Immunosuppression strategies in liver transplantation been classified into relatively distinct periods. These phases are referred to as induction (initial), maintenance, and treatment of acute and chronic rejection. The induction phase refers to events immediately associated with implantation and reperfusion of the allograft. Traditionally, this phase is characterized by a high level of immunosuppression. The goal of this treatment phase is the induction of a state of acute immunologic nonresponsiveness or immunoparalysis that prevents early cell-mediated rejection. Initial immunosuppression therapy based on a combination of high-dose glucocorticoids and calcineurin inhibitors has resulted in protection from acute cellular rejection that is comparable with the protection achieved with induction antilymphocyte based therapy.<sup>8Balan V., Abu-Elmagd K., Demetris A.J. Autoimmune liver diseases: recurrence after liver transplantation Surg Clin North Am 1999 ;  79 : 147 [cross-ref]

Cliquez ici pour aller à la section Références</sup> A nonantibody approach to initial immunosuppression has the benefits of a decrease in opportunistic infections, lower incidence of posttransplant lymphoproliferative disease,<sup>217Woodle E.S., Bruce D.S., Josephson M., et al. FK 506 therapy for refractory renal allograft rejection: lessons from liver transplantation Clin Transplant 1996 ;  10 : 323

Cliquez ici pour aller à la section Références</sup> lower overall cost of therapy, and the reservation of antilymphocyte antibody therapy for steroid-resistant rejection episodes. Transition from induction therapy to maintenance immunosuppression is usually gradual and is begun before hospital discharge.

Calcineurin inhibitors are the basis for the majority of maintenance immunosuppression protocols. The level of maintenance immunosuppression is adjusted according to the rejection history of the patient, underlying liver disease, the immunosuppression cocktail used, and the philosophic bias of the program. In general, patients who experience episode(s) of early or severe acute cellular rejection are maintained on higher levels of immunosuppression for longer periods of time. As patients demonstrate stable graft function without episodes of rejection, most programs make every effort to gradually reduce the level of immunosuppression. By protocol or by experience, the therapeutic goal is maintenance of the patient at the lowest level of immunosuppression necessary to avoid the onset of rejection and minimize the occurrence of immunosuppressant-related side effects. Further modifications are made based on the side effects experienced by the patients being treated, such as calcineurin-associated nephrotoxicity.<sup>159 Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. European FK506 Multicentre Liver Study Group [see comments] Lancet 1994 ;  344 (8920) : 423

Cliquez ici pour aller à la section Références, 193The US Multicenter FK506 Liver Study Group A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression in liver transplantation N Engl J Med 1994 ;  331 : 1110

Cliquez ici pour aller à la section Références</sup> Some patients have benefited from further reduction in calcineurin exposure or from switching to alternative immunosuppression with the newer agents.

There are a few therapeutic options for the treatment of acute cellular rejection in liver transplant patients. The mainstay of therapy is treatment with high-dose glucocorticoids. These agents are dosed as a pulse and taper or pulse without taper. Most episodes of mild-to-moderate rejection respond. Treatment for severe acute cellular rejection or steroid-resistant rejection may require use of antilymphocyte antibody therapy.<sup>179Solomon H., Gonwa T.A., Mor E., et al. OKT3 rescue for steroid-resistant rejection in adult liver transplantation Transplantation 1993 ;  55 : 87

Cliquez ici pour aller à la section Références</sup> Tacrolimus has reportedly been used to reverse mild, moderate, and severe acute cellular rejection,<sup>82Jonas S., Bechstein W.O., Tullius S.G., et al. Indications for tacrolimus anti-rejection therapy in liver allograft recipients Transpl Int 1996 ;  1 (9 Suppl) : S164

Cliquez ici pour aller à la section Références</sup> and steroid-resistant rejections.<sup>118Millis J.M., Bruce D.S., Newell K.A., et al. Treatment of steroid-resistant rejection with tacrolimus prior to OKT3 in liver transplant recipients Transplant Proc 1996 ;  28 : 1014

Cliquez ici pour aller à la section Références, 122Millis J.M., Woodle E.S., Piper J.B., et al. Tacrolimus for primary treatment of steroid-resistant hepatic allograft rejection Transplantation 1996 ;  61 : 1365

Cliquez ici pour aller à la section Références</sup>

Therapeutic options for the treatment of chronic allograft rejection, which is defined as centrolobular dropout, loss of bile ducts, and foam cell arteritis, are much more limited. Agents that have demonstrated some therapeutic benefit are discussed.

Many classifications have been used to group and discuss immunosuppressant agents used in transplantation; the authors group agents based on their mechanism of pharmacologic action. Under this classification both older and newer agents may appear in the same section. The pharmacology, pharmacokinetics, notable side effects, and toxicities of the immunosuppressive agents are described in this article. At the conclusion of each section the authors' current practice with these agents and treatment strategies are described.