Major Compatibility Complex & Transplantation
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The major histocompatibility complex (MHC) located on chromosome 6 encodes human leukocyte antigen (HLA) proteins that are important for the success of organ transplants. There are two classes of MHC proteins - class I proteins found on all cells and class II proteins found on antigen presenting cells. Compatibility of the HLA proteins between donor and recipient is important to prevent immune rejection, as mismatched HLA proteins will trigger an immune response. Laboratory tests such as HLA typing by DNA sequencing or serology are used to match donors and recipients as closely as possible based on their MHC genes to improve transplant success.
Major Compatibility Complex & Transplantation
- 1. Major Histocompatibility Complex & Transplantation Aman Ullah B.Sc. MLT M. Phil Microbiology Master in Health Research Certificate in Health Professional Education
- 2. Major histocompatibility complex • The success of tissue and organ transplants depends on the donor's and recipient's human leukocyte antigens (HLA) encoded by the HLA genes • These proteins are alloantigens; i.e., they differ among members of the same species • If the HLA proteins on the donor's cells differ from those on the recipient's cells, an immune response occurs in the recipient • The genes for the HLA proteins are clustered in the major histocompatibility complex (MHC), located on the short arm of chromosome 6. • Three of these genes (HLA-A, HLA-B, and HLA-C) code for the class I MHC proteins • Several HLA-D loci determine the class II MHC proteins, i.e., DP, DQ, and DR
- 3. Major histocompatibility complex • Each person has two haplotypes, i.e., two sets of these genes, one on the paternal and the other on the maternal chromosome 6 • These genes are very diverse (polymorphic) (i.e., there are many alleles of the class I and class II genes) • Expression of these genes is codominant; i.e., the proteins encoded by both the paternal and maternal genes are produced
- 4. MHC PROTEINS • Class I MHC Proteins • These are glycoproteins found on the surface of virtually all nucleated cells • The complete class I protein is composed of a 45,000- molecular-weight heavy chain noncovalently bound to a β2-microglobulin • The heavy chain is highly polymorphic and is similar to an • immunoglobulin molecule; it has hypervariable regions in its N-terminal region • The polymorphism of these molecules is important in the recognition of self and nonself • The heavy chain also has a constant region where the CD8 protein of the cytotoxic T cell binds
- 5. MHC PROTEINS • Class II MHC Proteins • These are glycoproteins found on the surface of certain cells, including macrophages, B cells, dendritic cells of the spleen, and Langerhans' cells of the skin • They are highly polymorphic glycoproteins composed of two polypeptides, that are noncovalently bound • Like class I proteins, they have hypervariable regions that provide much of the polymorphism • Unlike class I proteins, which have only one chain encoded by the MHC locus (β2-microglobulin is encoded on chromosome 15), both chains of the class II proteins are encoded by the MHC locus • The two peptides also have a constant region where the CD4 proteins of the helper T cells bind
- 6. BIOLOGIC IMPORTANCE OF MHC • The ability of T cells to recognize antigen is dependent on association of the antigen with either class I or class II proteins • Helper-cell activity depends in general on both the recognition of the antigen on antigen- presenting cells and the presence on these cells of "self" class II MHC proteins • This requirement to recognize antigen in association with a "self" MHC protein is called MHC restriction
- 7. BIOLOGIC IMPORTANCE OF MHC • Many autoimmune diseases occur in people who carry certain MHC genes • Success of organ transplants is, in large part, determined by the compatibility of the MHC genes of the donor and recipient
- 8. TRANSPLANTATION • An autograft (transfer of an individual's own tissue to another site in the body) is always permanently accepted, i.e., it always "takes." • A syngeneic graft is a transfer of tissue between genetically identical individuals, i.e., identical twins, and almost always "takes" permanently • A xenograft, a transfer of tissue between different species, is always rejected by an immunocompetent recipient • An allograft is a graft between genetically different members of the same species, e.g., from one human to another • Allografts are usually rejected unless the recipient is given immunosuppressive drugs • The severity and rapidity of the rejection will vary depending on the degree of the differences between the donor and the recipient at the MHC loci
