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Major Histocompatibility Complex & transplantation 3rd.pptx

  1. Major Histocompatibility Complex (MHC) Prof. Dr. Ahmed Mohammed Salih Ph.D. (MM), M.Sc. (Immuno.) M.Sc. (MMM)
  2. Major Histocompatibility Complex • Major Histocompatibility Complex : • The MHC is a collection (complex) of genes arrayed within a long continuous stretch of DNA on chromosome 6 in humans MHC Cell nucleus
  3. These genes encode Class I and class II MHC molecules, they are membrane bound glycoproteins that are closely related in structure and function. Cell membrane MHC – I MHC- II
  4. • Since the MHC was first defined in mice by Gorer and Snell in 1937, the World Health Organization (WHO) Nomenclature Committee has named HLA (Human Leukocyte Antigen) to the human MHC
  5. Why the name (Histocompatibility Antigen) ?? • Histocompatibility: (tissue compatibility in transplantation) • Antigens: Proteins on tissues and cells that determine their rejection when grafted between two genetically different individuals that cause a very strong immune response and are most important in rejection
  6. • Expression of MHC antigens on cells: MHC antigens are expressed on the cell surface in a co-dominant manner: products of both parental genes are found on the same cells.
  7. In all nucleated cell: Muscles Epithelial cells Nerve cells Blood cells In Antigen presenting cells (APC) Monocytes, macrophages Dendritic cells, B cells Expression of MHC antigens on cells:
  8. Antigen Processing in MHC I
  9. Antigen Processing in MHC II
  10. There are Three Classes of MHC: • Class I genes • encode glycoproteins expressed on the surface of nearly all nucleated cells, where they present antigens of altered self cells necessary for the activation of Tc cells.
  11. • Class II genes • encode glycoproteins expressed primarily on APCs (dendritic, MO, B cells) where they present processed Ag peptides to Th cells.
  12. • Class III genes • encode somewhat different products, some of which are also associated with the immune process. These include a number of soluble serum proteins such as some of the C' components, TNF, and steroid enzymes.
  13. Major Histocompatibility Complex (MHC) in response to infections • The major histocompatibility complex plays a central role in the development of both: • humoral • and cell mediated immune responses • and are the principal determinants of graft rejection.
  14. Major Histocompatibility Complex (MHC) in response to infections
  15. How can the MHC be involved in Immune response?? • T cells only recognize antigen when it is associated with an MHC molecule thus MHC molecules play a critical role in Ag recognition by T cells.
  16. MHC or HLA in Organ Transplantation • The clinical significance of the MHC is realized in organ transplantation. • Cells and tissues are routinely transplanted as a treatment for a number of diseases.
  17. • The transplant of organs is one of the greatest therapeutic achievements of the twentieth century. In organ transplantation, the adaptive immunity is considered the main response exerted to the transplanted tissue.
  18. In transplantation, the principal target of the immune response in recipient (patient) is the MHC (major histocompatibility complex)or the HLA (Human Leukocyte Antigen) molecules expressed on the surface of donor cells, because they vary between individuals.
  19. Tissue cells MHC or HLA molecules
  20. • Types of grafts • Xenograft Grafts between members of different species (also known as heterologous, xenogeneic or heterografts) • Allograft Grafts between two members of the same species (also known as allogeneic or homograft) • Isograft Grafts between members of the same species with identical genetic makeup (identical twins)
  21. • Because we get different HLA molecules, they are regarded as foreign antigens on the surface of the donor cells • The process by which the immune system recognizes pathogens, tumors, and transplantation antigens involves the same HLA antigen recognition molecules by the immune system of the recipient.
  22. • The rejection response to grafted tissue is caused by cell surface molecules (MHC or HLA) that induce an antigenic stimulus.
  23. Why we Don’t have the same HLA?
  24. Before Starting the Organ Transplantation : • HLA Testing for compatibility • To support the transplant programs, several clinical laboratories perform various HLA tests, including HLA typing of the recipient and the donor, screening of HLA antibodies in the recipient, and detection of antibodies in the recipient that are reactive with lymphocytes of a prospective donor (cross-matching)
  25. • Historically, HLA typing was conducted by serologic testing by using antiserum in complement-dependent cytotoxic assays. • Recently, more precise DNA-based HLA typing methods using molecular techniques, such as sequence-specific oligonucleotide probe hybridization, sequence-specific primer amplification, sequencing-based typing, and reference strand-based conformation analysis, have been developed and are frequently used
  26. Survival rate of grafts • There is a clear relationship between the degree of HLA matching (compatibility) and graft survival in transplants from living-related donors. • Simultaneous analysis of matched living- related allografts HLA allografts showed 10- year projected survival rates
  27. • To avoid hyperacute rejection, it is very important to identify recipient anti-HLA antibodies to antigens expressed on donor with blood cells.
