ABSTRACT
The advent of modern immunosuppressive agents is arguably the single most important
factor that has allowed liver transplantation to advance in the past several decades
from a dubious and dangerous venture to the treatment of choice for end-stage liver
disease. During the past two decades, a large array of immunosuppressants have greatly
expanded the armamentarium used by transplant physicians and surgeons to prevent and
treat liver allograft rejection. The availability of these drugs has resulted in the
excellent short-term and long-term outcomes achieved in liver transplantation. However,
these drugs continue to lack specificity and are associated with acute and chronic
toxicities. Although the liver is considered a relatively tolerogenic organ, we have
yet to attain the “Holy Grail” of transplantation, that is, transplantation tolerance,
in a consistent manner. Thus, the liver transplant recipient is still being sentenced
to a lifelong course of chronic immunosuppression. Small molecules, biologic agents
such as antibodies and fusion proteins, and corticosteroids continue to play a central
role in immunosuppressive regimens used in liver transplantation. In addition several
novel immunosuppressive agents have been used in preclinical and clinical trials that
show promise for use in the near future. We review current immunosuppressive medications
and describe the new developments that are on the horizon.
KEYWORDS
Immunosuppression - liver transplant
REFERENCES
- 1
Wiesner R H, Demetris A J, Belle S H et al..
Acute hepatic allograft rejection: incidence, risk factors, and impact on outcome.
Hepatology.
1998;
28
638-645
- 2
Ojo A O, Held P J, Port F K et al..
Chronic renal failure after transplantation of a nonrenal organ.
N Engl J Med.
2003;
349
931-940
- 3
Vezina C, Kudelski A, Sehgal S N.
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
721-726
- 4
Murgia M G, Jordan S, Kahan B D.
The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated
renal transplant patients.
Kidney Int.
1996;
49
209-216
- 5
Trotter J F, Wachs M E, Trouillot T E et al..
Dyslipidemia during sirolimus therapy in liver transplant recipients occurs with concomitant
cyclosporine but not tacrolimus.
Liver Transpl.
2001;
7
401-408
- 6
Legendre C, Campistol J M, Squifflet J P et al..
Cardiovascular risk factors of sirolimus compared with cyclosporine: early experience
from two randomized trials in renal transplantation.
Transplant Proc.
2003;
35
151S-153S
- 7
Chueh S C, Kahan B D.
Dyslipidemia in renal transplant recipients treated with a sirolimus and cyclosporine-based
immunosuppressive regimen: incidence, risk factors, progression, and prognosis.
Transplantation.
2003;
76
375-382
- 8
Eason J D, Blazek J, Mason A et al..
Steroid-free immunosuppression through thymoglobulin induction in liver transplantation.
Transplant Proc.
2001;
33
1470-1471
- 9
Eason J D, Nair S, Cohen A J et al..
Steroid-free liver transplantation using rabbit antithymocyte globulin and early tacrolimus
monotherapy.
Transplantation.
2003;
75
1396-1399
- 10
Calmus Y, Scheele J R, Gonzalez-Pinto I et al..
Immunoprophylaxis with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal
antibody, in combination with azathioprine-containing triple therapy in liver transplant
recipients.
Liver Transpl.
2002;
8
123-131
- 11
Neuhaus P, Clavien P A, Kittur D et al..
Improved treatment response with basiliximab immunoprophylaxis after liver transplantation:
results from a double-blind randomized placebo-controlled trial.
Liver Transpl.
2002;
8
132-142
- 12
Emre S, Gondolesi G, Polat K et al..
Use of daclizumab as initial immunosuppression in liver transplant recipients with
impaired renal function.
Liver Transpl.
2001;
7
220-225
- 13
Vincenti F, Ramos E, Brattstrom C et al..
Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation.
Transplantation.
2001;
71
1282-1287
- 14
Hirose R, Roberts J P, Quan D et al..
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
- 15
Halloran P F.
Immunosuppressive drugs for kidney transplantation.
N Engl J Med.
2004;
351
2715-2729
- 16
Vincenti F.
What's in the pipeline? New immunosuppressive drugs in transplantation.
Am J Transplant.
2002;
2
898-903
- 17
Brinkmann V, Cyster J G, Hla T.
FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and
endothelial barrier function.
Am J Transplant.
2004;
4
1019-1025
- 18
Podder H, Kahan B D.
