Download PDF
Semin Liver Dis 2006; 26(3): 201-210
DOI: 10.1055/s-2006-947290
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Immunosuppression: Today, Tomorrow, and Withdrawal

Ryutaro Hirose1 , Flavio Vincenti1 , 2
  • 1Department of Surgery, University of California, San Francisco
  • 2Department of Medicine, University of California, San Francisco
Further Information

Publication History

Publication Date:
19 July 2006 (online)

    Permissions and Reprints

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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 13 Vincenti F, Ramos E, Brattstrom C et al.. Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation.  Transplantation. 2001;  71 1282-1287
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 15 Halloran P F. Immunosuppressive drugs for kidney transplantation.  N Engl J Med. 2004;  351 2715-2729
    CrossrefPubMedGoogle Scholar
  • 16 Vincenti F. What's in the pipeline? New immunosuppressive drugs in transplantation.  Am J Transplant. 2002;  2 898-903
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 18 Podder H, Kahan B D. Janus kinase 3: a novel target for selective transplant immunosuppression.  Expert Opin Ther Targets. 2004;  8 613-629
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 25 Nicolls M R, Gill R G. LFA-1 (CD11a) as a therapeutic target.  Am J Transplant. 2006;  6 27-36
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 30 Pescovitz M D. The use of rituximab, anti-CD20 monoclonal antibody, in pediatric transplantation.  Pediatr Transplant. 2004;  8 9-21
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 32 Bretscher P, Cohn M. A theory of self-nonself discrimination.  Science. 1970;  169 1042-1049
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 38 Vincenti F, Larsen C, Durrbach A et al.. Costimulation blockade with belatacept in renal transplantation.  N Engl J Med. 2005;  353 770-781
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar

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

      >