FORUM EKSPERTÓW
Immunomodulation of cardiac allograft vasculopathy: beyond immunosuppression

Introduction
Following heart transplantation a rapid form of atherosclerosis develops known as cardiac allograft vasculopathy (CAV). As a leading cause of graft failure, CAV remains the dominant limiting factor for the long-term survival of human heart transplant recipients [1, 2]. The angiographically determined incidence of CAV is around 30% at 3 years post-transplantation [3] and by 10 years more than half of all surviving recipients have angiographic CAV [4].
Even though CAV appears to be related to the native form of atherosclerosis found in coronary artery disease (CAD), no direct association has been found between standard risk factors for CAD in the general population and the development of CAV in transplanted hearts [1, 5] and its etiology remains unknown. However, several immunological and nonimmunological mechanisms have been proposed, including mechanisms that result in the establishment of a prothrombotic microvasculature within the allografts.

Immunosuppression and CAV
The introduction of effective immunosuppressive regimens, along with a variety of therapies designed to target the immune response, have improved heart transplant outcome. Examples include the use of calcineurin inhibitors, which has been pivotal in reducing the frequency of acute rejection and improving early survival. The use of steroids, cyclosporine, tacrolimus and MMF has also had a significant beneficial impact, although these drugs have strong adverse side effects. Antiproliferative immunosuppressants have been used to inhibit T-cell and B-cell proliferation and proliferation-signal inhibitors have been used to block activation of T cells after autocrine stimulation by IL-2. The best results have been achieved with combined immunotherapy and, of the current commonly used immunosuppressive regimens, tacrolimus in combination with MMF appears to produce the greatest benefit [6].
Although the introduction of new immunosuppressive agents has shown beneficial effects on graft rejection and early survival, the development of CAV continues to be the principal limiting factor for long-term survival of heart transplant recipients, and the incidence of angiographically detected CAV has not changed appreciably over the past two decades [7]. Thus, current research is focused on identifying factors that stimulate or limit CAV in an effort to better understand the mechanisms of this disease and to develop new therapeutic...


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