- 9. Allograft Rejection • Allografts are rejected by a process called the allograft reaction unless immunosuppressive measure are taken • In an acute allograft reaction, vascularization of the graft is normal initially, but in 11–14 days, marked reduction in circulation and mononuclear cell infiltration occurs, with eventual necrosis • This is called a primary (first-set) reaction • A T-cell-mediated reaction is the main cause of rejection of many types of grafts, e.g., skin, but antibodies contribute to the rejection of certain transplants, especially bone marrow
- 10. Allograft Rejection • If a second allograft from the same donor is applied to a sensitized recipient, it is rejected in 5–6 days • This accelerated (second-set) reaction is caused primarily by presensitized cytotoxic T cells • The acceptance or rejection of a transplant is determined, in large part, by the class I and class II MHC proteins on the donor cells, with class II playing the major role • These alloantigens activate T cells, both helper and cytotoxic, which bear T-cell receptors specific for the alloantigens • The activated T cells proliferate and then react against the alloantigens on the donor cells • CD8-positive cytotoxic T cells do most of the killing of the allograft cells
- 11. Allograft Rejection • A graft that survives an acute allograft reaction can nevertheless become nonfunctional as a result of chronic rejection • This can occur months to years after engraftment • The main pathologic finding in grafts undergoing chronic rejection is atherosclerosis of the vascular endothelium • The immunologic cause of chronic rejection is unclear, but incompatibility of minor histocompatibility antigens and side effects of immunosuppressive drugs are likely to play a role
- 12. Allograft Rejection • In addition to acute and chronic rejection, a third type called hyperacute rejection can occur • Hyperacute rejection typically occurs within minutes of engraftment and is due to the reaction of preformed anti- ABO antibodies in the recipient with ABO antigens on the surface of the endothelium of the graft • Hyperacute rejection is often called the "white graft" reaction, because the graft turns white as a result of the loss of blood supply caused by spasm and occlusion of the vessels serving the graft • Inview of this severe rejection reaction, the ABO blood group of donors and recipients must be matched and a crossmatching test must be done
- 13. HLA Typing in the Laboratory • Prior to transplantation surgery, laboratory tests, commonly called HLA- typing or tissue-typing, are performed to determine the closest MHC match between the donor and the recipient • There are two methods commonly used in the laboratory to determine the haplotype (i.e., the class I and class II alleles on both chromosomes) of both the potential donors and the recipient • One method is DNA sequencing using polymerase chain reaction (PCR) amplification and specific probes to detect the different alleles • This method is highly specific and sensitive, and is the method of choice when available • The other method is serologic assays, in which cells from the donor and recipient are reacted with a battery of antibodies, each one of which is specific for a different class I and class II protein • Complement is then added, and any cell bearing an MHC protein homologous to the known antibody will lyse • This method is satisfactory in most instances but has failed to identify certain alleles that have been detected by DNA sequencing
- 14. HLA Typing in the Laboratory • If sufficient data cannot be obtained by DNA sequencing or serologic assays, then additional information regarding the compatibility of the class II MHC proteins can be determined by using the mixed lymphocyte culture (MLC) technique • This test is also known as the mixed lymphocyte reaction (MLR) • In this test, "stimulator“ lymphocytes from a potential donor are first killed by irradiation and then mixed with live "responder" lymphocytes from the recipient; the mixture is incubated in cell culture to permit DNA synthesis, which is measured by incorporation of tritiated thymidine • The greater the amount of DNA synthesis in the responder cells, the more foreign are the class II MHC proteins of the donor cells • A large amount of DNA synthesis indicates an unsatisfactory "match"; i.e., donor and recipient class II (HLAD) MHC proteins are not similar, and the graft is likely to be rejected • The best donor is, therefore, the person whose cells stimulated the incorporation of the least amount of tritiated thymidine in the recipient cells
- 15. HLA Typing in the Laboratory • In addition to the tests used for matching, preformed cytotoxic antibodies in the recipient's serum reactive against the graft are detected by observing the lysis of donor lymphocytes by the recipient's serum plus complement • This is called crossmatching and is done to prevent hyperacute rejections from occurrin • The donor and recipient are also matched for the compatibility of their ABO blood groups