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15th lecture لتحميل المحاضرة ادخل الرابط التالي https://app.box.com/folder/19854514021 1 15th lecture Type IV hypersensitivity involves primarily the T-cell branch of the immune system. It has traditionally been known as delayed hypersensitivity because the symptoms arise one to several days following the second contact with an antigen. In general, it result when T cells respond to self tissues or transplanted foreign cells (delayed allergic reactions to infectious agents, contact dermatitis and graft rejection). 2 15th lecture Infectious Allergy A classic example of a delayed-type hypersensitivity is tuberculin reaction is an acute skin inflammation at the injection site appearing within 24 to 48 hours. Other infections that use similar skin testing are leprosy, syphilis, histoplasmosis, toxoplasmosis, and candidiasis. This form of hypersensitivity arises from time-consuming cellular events involving the TD class of cells. After these cells receive processed microbial antigens from macrophages, they release broad-spectrum cytokines that attract inflammatory cells to the site particularly mononuclear cells, fibroblasts, and other lymphocytes. In a chronic infection (tertiary syphilis, for example), extensive damage to organs can occur through granuloma formation. 3 15th lecture Contact dermatitis, is caused by exposure to resins in poison ivy or poison oak, to simple haptens in household and personal articles ( jewelry, cosmetics), and to certain drugs. The allergen first penetrates the outer skin layers, is processed by Langerhans cells (skin macrophages), and is presented to T cells. When subsequent exposures attract lymphocytes and macrophages to this area, these cells give off enzymes and inflammatory cytokines that severely damage the epidermis in the immediate vicinity. This response accounts for the intensely itchy papules and blisters that are the early symptoms. As healing progresses, the epidermis is replaced by a thick, horny layer within week to 10 days. 4 Common delayed-type reactions. (a) Positive tuberculin test. Intradermal injection of tuberculin extract in a person sensitized to tuberculosis yields a slightly raised red bump greater than 10 mm in diameter. b) Contact dermatitis from poison oak, showing various stages of involvement: blisters, scales, and thickened patches. 5 15th lecture Transplantation or grafting of organs and tissues is a common medical procedure. Although it is life-giving, this technique is plagued by the natural tendency of lymphocytes to seek out foreign antigens and mount a campaign to destroy them. The bulk of the damage that occurs in graft rejections can be attributed to expression of cytotoxic T cells and other killer cells. 6 15th lecture In general, the genes and receptors in MHC classes I and II are extremely important in recognizing self and in regulating the immune response. The MHC genes of humans are inherited from among a large pool of genes, so the cells of each person can exhibit variability in the pattern of cell surface molecules. The pattern is identical in different cells of the same person and can be similar in related siblings and parents, but in the more distant relationship, less likely that the MHC genes and receptors will be similar. When donor tissue (a graft) displays surface receptors of a different MHC class, the T cells of the recipient (called the host) will recognize its foreignness and react against it. 7 15th lecture share antigen A identical HLA genes The pattern of inheritance of MHC (HLA) genes. A simplified version of the human leukocyte antigen (HLA) complex in a family. In this example, there are two genes in the complex, and each parent has a different set of genes (A/B and C/D). A child can inherit one of four different combinations. Out of six children, two sets (3 and 5) have identical HLA genes and are good candidates for exchange grafts. Children sharing one gene (for example, 1, 4, and 6 share antigen A) are close matches, but two pairs of children (2 and 4, 3 and 6) do not match at all. 8 15th lecture Host Rejection of Graft When the cytotoxic T cells of a host recognize foreign class I MHC receptors on the surface of grafted cells, they release IL-2. Receipt of this stimulus amplifies helper and cytotoxic T cells specific to the foreign antigens on the donated cells. The cytotoxic cells bind to the grafted tissue and secrete lymphokines that begin the rejection process within 2 weeks of transplantation. Late in this process, antibodies formed against the graft tissue contribute to immune damage. A final blow is the destruction of the vascular supply, promoting death of the grafted tissue. 