplantation. Transplantation . 1998; 65 1044-1046
70 Trouillot T E, Shrestha R, Kam I. Successful withdrawal of prednisone after adult liver transplantation for autoimmune hepatitis [see comments]. Liver Transpl Surg . 1999; 5 375-380
71 Watson C J, Friend P J, Jamieson N V. Sirolimus: a potent new immunosuppressant for liver transplantation. Transplantation . 1999; 67 505-509
72 Torras J, Figueras J, Lama C. Mycophenolate mofetil overlap in liver transplant recipients with chronic cyclosporine nephrotoxicity. Transplant Proc . 1999; 31 2430
73 Herrero J I, Quiroga J, Sangro B. Conversion of liver transplant recipients on cyclosporine with renal impairment to mycophenolate mofetil. Liver Transpl Surg . 1999; 5 414-420
74 Sher L S, Cosenza C A, Michel J. Efficacy of tacrolimus as rescue therapy for chronic rejection in orthotopic liver transplantation: a report of the U.S. Multicenter Liver Study Group. Transplantation . 1997; 64 258-263
75 McDiarmid S V, Busuttil R W, Ascher N L. FK506 (tacrolimus) compared with cyclosporine for primary immunosuppression after pediatric liver transplantation. Results from the U.S. Multicenter Trial. Transplantation . 1995; 59 530-536
76 Alvarez F, Atkison P R, Grant D R. NOF-11: a one-year pediatric randomized double-blind comparison of neoral versus sandimmune in orthotopic liver transplantation. Transplantation . 2000; 69 87-92
77 Cox K L, Lawrence-Miyasaki L S, Garcia-Kennedy R. An increased incidence of Epstein-Barr virus infection and lymphoproliferative disorder in young children on FK506 after liver transplantation. Transplantation . 1995; 59 524-529
78 Chiba K, Yanagawa Y, Masubuchi Y. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J Immunol . 1998; 160 5037-5044
79 Yanagawa Y, Sugahara K, Kataoka H. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. II. FTY720 prolongs skin allograft survival by decreasing T cell infiltration into grafts but not cytokine production in vivo. J Immunol . 1998; 160 5493-5499
80 Larsen C P, Elwood E T, Alexander D Z. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature . 1996; 381 434-438
81 Kirk A D, Burkly L C, Batty D S. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med . 1999; 5 686-693