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FOUNDATION OVERVIEW

Rejection is a primary barrier to 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 is mediated by donor-specific antibodies against human leukocyte antigens or other antigens and typically occurs intraoperatively or within days after receiving ABO blood type mismatched or positive crossmatch organ transplant. Avoiding mismatched transplant or desensitizing recipients with known detectable donor-specific antibodies may prevent this mode of rejection, but treating antibody-mediated rejection 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 (APCs) 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 following transplant, the risk is highest in the first several months after transplant. 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 graft site, fever, and lethargy. The diagnosis of rejection is made based on histologic evidence of tissue injury from a biopsy specimen of the transplant organ. Presence of circulating donor-specific antibodies is also required for the diagnosis of antibody-mediated rejection. If left untreated, rejection leads to clinically significant organ dysfunction and graft loss.

PREVENTION OF REJECTION

Immunosuppression Regimen

Over the last 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 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 (Table 17-1). 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-transplant, with dosages tapering down as the risk of ACR decreases. In addition to the maintenance immunosuppression, antibody induction (antithymocyte globulins [ATGs], alemtuzumab, or basiliximab) can be used at the time of transplant in select patients. Antibody induction therapy has shown to reduce ACR rates ...

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