The mainstay of preventing and treating the rejection of organ transplants is immunosuppression, using drugs that deplete T cells or inhibit T cell activation and effector functions (Fig. 1). The development of immunosuppressive drugs launched the modern era of organ transplantation because these drugs made it feasible to transplant organs from donors that were not HLA-matched with recipients, especially in situations when such matching was impractical, such as transplantation of heart, lung, and liver.

Fig1. Treatments for graft rejection. Agents used to treat rejection of organ grafts and their mechanisms of action. Like cyclosporine, tacrolimus (FK506) is a calcineurin inhibitor. CTLA4-Ig, Cytotoxic T lymphocyte–associated protein 4–immunoglobulin (fusion protein), not widely used; IL, interleukin; mTOR, mammalian target of rapamycin; NFAT, nuclear factor of activated T cells.

All of these immunosuppressive drugs carry the problem of nonspecific immunosuppression (i.e., the drugs inhibit responses to more than the graft). Therefore, patients receiving these drugs as part of their post-trans plantation treatment regimen become susceptible to infections, particularly by intracellular microbes, and the patients have an increased risk of developing cancers, especially skin cancers and others caused by oncogenic viruses.

The matching of donor and recipient HLA alleles by tissue typing had an important role in minimizing graft rejection before cyclosporine became available for clinical use. Although MHC matching is critical for the success of transplantation of some types of tissues (e.g., hematopoietic stem cell transplants) and improves survival of other types of organ grafts (e.g., renal allografts), modern immunosuppression is so effective that HLA matching is not considered necessary for many types of organ trans plants (e.g., heart and liver), mainly because the number of donors is limited and the recipients often are too sick to wait for well-matched organs to become available.

T he long-term goal of transplant immunologists is to induce immunological tolerance specifically for the graft alloantigens. If this is achieved, it will allow graft acceptance without shutting off other immune responses in the host. However, many years of experimental and clinical attempts to induce graft-specific tolerance have not yet resulted in clinically practical methods.

A major problem in transplantation is the shortage of suitable donor organs. Xenotransplantation has been considered a possible solution for this problem. Experimental studies show that hyperacute rejection is a frequent cause of xenotransplant loss. The reasons for the high incidence of hyperacute rejection of xenografts are that individuals often contain antibodies that cross-react with cells from other species and the xenograft cells lack regulatory proteins that can inhibit human complement activation. These antibodies, similar to anti bodies against blood group antigens, are called natural antibodies because their production does not require prior exposure to the xenoantigens. It is thought that these antibodies are produced against bacteria that normally inhabit the gut and that the antibodies cross-react with cells of other species. Xenografts also are subject to acute rejection, much like allografts but often even more severe than rejection of allografts. Because of the problem of rejection, and difficulty in procuring organs from animals that are evolutionarily close to humans, clinical xenotransplantation remains a distant goal. 

مواضيع ذات صلة

Hypersensitivity Disorders Caused by Immune Responses : Clinical Syndromes and Therapy

Activation of Mast Cells and Secretion of Mediators

Activation of Th2 Cells and Production of IgE Antibody

Transplantation of Blood Cells and Hematopoietic Stem Cells

Monocytes–Macrophages: Host Defense Functions: Phagocytosis

Mononuclear Phagocyte System

Immune Mechanisms of Graft Rejection

Induction of Immune Responses Against Transplants

Transplantation Antigens

Glycans and Immunity

Immune Responses Against Transplants

Cancer Immunotherapy : Stimulation of Host Antitumor Immune Responses by Vaccination With Tumor Antigens