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Successful organ and tissue transplantation depend on matching major histocompatibility antigens and using immunosuppressive agents such as cyclosporin and tacrolimus to minimize the immune response to other antigens of the graft. Rejection of transplants is complex, but type IV cellular immune responses are the major mechanism of rejection for allografts.

■ What are the antigens primarily responsible for allograft rejection?

■ How are allografts rejected?

■ Why is matching of transplant donors and recipients important?

■ What would happen if administration of the antirejection drugs were discontinued?

Chapter 18 Immunologic Disorders

PERSPECTIVE 18.1 The Fetus As an Allograft

Grafts between non-identical members of the same species are allografts, and they are normally rejected by immunological mechanisms.The rejection time for grafts that differ in their major histocompatibility antigens is measured in days, about 10 to 14 days in most instances. The rejection process is complex, but it depends principally on host T-cell destruction of grafted cells. For example, when skin allografts are transplanted, the grafted skin appears normal for about a week. Gradually it begins to look bruised and unhealthy, until 10 days to 2 weeks after transplantation. By that time the grafted skin becomes dried and is sloughed off. Microscopic examination of the graft shows that by the end of the first week T cells invade the tissues and within the next few days the lymphocytes have killed the grafted cells.The same events occur in allografts of kidney or other organs, unless effective immunosuppressive therapy is given.There is one kind of allograft that does not follow this sequence and that is not rejected, however—the human or other mammalian fetus.

The fetus is an allograft, with half of its antigens of paternal origin and likely to differ from the other half contributed by the mother. In spite of these major immunological differences, the fetus lives and thrives in the uterus for 9 months and is not rejected. In fact, over a period of years a mother often has several (or even occasionally as many as 20!) children by the same father without showing any signs of immunological rejection of the fetus.The mechanisms for survival of the fetal allograft have been the subject of research for many years, but they are not yet fully understood.

It cannot be that paternal antigens from the fetus do not reach the mother's immune system to cause a response. Mothers are known to make antibodies to paternal antigens, such as the Rhesus red blood cell antigens. Also, the antibodies used for typing major histocompatibility antigens have long been obtained from women who have borne several children by the same father and have made antibodies to his MHC antigens. Furthermore, various techniques show the presence of small numbers of fetal cells in the maternal circulation during pregnancy. Clearly, paternal antigens can reach the mother's immune system and cause a response.The placenta, however, does prevent most fetal cells from entering the mother and most maternal T cells from reaching the fetus.

The outer layer of the placenta, the trophoblast, forms sort of a buffer zone between the fetus and the mother. The trophoblast does not express MHC class I or II antigens and is not subject to T-cell attack; it also has a mechanism for avoiding destruction by natural killer cells.Thus, the fetus is protected by being in an immunologically privileged site. A few other areas in the body—the brain, the eyes, and the testes—are also immunologically privileged sites. Antigens leaving these sites do not drain through lymphatic vessels and reach lymphoid tissues where antigen-presenting cells are abundant. Also, antigen leaves these privileged sites accompanied by cytokines that are immunosuppressive and direct the immune response toward tolerance, rather than toward active harmful responses. It is well recognized that maternal immune responses are suppressed to some extent during pregnancy, though the reasons for this are not clear.

Thus, one major factor responsible for preventing the rejection of the fetal allograft is the location of the fetus in the pregnant uterus, protected by the placental barrier. A second factor is the ability of the pregnancy to cause an immunosuppressive response in the mother.

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