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Histocompatibility, or tissue compatibility, is the property of having the same, or mostly the same, alleles of a set of genes called human leukocyte antigens (HLA). Each HLA allele represents a distinct immunological tissue type. On a populational level there is a great number of different alleles at each HLA loci on Chromosome 6 at 6p21.3 in humans. However on an individual level a person can only inherit two alleles for each HLA gene locus due to the limits of sexually reproductive meiosis. This creates a situation where a person's spread of HLA alleles (or tissue types) may or may not match another's. Histocompatibility is thus a measure of how similarly two people's HLA alleles or tissue types matches up. The more closely two people's HLA alleles match up, the less one's donor tissue graft will be rejected by the recipient's immune system.

The gene products of HLA code for major histocompatibility complex (MHC) molecules, found in all vertebrates. These genes are expressed on the surface of most tissues as self-antigens, to which the immune system raises antibodies to recognise, but becomes tolerant to. The immune system at first makes antibodies to all sorts of antigens, including those it has never been exposed to, but stops making them to self antigens (MHCs) present on own tissues. When receiving a tissue graft, the recipient's immune system will react to and attack the donor tissue unless it expresses the same set of MHC tissue antigens as the recipient's, for which it has learned not to react against. Which is to say the more similar the spread of HLA alleles are between two people, the more tolerant they would be to each other's tissue or organ MHC antigens. Practically organising transplant operations means seeking out donors with similar tissue types, most often siblings, though due to the number of HLA loci involved it is rare to find a complete tissue type match even between siblings (unless they are identical twins). This is why most transplants will require post-operative immunosuppressant therapy - unless the transplanted tissue enjoys immune privilege, such as with corneal transplants.

A similar system exists in many plants; its purpose is not to reject grafts but to prevent inbreeding. Pollen from a plant sharing a histocompatibility gene with the female either fails to grow or dies soon after germinating.

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