【正文】 agents such as platelets, neutrophils, plement, and coagulation factors, are difficult to suppress. The suppression of only one or two effectors is ineffective. In the early days of an transplantation, the major problem was suppression of allograft rejection. Even though this can be achieved, its consequences and potential dangers are apparent. Immunosuppressive agents that are in widespread use today act largely in a broad, nonspecific manner to suppress the entire immune response. As a result, there is increased risk of opportunistic infections and 3 malignancy. At present, clinical immunosuppression relies on three general approaches. The first is to simply deplete circulating lymphocytes by destroying them. The second is to use an inhibitor of lymphocyte activation (cyclosporine or tacrolimus) to interrupt the early events of antigeninduced Tlymphocyte activation and cytokine production crucial for the subsequent cascade of immunologic events leading to graft rejection. The third is to use various metabolic inhibitors (., azathioprine, mycophenolate mofetil) to interfere with lymphocyte proliferation essential to amplify the response. These agents are biochemically specific but do not distinguish between dividing lymphocytes and other proliferating cells. Future progress in immunosuppressive therapy concerns the successful implementation of an antigenspecific approach in which the goal is to induce longlasting donorspecific unresponsiveness (immunologic tolerance) in the host while preserving general immunopetence. The full promise of transplantation will not be fulfilled until graft rejection can be specifically and safely prevented while the integrity of the immune system as a whole is maintained. Such tolerance of the recipient to allografted ans without the requirement for nonspecific immunosuppression is the ultimate goal in clinical transplantation. Approaches to achieve this state are discussed later. Finally, because the number of individuals who can benefit from a transplant far exceed the number of donors available, xenotransplantation is considered by some to hold promise for the future. 4 TABLE 161 Summary of Cytokines and Their Associated Functions * Cytokine Cell Source Functions Interleukin1 IL1 Mononuclear phagocytes。 neutrophils。 increases liver protein synthesis. Binds to CD121 Interleukin2 IL2 Activated T cells Tcell growth factor, cytotoxic Tcell generation。 T and mast cells growth factor. Binds to CDw124 Interleukin5 IL5 T cells Eosinophil proliferation/activation. Binds to CD125 Interleukin6 IL6 Mononuclear phagocytes。 increases liver acute phase reactants。 inhibition。 dendritic cells INFγ synthesis。 stimulates IgE and IgG isotype switching Interleukin14 IL14 T cells and some B cell tumors Enhances proliferation of activated B cells。 augments 5 TABLE 161 Summary of Cytokines and Their Associated Functions * Cytokine Cell Source Functions NKcell activity。 NKcell activation. Binds to CD118 Tumor necrosis factoralpha and beta TNFα, β NK and T cells。 neutrophil activator. Binds to CD120 Transforming growth factorbeta TGFβ T cells。 ε is required for both expression and signal transduction CD4 Class II restricted T cells, thymocyte subsets, monocytes, and macrophages Adhesion molecule, binds to class II MHC。 signal transduction, thymocyte development CD28 T cells (most CD4+ , some CD8+ ) Tcell receptor for costimulatory molecules CD80 (B71) and CD86 (B7–2) CD152 Activated T lymphocytes Inhibitory signaling in T cells, binds CD80 (B71) and CD86 (B72) on antigenpresenting cells CD154 Activated CD4+ T cells Activates B cells, macrophages, and endothelial cells。 receptor for CD154 (CD40 ligand)。 phagocytosis of iC3bcoated particles CD11c Granulocytes, monocytes, NK cells, dendritic cells Similar to CD11b。 celltocell adhesion CD55 Broad Regulation of plement activation。 EBV, EpsteinBarr virus。 LFA, leukocyte functionassociated。 TCR, Tcell receptor. THE CELLS INVOLVED IN ALLOREACTIVITY The key ponents of the immune system—T cells, B cells, and APCs—are produced by the hematopoietic stem cell. As the fetus matures, the bone marrow bees the primary site for lymphopoiesis. The pre–T cells migrate to the thymus, which bees the primary lymphoid an wherein CD3+ T lymphocytes mature and bee ―educated‖ to self. The mature T cells are then released to populate the peripheral lymphoid tissues, including lymph nodes, spleen, and gut. Another lymphocyte subpopulation produced by the hematopoietic stem cell is the B cell. B cells derive their name from the primary lymphoid an that produces B cells in 8 birds, the bursa of Fabricius. In the human and other mammals, the bone marrow is the primary site of Bcell development. The T cells, B cells, and APCs have unique roles in orchestrating the immune response. It is a very tightly controlled work, with most munication mediated by cytokines. B cells have the unique capacity to synthesize antibody. A behavioral difference between B and T cells reflects their functional abilities. When an an is transplanted, responsive clones of T cells are activated in the an itself. In addition, donor dendritic cells leave the graft, home to host lymph nodes, and stimulate both host T cells and B cells therein. Activated T cells leave the lymph nodes and can augment the cellular response in the graft. B cells send out antibody molecules that bind to antigens in the graft within a few days, mediating destructive reactions. Considerable progress has been made in dissecting the mechanisms of Tcell maturation in the thymus. Precursor T cells migrate to the thymus where they undergo maturational changes. All T cells express on their surface an antigenspecific TCR, which is the site for antigen binding