9 15th lecture In certain severe immunodeficiencies, the host cannot or does not reject a graft. But this failure may not protect the host from serious damage, because graft incompatibility is a two-way phenomenon. Some grafted tissues (especially bone marrow) contain an indigenous population called passenger lymphocytes. This makes it quite possible for the graft to reject the host, causing graft versus host disease (GVHD). Since any host tissue bearing MHC receptors foreign to the graft can be attacked, the effects of GVHD are widely systemic and toxic. A skin rash is the most common symptom. Other organs affected are the liver, intestine, muscles, and mucous membranes. GVHD occurs in approximately 30% of bone marrow transplants within 100 to 300 days of the graft. 10 15th lecture 11 15th lecture Grafts are generally classified according to the genetic relationship between the donor and the recipient Autograft: Is tissue transplanted from one site on an individual’s body to another site on his body (skin replacement in burn repair and the use of a vein to fashion a coronary artery bypass). Isograft: tissue from an identical twin is used. Because isografts do not contain foreign antigens, they are not rejected. Allografts: the most common type of grafts, are exchanges between genetically different individuals belonging to the same species (two humans).. Xenograft is a tissue exchange between individuals of different species (for temporary therapy only). 12 15th lecture Graft rejection can be lessened by directly comparing the tissue of the recipient with that of potential donors. Several tissue matching procedures are used. In the mixed lymphocyte reaction (MLR), lymphocytes of the two individuals are mixed and incubated. If an incompatibility exists, some of the cells will become activated and proliferate. Tissue typing is similar to blood typing, except that specific antisera are used to disclose the HLA antigens on the surface of lymphocytes. In most grafts (one exception is bone marrow transplants), the ABO blood type must also be matched. Although a small amount of incompatibility is tolerable in certain grafts (liver, heart, kidney). 13 15th lecture Some sort of immunosuppressive therapy to overcome rejection is usually required. Rejection can be controlled with agents such as cyclosporin A, methotrexate, prednisone, and a monoclonal antibody OKT3. Except for cyclosporin A, intervention with drugs can be complicated by general suppression of the immune system (especially T cells) and frequent opportunistic infections. Cyclosporin A is a polypeptide isolated from a fungus. It has dramatically improved the survival rate of allograft patients (kidney, heart, liver, and bone marrow) and has reduced the incidence of fatal infections. 14 15th lecture Cyclosporin appears to block the activation of T helper cells and interfere with the release of IL-2. What makes this drug so valuable is that it does not inhibit important lymphoid cells and phagocytes, and the body is better able to ward off infections. Its adverse effects of kidney toxicity and increased blood pressure can be reduced by adjusting the dose and monitoring blood levels of the drug. Because of its ability to inhibit undesirable T-cell activity. Newer drugs aim to block the binding of IL-2 on T cells. 15 15th lecture The most frequent transplant operations involve skin, heart, kidney, coronary artery, cornea, and bone marrow. The sources of organs and tissues are live donors (kidney, skin, bone marrow, liver). cadavers (heart, kidney, cornea) Fetal tissues. we have witnessed some unusual types of grafts: For instance, the fetal pancreas has been implanted as a potential treatment for diabetes, fetal brain tissues for Parkinson disease. Part of a liver has been transplanted from a live parent to a child, parents have donated a lobe from their lungs to help restore function in their children with severe cystic fibrosis. 16 15th lecture 17 15th lecture Bone marrow transplantation is a rapidly growing medical procedure for patients with immune deficiencies, aplastic anemia, leukemia and other cancers, and radiation damage. This procedure is extremely expensive, costing up to $200,000 per patient. Before bone marrow from a closely matched donor can be infused, the patient is pretreated with chemotherapy and whole-body irradiation,(why??) a procedure designed to destroy his own blood stem cells and thus prevent rejection of the new marrow cells. Within 2 weeks to a month after infusion, the grafted cells are established in the host. Because donor lymphoid cells can still cause GVHD, anti-rejection drugs may be necessary. An amazing consequence of bone marrow transplantation is that a recipient’s blood type may change to the blood type of the donor. 18 لتحميل المحاضرة ادخل الرابط التالي https://app.box.com/folder/198545140 21 19