Cardiac transplantation and disease
Sirolimus therapy in cardiac transplantation

https://doi.org/10.1016/S0041-1345(03)00229-XGet rights and content

Abstract

Rapamycin powerfully inhibits the progression of antigen-activated T cells through the cell cycle. In animal heart transplantation models, rapamycin therapy has been associated with profound immunosuppressive effects on host humoral and cellular responses. In consequence, further studies have been conducted to evaluate the efficiency of rapamycin in preventing acute heart allograft rejection, treating refractory acute heart allograft rejection, inducing transplantation tolerance, and preventing and treating transplant coronary artery disease. The results of these studies indicated that rapamycin can effectively prevent acute graft rejection and inhibit refractory acute graft rejection in heart transplant recipients by exerting potent immunosuppressive and antiproliferative effects without adversely affecting renal function. This supports the use of rapamycin therapy in heart transplant recipients, especially in those with renal dysfunction, for whom treatment with calcineurin inhibitors is contraindicated. Rapamycin may also halt and even reverse the progression of cardiac allograft vasculopathy, which warrants further clinical trials in humans. Finally, rapamycin may be able to induce transplantation tolerance, thus making it one of the most promising modalities for improving the long-term survival of heart transplant recipients.

Section snippets

Prevention of acute heart allograft rejection

The efficiency of de novo rapamycin therapy in preventing acute allograft rejection in human heart transplant recipients was first tested in a pilot clinical trial in 2001.11 Eleven heart transplant recipients received an initial rapamycin loading dose of 10 to 15 mg followed by a daily dose of 10 mg up to a target plasma level of 10 ng/mL. All patients were treated with a standard prednisone regimen, and eight also received basilixicimab (20 mg) on postoperative days 1 and 4. On average,

Treatment of refractory acute allograft rejection

Rapamycin therapy has been proposed by some as a useful adjunct in the treatment of acute allograft rejection that is not reversible with a standard treatment regimen. The rationale for this is that (a) rapamycin in vitro displays an immunosuppressive potency 10 to 100 times greater than that of calcineurin inhibitors13; (b) rapamycin and calcineurin inhibitors have different sites of action2; and (c) rapamycin appears to be less nephrotoxic than calcineurin inhibitors.11 In animal models,

Induction of transplantation tolerance

Although advances in immunosuppressive therapy have led to improved posttransplantation survival, the central long-term aim of posttransplantation therapy remains transplantation tolerance. The most critical mechanism of transplantation tolerance is depletion of antigen-activated T cells.20 Therefore, drugs that interfere with the death of activated T cells (eg, cyclosporine) can inhibit tolerance, whereas drugs that induce their death can promote it. When not dividing, T cells become

Prevention and treatment of cardiac allograft vasculopathy

Because mTOR is widely distributed among signaling pathways in many tissues, the antiproliferative effects of rapamycin are not limited to lymphoid cells. Blockade of mTOR by rapamycin results in inhibition of cell cycle in several tissue types, including endothelial, fat, myocardial, skeletal muscle, macrophage, fibroblast, pancreatic, hepatic, bone marrow, and kidney cells.24

Because the growth and migration of vascular smooth muscle cells are important for neointimal proliferation after

Conclusions

Rapamycin can effectively prevent acute graft rejection and inhibit refractory acute graft rejection in heart transplant recipients by exerting potent immunosuppressive and antiproliferative effects without adversely affecting renal function. This supports the use of rapamycin therapy in heart transplant recipients. especially in those with renal dysfunction, for whom treatment with calcineurin inhibitors is contraindicated. Rapamycin may also halt and even reverse the progression of cardiac

References (41)

  • B. Radovancevic et al.

    Transplant Proc

    (2001)
  • S.M. Pham et al.

    Transplant Proc

    (2002)
  • A. Jain et al.

    Surg Clin North Am

    (1999)
  • G.I. Snell et al.

    Transplant Proc

    (2001)
  • X. Yu et al.

    Lancet

    (2001)
  • B.D. Kahan

    Transplant Proc

    (2002)
  • M. Poon et al.

    Lancet

    (2002)
  • S.M. Pham et al.

    Transplant Proc

    (1998)
  • P. Ambrosi et al.

    Atherosclerosis

    (1998)
  • B.D. Kahan

    Lancet

    (2000)
  • K.L. Napoli et al.

    Ther Drug Monit

    (2001)
  • B.D. Kahan et al.

    Transplantation

    (2001)
  • B.D. Kahan

    Expert Opin Pharmacother

    (2001)
  • A. MacDonald

    Transplantation

    (2001)
  • M. Ferraresso et al.

    J Immunol

    (1994)
  • G. Schmidbauer et al.

    Transplant Proc

    (1995)
  • S.M. Stepkowski et al.

    Clin Exp Immunol

    (1997)
  • J. Fryer et al.

    Transplantation

    (1993)
  • D.A. Baran et al.

    Curr Opin Cardiol

    (2002)
  • M.D. Vu et al.

    Transplantation

    (1997)
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