Transplantation genetics and immunology

There are several different types of transplantation. An autograft is a graft from one part of the body to another site on the same individual. An isograft is one between individuals that are genetically alike, as in identical twins. An allograft is a graft between members of the same species but who are not genetically alike. A xenograft is one between members of different species. The allograft we are most familiar with is that of a blood transfusion. Nonetheless, the replacement of diseased organs by transplantation of healthy tissues has frustrated medical science because the immune system of the recipient recognizes that the donor organ is not "self" and rejects the new organ.

The ability to discriminate between self and nonself is vital to the functioning of the immune system so it can protect the body from disease and invading microorganisms . However, the same immune response that serves well against foreign proteins prevents the use of organs needed for life saving operations. Virtually every cell in the body carries distinctive proteins found on the outside of the cell that identify it as self. Central to this ability is a group of genes that are called the (MHC ), or major histocompatibility complex . The genes that code for those proteins in humans are called the HLA or Human Leukocyte Antigen . These are broken down to class I (HLA-A, B, and Cw), class II (HLA-DR, DQ, and DP) and class III (no HLA genes).

The MHC was discovered during tumor transplantation studies in mice by Peter Gorer in 1937 at the Lister Institute, and was so named because "histo" stands for tissue in medical terminology. The genes that compose the MHC are unique in that they rarely undergo recombination and so are inherited as a haplotype, one from each parent. They are also highly polymorphic. This means that the genes and the molecules they code for vary widely in their structure from one individual to another and so transplants are likely to be identified as foreign and rejected by the body. Scientists have also noted that this area of the genome undergoes more mutational events then other regions, which probably accounts for some of its high degree of polymorphism. As previously mentioned, there are several classes of the MHC. The role of the MHC Class I is to make those proteins that identify the cells of the body as "self," and they are found on nearly every cell in the body that has nucleus . Nonself proteins are called antigens and the body first learns to identify self from nonself just before birth, in a selection process that weeds out all the immature T-cells that lack self-tolerance. Normally, this process continues throughout the lifespan of the organism. A breakdown in this process leads to allergies and at the extreme, results in such autoimmune diseases as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. The job of the Class I proteins is to alert killer T cells that certain cells in the body have somehow been transformed, either by a viral infection or cancer, and they need to be eliminated. Killer T-cells will only attack cells that have the same Class I glycoproteins that they carry themselves. The Class II MHC molecules are found on another immunocompetant cell called the B-cells. These cells mature into the cells that make antibodies against foreign proteins. The class II molecules are also found on macrophages and other cells that present foreign antigens to T-helper cells. The Class II antigens combine with the foreign antigen and form a complex with the antibody , which is subsequently recognized and then eliminated by the body.

The ability of killer T-cells to respond only to those transformed cells that carry Class I antigen, and the ability of helper T-cells to respond to foreign antigens that carry Class II antigen, is called MHC restriction. This is what is tested for when tissues are typed for transplantation. Most transplantation occurs with allogeneic organs, which by definition are those that do not share the same MHC locus. The most sensitive type of transplantation with respect to this are those involving the bone marrow (Haematopoietic Stem Cell Transplantation) HLA matching is an absolute requirement so its use is limited to HLA-matched donors, usually a brother or sister. The major complications include graft-versus-host disease (GvHD is an attack of immunocompetant donor cells to immunosuppressed recipient cells) and rejection, which is the reverse of GvHD. The least sensitive are corneal lens transplantation, probably because of lack of vascularisation in the cornea and its relative immunological privilege. Drugs like cyclosporin A have made transplant surgery much easier, although the long term consequences of suppressing immune function are not yet clear. This antirejection drug is widely used in transplant surgery and to prevent and treat rejection and graft-versus-host disease in bone marrow transplant patients by suppressing their normal immune system. Newer strategies, including gene therapy, are being developed to prevent the acute and chronic rejection of transplanted tissues by introducing new genes that are important in preventing rejection. One promising aspect is the delivery of genes that encode foreign donor antigens (alloantigens). This might be an effective means of inducing immunological tolerance in the recipient and eliminate the need for whole-body immunosuppression.

See also Antibody and antigen; Immunogenetics; Immunologic therapies; Immunosuppressant drugs; Major histocompatibility complex (MHC)