Left‑hand panel: chronic rejection is initiated by the interaction of anti‑HLA class I alloantibodies with blood vessels of the transplanted organ. Antibodies bound to endothelial cells recruit Fc receptor‑bearing monocytes and neutrophils. Right‑hand panel: accumulating damage leads to thickening of the internal elastic lamina and to infiltration of the underlying intima with smooth muscle cells, macrophages, granulocytes, alloreactive T cells, and antibodies. The net effect is to narrow the lumen of the blood vessel and create a chronic inflammation that intensifies tissue remodeling. Eventually the vessel becomes obstructed, ischemic, and fibrotic.
Rabbit anti‑thymoglobulin and anti‑CD52 monoclonal antibody (alemtuzumab) are used to deplete T cells and other leukocytes before transplantation. Anti‑CD3 monoclonal antibody prevents the generation of signaling by the T‑cell receptor complex, whereas cyclosporin and tacrolimus interfere with the translocation of nuclear factor of activated T cells (NFAT) to the nucleus by inhibiting calcineurin. The CTLA‑4–Fc fusion protein belatacept binds B7 and prevents the generation of co‑stimulation via CD28. Basiliximab, an anti‑CD25 antibody, binds to the high‑affinity IL‑2 receptor on partially activated T cells and prevents IL‑2 signaling. Sirolimus interferes with activation of the mTOR cascade, which is required for differentiation of effector T cells. Azathioprine and mycophenolate inhibit the replication and proliferation of activated T cells.
that inhibit T-cell activation, thereby limiting the development of anti-allograft effector T cells and antibodies, has markedly increased graft survival rates (Fig. 15.52). The different organs or tissues that are frequently transplanted and allograft survival rates are listed in Fig. 15.53. The most frequently transplanted solid organ is the kidney, the organ first successfully transplanted between identical twins in the 1950s. Transplantation of the cornea is even more frequent; this tissue is a special case because it is not vascularized, and corneal grafts between unrelated people are usually successful without immunosuppression.
Many problems other than graft rejection are associated with organ transplantation. First, donor organs are difficult to obtain. Second, the disease that destroyed the transplant recipient’s organ might also destroy the graft, as in the destruction of pancreatic β cells in autoimmune diabetes. Third, the immunosuppression required to prevent graft rejection increases the risk of cancer and infection. The problems most amenable to scientific solution are the development of more effective means of immunosuppression that prevent rejection with minimal impairment of more generalized immunity, the induction of graft-specific tolerance, and the development of xenografts as a practical solution to organ availability.