ORGAN TRANSPLANTATION

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TRANSPLANTATION IMMUNOLOGY:

TRANSPLANTATION IMMUNOLOGY PRESENTATION BY: NISHIKA BHAN

Transplantation :

Transplantation refers to the act of transferring cells, tissues, or organs from one site to another. Is the process of taking cells, tissues, or organs, called a graft, from one individual and placing them into a different individual.

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Individual who provides the graft DONOR Individual who receives the graft RECIPIENT

Transplantable Organs/Tissues:

Transplantable Organs/Tissues Liver Kidney Pancreas Heart Lung Intestine Face Bone Marrow Cornea

Types of donor:

Types of donor Living : the donor remains alive and donates a renewable tissue, cell, or fluid (e.g. blood, skin), or donates an organ or part of an organ in which the remaining organ can regenerate or take on the workload of the rest of the organ (primarily single kidney donation, partial donation of liver). Deceased (formerly cadaveric) : are donors who have been declared brain-dead and whose organs are kept viable by ventilators or other mechanical mechanisms until they can be excised for transplantation.

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Types of Transplant Autograft is self-tissue transferred from one body site to another in the same individual. Isograft is tissue transferred between genetically identical individuals. Allograft is tissue transferred between genetically different members of the same species. Xenograft is tissue transferred between different species

Pre-Transplantation Evaluation:

Pre-Transplantation Evaluation Blood Type (A, B, AB, and O) Human Leukocyte Antigen (HLA) Tissue Typing Serology; for HIV, CMV, hepatitis Cardiopulmonary, cancer screening

HLA TISSUE TYPING:

HLA TISSUE TYPING Matching of stem cell donor to a recipient is determined by comparing their tissue types An individual's HLA type is present on nearly all tissues in the body. The white cells from a blood sample are a convenient source of "tissue" that the laboratory can use to determine an individual's HLA type.

Why is HLA typing important? :

Why is HLA typing important? because the degree of HLA compatibility between donor and recipient will influence the outcome of the transplant. The function of the immune system is to fight against foreign particles that the body sees as "non-self", such as bacteria and viruses. A stem cell transplant from an HLA mismatched donor can result in the recipient's immune system recognising the transplanted cells as "non-self" and attacking the cells as it would for bacteria or viruses. This can lead to rejection of the transplanted stem cells. Likewise cells from the donor's immune system which are introduced along with the transplanted stem cells ("graft") can also recognise HLA mismatches and attack vital organs of the recipient's body ("host"). This is called graft versus host disease (GvHD). The more compatible the donor-recipient match, the less likely it is that rejection or severe GvHD will occur.

How is HLA typing performed? :

How is HLA typing performed? A 20-30 ml blood sample is required to perform HLA typing. The white cells are isolated from the blood and typing is performed by two different methods: 1. Serological testing : where the white cells are used 2. DNA testing : where DNA extracted from the white cells is used. Preliminary tissue typing takes about 2 weeks. Further high resolution (more detailed) tissue typing performed on the patient and any potentially matched donor samples may take another 2 to 4 weeks.

Searching for a related donor :

Searching for a related donor An HLA type consists of two main groups: Class I antigens (HLA-A, -B, -C) and Class II antigens (HLA-DR, -DQ, -DP). There are six HLA antigens considered most important for determining compatibility: two A antigens, two B antigens, and two DR antigens. We inherit a set (or haplotype ) of HLA-A, B and DR antigens from each parent.

HLA region of Chromosome 6:

HLA region of Chromosome 6

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HLA antigens corresponding to MHC class I ( A , B & C ) present peptides from inside the cell (including viral peptides if present). HLA antigens corresponding to MHC class II ( DP , DQ , & DR ) present antigens from outside of the cell to T-lymphocytes.

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HLA typing of potential donors and a recipient can be accomplished with a microcytotoxicity test. In this test, white blood cells from the donors and recipient are distributed into a series of wells on a microtiter plate, and then specific antibodies are added to different wells. After incubation, complement is added to the wells, and cytotoxicity is assessed by the uptake or exclusion of various dyes (e.g., trypan blue or eosin Y) by the cells. If the white blood cells express the MHC allele for which a particular monoclonal antibody is specific, then the cells will be lysed upon by addition of complement, and these dead cells will take up a dye such as trypan blue. HLA typing based on antibody-mediated microcytotoxicity can thus indicate the presence or absence of various MHC alleles.