Janus kinase 3: a novel target for selective transplant immunosuppression.
Expert Opin Ther Targets.
2004;
8
613-629
- 19
Changelian P S, Flanagan M E, Ball D J et al..
Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor.
Science.
2003;
302
875-878
- 20
Borie D C, Changelian P S, Larson M J et al..
Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly
prolongs kidney allograft survival in nonhuman primates.
Transplantation.
2005;
79
791-801
- 21
Birsan T, Dambrin C, Klupp J et al..
Effects of the malononitrilamide FK778 on immune functions in vitro in whole blood
from non-human primates and healthy human volunteers.
Transpl Immunol.
2003;
11
163-167
- 22
Bilolo K K, Ouyang J, Wang X et al..
Synergistic effects of malononitrilamides (FK778, FK779) with tacrolimus (FK506) in
prevention of acute heart and kidney allograft rejection and reversal of ongoing heart
allograft rejection in the rat.
Transplantation.
2003;
75
1881-1887
- 23
Yamamoto S, Okuda T, Yamasaki K et al..
FK778 controls acute rejection after rat liver allotransplantation showing positive
interaction with FK506.
Transplant Proc.
2005;
37
126-129
- 24
Joshi A, Bauer R, Kuebler P et al..
An overview of the pharmacokinetics and pharmacodynamics of efalizumab: a monoclonal
antibody approved for use in psoriasis.
J Clin Pharmacol.
2006;
46
10-20
- 25
Nicolls M R, Gill R G.
LFA-1 (CD11a) as a therapeutic target.
Am J Transplant.
2006;
6
27-36
- 26
Corbascio M, Ekstrand H, Osterholm C et al..
CTLA4Ig combined with anti-LFA-1 prolongs cardiac allograft survival indefinitely.
Transpl Immunol.
2002;
10
55-61
- 27
Zheng X X, Sanchez-Fueyo A, Sho M et al..
Favorably tipping the balance between cytopathic and regulatory T cells to create
transplantation tolerance.
Immunity.
2003;
19
503-514
- 28
Knechtle S J, Pirsch J D, Fechner J J et al..
Campath-1H induction plus rapamycin monotherapy for renal transplantation: results
of a pilot study.
Am J Transplant.
2003;
3
722-730
- 29
Kirk A D, Hale D A, Mannon R B et al..
Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific
monoclonal antibody alemtuzumab (CAMPATH-1H).
Transplantation.
2003;
76
120-129
- 30
Pescovitz M D.
The use of rituximab, anti-CD20 monoclonal antibody, in pediatric transplantation.
Pediatr Transplant.
2004;
8
9-21
- 31
Larsen C P, Pearson T C, Adams A B et al..
Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with
potent immunosuppressive properties.
Am J Transplant.
2005;
5
443-453
- 32
Bretscher P, Cohn M.
A theory of self-nonself discrimination.
Science.
1970;
169
1042-1049
- 33
Linsley P S, Ledbetter J A.
The role of the CD28 receptor during T cell responses to antigen.
Annu Rev Immunol.
1993;
11
191-212
- 34
Sayegh M H, Turka L A.
The role of T-cell costimulatory activation pathways in transplant rejection.
N Engl J Med.
1998;
338
1813-1821
- 35
Turka L A, Linsley P S, Lin H et al..
T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection
in vivo.
Proc Natl Acad Sci USA.
1992;
89
11102-11105
- 36
Larsen C P, Elwood E T, Alexander D Z et al..
Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways.
Nature.
1996;
381
434-438
- 37
Kirk A D, Harlan D M, Armstrong N N et al..
CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates.
Proc Natl Acad Sci USA.
1997;
94
8789-8794
- 38
Vincenti F, Larsen C, Durrbach A et al..
Costimulation blockade with belatacept in renal transplantation.
N Engl J Med.
2005;
353
770-781
- 39
Adams A B, Shirasugi N, Jones T R et al..
Development of a chimeric anti-CD40 monoclonal antibody that synergizes with LEA29Y
to prolong islet allograft survival.
J Immunol.
2005;
174
542-550
Ryutaro HiroseM.D.
Department of Surgery, Division of Transplantation, University of California, San
Francisco
505 Parnassus Avenue, Box 0780, Room M-884, San Francisco, CA 94143-0780