  28. ALLOGRAFT REJECTION • However, reaction of the host immune system against allo-antigens of the graft (HVG) results in its rejection and is the major obstacle in organ transplantation. • The rejection time of a graft may vary with the antigenic nature of the graft and the immune status of the host and is determined by the immune mechanisms involved
  29. Types of Graft Rejection • Hyper - acute rejection: This occurs in instances when the recipient has preformed high titer antibodies. • A graft may show signs of rejection within minutes to hours due to immediate reaction of antibodies and complement system activation that leads to lysis of the grafted cells.
  30. • Accelerated (2nd set; secondary) rejection Transplantation of a second graft, which shares a significant number of antigenic determinants with the first one, results in a rapid (2 - 5 days) rejection. • It is due to presence of T-lymphocytes sensitized during the first graft rejection. • Accelerated rejection is mediated by immediate production of lymphokines, activation of monocytes and macrophages, and induction of cytotoxic lymphocytes.
  31. • Acute (1st set; primary) rejection The normal reaction that follows the first grafting of a foreign transplant takes 1 - 3 weeks. • This is known as acute rejection and is mediated by T lymphocytes sensitized to class I and class II antigens of the allograft, elicitation of lymphokines and activation of monocytes and macrophages.
  32. • Chronic rejection Some grafts may survive for months or even years, but suddenly exhibit symptoms of rejection. • This is referred to as chronic rejection, the mechanism of which is not entirely clear. • The hypotheses are that this may be due to: - infection causes, - loss of tolerance induced by the graft, etc.
  33. Graft Versus Host Disease (Rejection) (GVHD) • Graft versus host disease (GVHD) is an immune-mediated disease resulting from a complex reaction of the donor adaptive immunity against the recipient tissues.
  34. • Most severely occurs with allogeneic hematopoietic-cell transplantation (HCT)(Bone marrow transplant).
  35. • The acute GVHD develops within 100 days of transplantation, describes a distinctive syndrome of: - Dermatitis (Pruritic painful rash (median onset, day 19 post-transplantation; range, 5-47 days) - Hepatitis (liver involvement, anorexia, weight loss, followed rarely by hepatic coma - Enteritis (Diarrhea, intestinal bleeding, cramping abdominal pain)
  36. Dermatitis associated with GVHD
  37. • Chronic GVHD describes a more diverse syndrome developing after day 100. • In addition to allogeneic HCT, procedures associated with high risk of GVHD include transplantation of solid organs rich of lymphoid tissue.
  38. Immunologically privileged sites and tissues • There are certain locations in the body in which allografts are not readily rejected. These include: - the brain, - anterior chamber of the eye, - testis, - renal tubule, - uterus, etc. • This stems from the fact that such sites may lack of good lymphatic drainage.
  39. • Similarly, corneal graft is an excellent example that enjoys the highest success rate of any form of organ transplantation.
  40. PROCEDURES TO ENHANCE GRAFT SURVIVAL • 1- Donor selection Based on extensive experiences with renal transplants, certain guidelines can be followed in donor selection and recipient preparation for most organ transplants. The most important in donor selection is the MHC identity with the recipient; an identical twin is the ideal donor. Grafts from an HLA-matched sibling have 95-100% chance of success.
  41. • 2- Recipient preparation The recipient must be infection-free and must not be hypertensive. One to five transfusions of 100-200 ml whole blood from the donor at 1-2 week intervals improves the graft survival and is practiced when possible.
  42. • 3- Immunosuppression Immunosuppressive therapy is most essential part of allo-transplantation.
  43. • Q- Why the fetus isn't rejected by the maternal immune system during pregnancy?????
  44. • The researchers discovered that embryo implantation sets off a process that ultimately turns off a key pathway required for the immune system to attack foreign bodies. As a result, immune cells are never recruited to the site of implantation and therefore cannot harm the developing fetus.
  45. - The research team has discovered that the onset of pregnancy causes the genes that are responsible for recruiting immune cells to sites of inflammation to be turned off within the decidua. - As a result of these changes, T cells are not able to accumulate inside the decidua and therefore do not attack the fetus and placenta.
  46. Questions ???