Rejection is a primary barrier to the success of solid organ transplantation. There are three types of graft rejection that can occur after solid organ transplantation: antibody-mediated, acute cellular, and chronic rejection. Antibody-mediated rejection (AMR) is mediated by donor-specific antibodies against human leukocyte antigens or other antigens, and typically occurs intraoperatively or within days after receiving an ABO blood type mismatched or positive crossmatch organ transplantation. Strategies used to prevent AMR include avoiding mismatched transplants or desensitizing recipients with known detectable donor-specific antibodies prior to transplantation. These strategies are critical, as treating ANR remains challenging. Acute cellular rejection (ACR) is the most common type of rejection and is generally reversible with appropriate diagnosis and timely treatment. It results from an orchestrated immune response that involves alloantigen presentation by antigen presenting cells that leads to alloreactive T cells. The cytotoxic T cells infiltrate the graft and cause direct tissue damage, whereas the helper T cells produce cytokines to cause subsequent immunological and inflammatory events. Although ACR can occur anytime, the risk is highest in the first several months after transplantation. Prevention and treatment of ACR is of utmost importance, as it is a significant predictor of chronic rejection. The exact etiology of chronic rejection is unknown. It is a slow process of graft fibrosis and arteriopathy, which results in graft dysfunction, usually manifested years after transplantation. While ACR can be treated pharmacologically, the only therapy for chronic rejection is retransplantation.
Signs and symptoms of rejection are nonspecific pain and tenderness over the graft site, fever, and lethargy. The diagnosis of rejection is made based on histologic evidence of tissue injury from a biopsy specimen of the transplanted organ. Presence of circulating donor-specific antibodies is also required in most cases for the diagnosis of AMR. If left untreated, rejection leads to clinically significant organ dysfunction and graft loss.
Over the past 40 years, advances in immunosuppression have contributed to the improvement in patient and graft survival rates following solid organ transplantation largely by preventing ACR. The goal of immunosuppression after solid organ transplantation is to prevent graft rejection and to minimize the undue side effects such as infection, malignancy, and drug toxicity. In order to achieve this goal, a combination of immunosuppressant drugs (Table 17-1) with different mechanisms of action is employed at relatively low doses. The mainstay of current maintenance immunosuppressive regimens (the “triple-drug regimen”) includes a calcineurin inhibitor (tacrolimus or cyclosporine), an antiproliferative agent (mycophenolate or azathioprine), and corticosteroids. The most common initial regimen consists of tacrolimus, mycophenolate mofetil, and prednisone. Typically, these agents are used in high doses in the early weeks post-transplantation, with dosages tapering down as the risk of ACR decreases. In addition to the maintenance immunosuppression, antibody induction (antithymocyte globulins, alemtuzumab, or basiliximab) can be used at the time of transplantation in select ...