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the incompatibility of cells and tissues with different antigens and from genetically different individuals.
Owing to the genetic diversity in nature, the cells and tissues of any two individuals differ in many tissue-compatibility antigens (also called histocompatibility antigens, transplant antigens, isoantigens, and alloantigens). During the course of evolution, histoincompatibility, which is based on immunologic reactions, first occurred in lower vertebrates—the lampreys and hagfishes. In its primitive form, the incompatibility of genetically heterogeneous organisms occurs even in unicellular organisms, as a number of biochemical reactions whose function is to maintain homeostasis.
All vertebrate animals have a well-developed system of immunological discrimination and elimination of foreign antigens. When organs or tissues are transplanted, a transplant that has been injured by the lymphocytes and cytotoxic antibodies of the host organism (recipient) is rejected soon after implantation. If the host’s immunologic system has been altered by immunosuppressives, the donor’s lymphocytes present in the graft, for example, in transplanted bone marrow, attack and injure the host’s tissues. Histoincompatibility may be observed experimentally outside an organism. For example, lymphocytes in a mixed culture derived from different individuals activate one another until they become lymphoblasts and undergo cell division.
In man, the fate of a transplant is determined by the differences in the three basic systems of alloantigens: the ABO blood-group antigens, the P-group antigens, and the HL-A leukocyte antigens (human leukocyte antigens). The smaller the antigenic difference between donor and recipient, the easier it is to achieve longer acceptance and immunologic tolerance of the transplant. The greatest difficulties in achieving compatibility of organs and tissues are associated with the HL-A system, which includes at least 60 alloantigens. The HL-A alloantigens are glycoproteins with a molecular weight of over 200,000 that are present in the membranes of all cells and exist in a dissolved state in the blood plasma.
An alloantigen molecule is composed of two polypeptide chains linked by a carbohydrate component; alloantigens differ only in terms of the amino-acid sequence in a long polypeptide chain with a molecular weight of approximately 30,000. A short polypeptide chain that has a molecular weight of approximately 10,000 and is similar in different alloantigens is a β2-microglobulin molecule, which is found in plasma in a free state. The amino-acid sequence in β2-microglobulin is the same as those in the permanent components of light and heavy immunoglobulin chains. The multicomponent aspect of the HL-A system causes even closely related individuals (with the exception of monozygotic twins) to differ according to their sets of alloantigens. More than 9,000 different sets of alloantigens are known.
The biological significance of histocompatibility variations is not yet completely understood. It is assumed that the complex system of cellular surface antigens, together with the highly sensitive reaction of the immune system to foreign alloantigens, serves as a mechanism for rejecting the organism’s own malignant cells that appear owing to mutation. According to the Australian immunologist F. Burnet, cancer would be an infectious disease if it were not for this defense mechanism.
The alloantigenic differences between husband and wife, spermatozoon and ovum, and fetus and maternal organism may be an important factor in natural selection. The fusion of the spermatozoon with the ovum apparently does not occur in a random manner; rather, the ovum selects the most compatible spermatozoon, thus creating favorable conditions for certain HL-A sets. During pregnancy the mother’s immunity system creates antibodies to the alloantigens inherited by the fetus from the father. In the placenta, a reaction similar to that of a transplant to its host takes place, although the reaction is weak and generally does not lead to miscarriage. Diseases with a hereditary factor, such as leukemia, Hodgkin’s disease, lupus erythematosis, psoriasis, and allergic disorders, are more common in individuals with specific sets of HL-A. The formation of HL-A alloantigens is encoded by the alleles of three loci situated in the sixth chromosome.
Laboratory classification of the alloantigens of the HL-A system (tissue identification) is achieved by means of sets of monospecific, purified, alloimmune serums. The serums are prepared from the blood serum of women who have borne many children, from patients who have had frequent blood transfusions or from volunteers who have received skin transplants or injections of donor lymphocytes. The antibodies to HL-A contained in the serums manifest serological reactions to the lymphocytes, making it possible to determine the presence or absence of corresponding alloantigens on the surfaces of the lymphocytes.
Only genetically homogeneous tissues are compatible, such as those of monozygotic twins. In order to achieve tissue compatibility of genetically different individuals, it is necessary to intervene in the manifestation of histocompatible genes, to repress certain genes, and to compensate for the insufficient activity of missing genes, but up to now this has not been achieved.
In interbreeding laboratory animals by crossing brother and sister or offspring and parent, it is relatively easy to produce genetically similar, compatible animals. In transplantation immunology, histoincompatibility is overcome by suppressing the recipient’s immune response and creating an immunologic tolerance. This does not eliminate incompatibility, but it does ensure the coexistence of genetically heterogeneous tissues. It is hoped that immunologic tolerance may be created by injecting the recipient with small amounts of purified histocompatible antigens combined with immunosuppressives. In man and a number of laboratory animals, for example, mice, there is a genetic, structural, and functional interconnection between histoincompatibility and the ability to respond immunologically.
REFERENCESBrondz, B. D. “Immunologicheskoe raspoznavanie i reaktsii kletoch-nogo immuniteta in vitro.” Uspekhi sovremennoi biologii, 1972, vol. 73, no. 1.
Vvedenie v immunogenetiku. Moscow, 1975. (Translated from English.)
Batchelor, J. R., and L. Brent. “Histocompatibility in Transplantation Immunity.” In Immunogenicity. Amsterdam-London, 1972.
Nathanson, S. G. “Histocompatibility Antigens.” In Transplantation. Philadelphia, Pa., 1972.
Immunological Aspects of Transplantation Surgery. New York, 1974.
Immunological Approaches to Fertility Control. [Stockholm] 1974.
A. N. MATS