Immunology of Transplant Rejection:

Immunology of Transplant Rejection Components of the Immune system involved in graft Rejection : 1 ) Antigen presenting cells – Dendritic cells Macrophages Activated B Cells 2) B cells and antibodies 3) T cells 4) Other cells – Natural killer cells Monocytes

The Immunology of Allogeneic Transplantation:

The Immunology of Allogeneic Transplantation Recognition of transplanted cells that are self or foreign is determined by polymorphic genes (MHC) that are inherited from both parents and are expressed co-dominantly. Alloantigens elicit both cell-mediated and humoral immune responses.

Recognition of Alloantigens:

Recognition of Alloantigens Direct Presentation Recognition of an intact MHC molecule displayed by donor APC in the graft Basically, self MHC molecule recognizes the structure of an intact allogeneic MHC molecule Involves both CD8 + and CD4 + T cells.

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Indirect Presentation Donor MHC is processed and presented by recipient APC Basically, donor MHC molecule is handled like any other foreign antigen Involve only CD4+ T cells. Antigen presentation by class II MHC molecules.

Role of CD4+ and CD8+ T Cells:

Role of CD4 + and CD8 + T Cells CD4 + differentiate into cytokine producing effector cells Damage graft by reactions CD8 + cells activated by direct pathway kill nucleated cells in the graft

Effector Mechanisms of Allograft Rejection :

Effector Mechanisms of Allograft Rejection Hyperacute Rejection Acute Rejection Chronic Rejection

Hyperacute Rejection:

Hyperacute Rejection Characterized by thrombotic occlusion of the graft Begins within minutes or hours after hosts blood vessels are anastamosed to graft vessels Pre-existing antibodies in the host circulation bind to donor endothelial antigens Activates Complement Cascade

Hyperacute Rejection:

Hyperacute Rejection 1. Preformed Ab, 2. complement activation, 3. Endothelial damage, 4. inflammation, 5. Thrombosis

Acute Rejection:

Acute Rejection Vascular and parenchymal injury mediated by T cells and antibodies that usually begin after the first week of transplantation Incidence is high (30%) for the first 90 days

Acute Rejection:

Acute Rejection T-cell, macrophage and Ab mediated, Parenchymal cell damage, Interstitial inflammation (endothelitis)

Chronic Rejection:

Chronic Rejection Occurs in most solid organ transplants Heart Kidney Lung Liver Characterized by fibrosis and vascular abnormalities with loss of graft function over a prolonged period.

Chronic Rejection:

Chronic Rejection Macrophage – T cell mediated Fibrosis Vascular abnormalities

Tissue and Organ Transplantation:

Tissue and Organ Transplantation Today it is possible to transplant many different organs and tissues including. blood transfusion (most common) Bone Marrow Organs : Heart, kidneys, pancreas, lungs, liver and intestines. Tissues include bones, cornea, skin, heart valves, veins, cartilage and other connective tissues.

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Most Common Transplantation -Blood Transfusion- Transfuse Not transfused

Bone Marrow Transplantation:

Bone Marrow Transplantation Used in Leukemia, Anemia and immunodeficiency, especially severe combined immunodeficiency diseases (SCID). About 10 9 cells per kilogram of host body weight, is injected intravenously into the recipients. Recipient of a bone marrow transplant is immunologically suppressed before grafting. Eg . Leukemia patients are often treated with cyclo-phosphamide and total body irradiation to kill all cancerous cells. Because the donor bone marrow contains immunocompetent cells, the graft may reject the host, causing graft versus host disease ( GvHD ).

Graft vs. Host Disease:

Graft vs. Host Disease Caused by the reaction of grafted mature T-cells in the marrow inoculum with alloantigens of the host Acute GVHD Characterized by epithelial cell death in the skin, GI tract, and liver Chronic GVHD Characterized by atrophy and fibrosis of one or more of these same target organs as well as the lungs

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Kidney Transplantation : Diseases like diabetes and various type of nephritis can be alleviated by kidney transplantation. Survival rate after one year transplantation is >90%. Liver transplantation : Used to treat congenital defects and damage from viral (hepatitis) or chemical agents. (Chronic alcoholism). Survival rate after one year exceeds 75% and five years is 70%.

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Pancreas Transplantation : Offers a cure for diabetes mellitus. Graft survival is 72% at one year. Further improved if a kidney is transplanted simultaneously. Overall goal - to prevent the typical diabetic secondary complications. Skin grafting : It is used to treat burn victims. In severe burn, grafts of foreign skin may be used and rejection must be prevented by the use of immunosuppressive therapy.

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Ch. 17 p. 440

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References Kuby Janis, Immunology Abbas Abdul , Cellular and Molecular Immunology Roitt, Immunology Paul William E. , Fundamental Immunology www.organtransplants.org www.transweb.org www.organdonor.web

Thank you :

Thank you