Most of the different antigens of red blood cells that cause transfusion reactions are also widely present in other cells of the body, and each bodily tissue has its own additional complement of antigens. Consequently, foreign cells transplanted anywhere into the body of a recipient can produce immune reactions. In other words, most recipients are just as able to resist invasion by foreign tissue cells as to resist invasion by foreign bacteria or red cells.
Autografts, Isografts, Allografts, and Xenografts. A transplant of a tissue or whole organ from one part of the same animal to another part is called an autograft; from one identical twin to another, an isograft; from one human being to another or from any animal to another animal of the same species, an allograft; and from a lower animal to a human being or from an animal of one species to one of another species, a xenograft.
Transplantation of Cellular Tissues. In the case of auto-grafts and isografts, cells in the transplant contain virtually the same types of antigens as in the tissues of the recipient and will almost always continue to live normally and indefinitely if an adequate blood supply is provided.
At the other extreme, in the case of xenografts, immune reactions almost always occur, causing death of the cells in the graft within 1 day to 5 weeks after transplantation unless some specific therapy is used to prevent the immune reactions.
Some of the different cellular tissues and organs that have been transplanted as allografts, either experimentally or for therapeutic purposes, from one person to another are skin, kidney, heart, liver, glandular tissue, bone marrow, and lung.With proper "matching" of tissues between persons, many kidney allografts have been successful for at least 5 to 15 years, and allograft liver and heart transplants for 1 to 15 years.
Attempts to Overcome Immune Reactions in Transplanted Tissue
Because of the extreme potential importance of transplanting certain tissues and organs, serious attempts have been made to prevent antigen-antibody reactions associated with transplantation. The following specific procedures have met with some degrees of clinical or experimental success.
Tissue Typing—The HLA Complex of Antigens
The most important antigens for causing graft rejection are a complex called the HLA antigens. Six of these antigens are present on the tissue cell membranes of each person, but there are about 150 different HLA antigens to choose from. Therefore, this represents more than a trillion possible combinations. Consequently, it is virtually impossible for two persons, except in the case of identical twins, to have the same six HLA antigens. Development of significant immunity against any one of these antigens can cause graft rejection.
The HLA antigens occur on the white blood cells as well as on the tissue cells. Therefore, tissue typing for these antigens is done on the membranes of lymphocytes that have been separated from the person's blood. The lymphocytes are mixed with appropriate antisera and complement; after incubation, the cells are tested for membrane damage, usually by testing the rate of trans-membrane uptake by the lymphocytic cells of a special dye.
Some of the HLA antigens are not severely anti-genic, for which reason a precise match of some antigens between donor and recipient is not always essential to allow allograft acceptance. Therefore, by obtaining the best possible match between donor and recipient, the grafting procedure has become far less hazardous. The best success has been with tissue-type matches between siblings and between parent and child. The match in identical twins is exact, so that transplants between identical twins are almost never rejected because of immune reactions.
Prevention of Graft Rejection by Suppressing the Immune System
If the immune system were completely suppressed, graft rejection would not occur. In fact, in an occasional person who has serious depression of the immune system, grafts can be successful without the use of significant therapy to prevent rejection. But in the normal person, even with the best possible tissue typing, allografts seldom resist rejection for more than a few days or weeks without use of specific therapy to suppress the immune system. Furthermore, because the T cells are mainly the portion of the immune system important for killing grafted cells, their suppression is much more important than suppression of plasma antibodies. Some of the therapeutic agents that have been used for this purpose include the following:
1. Glucocorticoid hormones isolated from adrenal cortex glands (or drugs with glucocorticoid-like activity), which suppress the growth of all lymphoid tissue and, therefore, decrease formation of antibodies and T cells.
2. Various drugs that have a toxic effect on the lymphoid system and, therefore, block formation of antibodies and T cells, especially the drug azathioprine.
3. Cyclosporine, which has a specific inhibitory effect on the formation of helper T cells and, therefore, is especially efficacious in blocking the T-cell rejection reaction. This has proved to be one of the most valuable of all the drugs because it does not depress some other portions of the immune system.
Use of these agents often leaves the person unprotected from infectious disease; therefore, sometimes bacterial and viral infections become rampant. In addition, the incidence of cancer is several times as great in an immunosuppressed person, presumably because the immune system is important in destroying many early cancer cells before they can begin to proliferate.
To summarize, transplantation of living tissues in human beings has had very limited but important success. When someone does finally succeed in blocking the immune response of the recipient without at the same time destroying the recipient's specific immunity for disease, the story will change overnight.
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