Transplantation And Alloimmunity Lecture Notes PDF

[Transplantation and alloimmunity ] One of the significant advances in modern medicine that has greatly extended the lives of many people is organ transplantation. A key problem lies in the fact that transfer of cells/tissue from one individual to another will often result in rejection and/or dest...

[Transplantation and alloimmunity ] One of the significant advances in modern medicine that has greatly extended the lives of many people is organ transplantation. A key problem lies in the fact that transfer of cells/tissue from one individual to another will often result in rejection and/or destruction due to the fact that it is recognized as foreign. This is known as alloreaction against alloantigens WHY does it occur? - highly polymorphic nature of MHC. Another problem is finding tissue to transplant, most of which are derived from recently deceased in auto accidents. **Immune responses against blood group antigens** Blood transfusion is a form of transplantation but not as complex (lack MHC Class I or II). Blood groups = O, A, B, and AB; based on differential glycosylation of proteins and lipids on RBC surface. "Natural" IgM Abs are directed against some of these blood group Ag. **Skin grafts in mice** Tissue transplantation more complex as the difficulty in finding a MHC match is increased. Basic rules are illustrated from skin-graft experiments in mice. These results demonstrate that allorejection is accompanied by the development of memory T cells. Such memory T cells are a major problem in chronic rejection responses. **Allograft rejection types** **Two basic forms of rejection/disease occur:** **1)Transplant rejection** **2)Graft-versus-host reaction (GVHR)** ***[Additonal Key terms to be aware:]*** **Autograft - tissue transplanted from one site of the body to another** **within the same individual** **Syngeneic/isograft - transplant between two people that are genetically** **identical or similar (ex. Twins)** **Allograft/allogeneic transplant - transplant between genetically different** **Individuals** **Mixed lymphocyte reaction (MLR) can be used to detect HLA differences. Peripheral blood mononuclear cells are isolated from 2 individuals to be tested. Cells from the person who serves as the stimulator (yellow) are first irradiated to prevent their proliferation. Then, they are mixed with cells from the other person who serves as the responder (blue) and cultured for 5 days. In the culture, responder cells are stimulated by allogeneic HLA class I and II molecules expressed by stimulators monocytes and DCs. Culture is assessed for T cell proliferation and CTL activity.** **[Hyperacute rejection] - occurs when pre-existing antibodies specific for donor antigens exist. Usually occurs within the context of antibodies to blood group antigens.** **Results in extremely rapid rejection as a result of antibodies binding, fixing C' and tissue destruction.** **[*Acute Rejection*] - more common type of tissue rejection involving T cell responses to HLA antigens. Unlike hyperacute, this takes several days to develop due to the fact that a allogeneic response needs to evolve.** **Prevention - massive doses of immunosuppressive drugs** **[How does acute rejection take place?]** **Donor DCs within graft migrate to secondary lymphoid tissue and activate recipient T cells that bind directly to allongeneic class I or II molecules (contain donor peptides). Effector T cells migrate to grafted organ and attack.** ***[Chronic rejection]* - takes much longer (on the order of years).** **This type of response is characterized by reactions within the vasculature of the graft that ultimately results in thickening and lack of blood supply -\> ischemia** **Antibodies (particularly to Class I antigen) are important in this type of response.** **Damage of tissue vasculature by alloreactive Abs: Anti-HLA class I Ab's bind to target and initiate inflammatory response that results in damage to cell wall of donor tissue and gradual thickening - leading to decrease in blood flow.** **Minor histocompatability antigens: Very rare to have perfect matches -- even when identical at MHC locus because differences at other genetic loci can prove to be difficult.** **Ex. minor histocompatibility Ag i.e. minor H Ag** **Mainly CD8 T cell-mediated -\> minor H Ag=complex peptide + MHC I i.e. mainly derived due to protein polymorphism meaning different peptides will be presented via MHC I -\> recognized as foreign upon transfer into recipient.** **Other example -- male-specific Y chromosome: females to not express and is not tolerized.** **Immune suppression to block allograft rejection** **How is recipient immune system suppressed in order to tolerate donor tissue?** ***Corticosteroids:* Immunosuppresive drugs - corticosteroids very powerful in suppressing immune responses, drawback is the toxic effect to recipient organs/tissues.** **Steroids work by modulating gene expression (e.g. NF-κB targets, by increasing IκB expression).** ***Inhibitors of NFAT transcriptional activity as immunosuppressants*** **NFAT is an important transcription factor activated following calcium mobilization in T cells. Cyclosporin A (CsA) blocks activation of NFAT, thereby inhibiting T cell responses that mediate graft rejection. FK506 is another drug that has similar mode of action.** **Maternal fetal tolerance** **-Fetus expresses father's MHC, but fetus is not recognized as foreign.** **-Placenta is fetal-derived -- helps protect from mother's T cells.** **-Placenta does not express MHC I or II nor is this tissue targeted by NK cells.** **-Possible that expression of suppressive cytokines contributes to non-recognition ex. IL-4, IL-10 are expressed by uterine epithelium which tend to suppress Th1 response** **placenta may starve T cells of nutrients ex. tryptophan which results in reduced responsiveness.** **KEY: fetus is tolerated for two main reasons:** **1) occupies a site protected by nonimmunogenic tissue barrier** **2) promotes local immunosuppresive response** **Treatment of genetic diseases: Transplantation of hematopoietic stem cells is used to correct genetic defects of the immune system.** **-**Patient's diseased hematopoietic system is destroyed by chemotherapy/irradiation. An infusion of bone marrow obtained from healthy HLA-matched donor is given. Over months, the hematopoietic stem cells in the graft reconstitute the patient with a healthy hematopoietic system. \- Donor and recipient must share HLA class I and II for protective T cell response to infection. After bone marrow transplantation, donor-derived thymocytes are positively selected on HLA molecules expressed on recipients thymic epithelium. Top panel: If none of the recipients HLA allotypes (red) are same as donors HLA allotypes (blue), the recipient will not generate a working T cell system & will suffer from severe combined immunodeficiency. Why? T cells won't be able to recognize Ag following infection because APCs will present through donor HLAs expressed on APCs derived from bone marrow transplant. Lower panel: If recipient and donor share HLA allotypes (indicated in blue), T cells will be able to respond following infection as they will recognize Ag presented by HLA's on APCs. (See Fig. 15.32).