T-lymphocyte-antigen interactions in transplant rejection

Article Abstract:

The numerous interactions which result in an immune response are very complex. Not only do these interactions provide the major force for the resolution of viral infections, but they also are primarily responsible for the rejection of organ transplants. Virtually all tissues of the body express some molecules collectively called histocompatibility antigens, though some organs do so in small amounts. These histocompatibility antigens, which serve as the basis for the molecular recognition of differences between individuals, consist primarily of Class I and Class II antigens. The genes for these antigens are referred to as the major histocompatibility complex, or MHC, and the molecules are often called HLA antigens, for human leukocyte antigens. Class I antigens, called HLA-A, B, and C, can be directly recognized as foreign by cytotoxic T lymphocytes, which attach to the antigen and destroy the integrity of the foreign cell's membrane. The hapless antigen or target cell cannot maintain its internal environment, and quickly dies. In the case of Class II antigens, HLA-DP,DQ, and DR, the situation is more complex. These antigens are recognized by helper/inducer T cells which do not kill the foreign renegades directly. They secrete a complex mixture of substances called lymphokines, which stimulate other lymphocytes to take up the fight. B lymphocytes are stimulated to secrete specific antibodies, and other T cells are stimulated to develop effector functions, like cytotoxicity. The recognition of molecules foreign to the body is accomplished by the T cell receptor, which is a molecular complex consisting of several individual parts. Alpha and beta chains make up the part of the molecule specifically charged with the recognition of the foreign antigen, and the structure of these chains is highly analogous to the antibody molecule. The alpha and beta chains exist in a complex with the CD3 polypeptides, which consist of gamma, delta, and epsilon chains. Monoclonal antibodies to CD3 are the primary defense against graft-versus-host disease in bone marrow transplantation; only T cells have these antigens, and they are selectively removed from bone marrow cells before transplantation by antibody treatment. The rejection of transplanted organs by T cells can be suppressed somewhat by glucocorticoids and cyclosporine, both of which inhibit early gene activation in the T cell. As more is learned about the molecular mechanisms underlying the rejection of tissues by T cells, it may be possible to suppress more specifically and more effectively the response which leads to transplant rejection. (Consumer Summary produced by Reliance Medical Information, Inc.)

T cells, Transplantation immunology, Immunological tolerance, Immunologic tolerance

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Immunosuppression in organ transplantation

Article Abstract:

Suppression of the immune system is essential for the success of organ transplants, and two types of immunosuppressant drugs have been developed to this end. One is the group of compounds called mercaptopurine derivatives, the most successful of which is azathioprine, first used in 1962. Almost 20 years later came cyclosporine, leading to an increase of 10 to 15 percent in survival of kidney recipients. Cyclosporine is also effective in reducing rejection after heart and liver transplantation. Both drugs are usually administered with corticosteroids, which act as immunosuppressants and anti-inflammatory agents. A new immunosuppressive drug is FK 506, still under clinical evaluation. Although the structure of this compound is quite different from that of cyclosporine, it exerts similar effects on white blood cells. New drugs are necessary because current treatments cause toxicity to other organs, such as bone marrow (azathioprine) or kidneys (cyclosporine). In addition, even if their side effects could be eliminated, use of the current agents would still necessitate balancing the risks of infection against the risks of too little immunosuppression, since these drugs reduce the functioning of the immune system so thoroughly. Antibodies that attack a patient's lymphoid cells (white blood cells) have been used to prevent graft rejection, but immune globulins, which contain such antibodies, can contain antibodies against other tissues, as well. For this reason, considerable undesired side effects are associated with administering immune globulins. Development of more specific agents would eliminate such problems. Modern methods allow specific molecules to be targeted for destruction by antibodies, such as molecules in the cell membranes of certain immune system components. One such antibody is called OKT3 and is directed against the CD3 molecules on the surfaces of some T cells. Another antibody binds only to T cells that have been recently activated in an immune response (in other words, those that respond to the graft). Two articles in the April 26, 1990, issue of The New England Journal of Medicine discuss promising developments in research on new drugs for use in kidney recipients. A major question in transplantation research is whether true tolerance to the graft can ever be achieved without lifelong immunosuppressant drug therapy. (Consumer Summary produced by Reliance Medical Information, Inc.)

Health aspects, Evaluation, Prevention, Graft rejection, Cyclosporine, Cyclosporins, Immunosuppression, Azathioprine, editorial

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ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia

Article Abstract:

The chronic lymphocytic leukemia (CLL) B cells from 307 patients with CLL for zeta-associated protein (ZAP-70) and mutations in the rearranged immunoglobin heavy-chain variable-region gene (IgV(sub H)) gene are evaluated. Although the presence of an unmutated IgVH gene is strongly associated with the expression of ZAP-70, ZAP-70 is a stronger predictor of the need for treatment in B-cell CLL.

Science & research, Diagnosis, Gene mutations, Gene mutation, Chronic lymphocytic leukemia, Immunoglobulin allotypes

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