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Transplantation, Rejection and Immunity to Cancer (2/5) 3/16/2015 C.K.Shieh § By investigating the barrier of tissue transplantation between different individuals, we came to get hold of a plethora of information that is not only important for the clinical practice of organ transplantation but also critical for other immune responses. From this lecture, we will understand the molecular basis of histocompatibility (feasibility of tissue transplantation) and the cells that are involved in this immune-mediated barrier. Transplantation Immunology • Study of tissue transplantation lead to the discovery of MHC molecules and the subsequent discovery of T cell receptor. • Organ transplantation is now an important clinical practice. Saintly Transplantation by Sts. Cosmas and Damian the 3rd Century Immune barrier between individuals with different inheritance is the main limiting factor of clinical transplantation Humoral immune barriers: e.g. ABO incompatibility H-2 (MHC) MHC class I molecules are expressed on most cells in the body, while MHC class II are usually expressed only on antigen presenting cells. Tolerance Induction in Transplantation • Thymic negative selection mediated by dendritic cells Host vs. graft reaction First and Second-set Rejection Previous sensitization by alloantigens leads to rapid (secondary) rejection. rejection can be transferred with lymphocytes from sensitized animals. This The genetics of allo-recognition The gene determining allo-rejection (H2 or major histocompability gene (MJC)) is very polymorphic and codominantly expressed. The recognition of allo-MHC by TCR is responsible for almost all strong rejection reactions. There are evidences from human transplantation showing that indirect antigen presentation may contribute to late rejection of allografts. Types of Rejection Hyperacute Rejection Acute Rejection Chronic Rejection Accelerated rejection Prevention of Rejection • Tissue matching • Immunosuppression with immunomodulators and anti-mitotic drugs Glucocorticosteroids, cyclosporine, tacrolimus (FK506), azathioprine and others Cyclosporine and tacrolimus are the so called “T cell-specific” immunosuppressants. The binds to their respective receptors and inhibits the enzymatic activity of the calcinurin ( a protein phosphatase) and lead to suppression of IL-2 dependent cell growth. • Specific immunosuppression (enhancement) Blood transfusion for kidney transplant patients Tissue Typing (I): Serotyping Tissue Typing (II): MLR Graft vs. Host Reaction Bone marrow transplantation and graft versus host disease (GVHD) Immunological Enhancement: Peripheral Tolerization and regulatory T cells Figure: Direct and indirect recognition for rejection Tumor Immunology 2016 C.K.Shieh § In this lecture, we will discuss about how immune cells recognize cancer cells and keep our body tumor-free. Both innate immunity and acquired immunity participate in this process which has been extensively investigated for potential approaches to manipulate. Tumor Immunology -Outlines • Tumor surveillance: the same machinery against virally infected cells is used • Tumor antigen: defined by antibody and cellular immunity • Evasions of tumor from immune attacks • How to revive the ineffective immunity against tumors Specific Immune Responses Are Present in Chemical-induced Tumors Tumor-specific immune responses can be transferred by T cells (adopted immunity). This fact was proved only after syngeneic animals became available and valid controls were possible. Tumor antigens Several approaches have been used to search for tumor antigens in human cancer patients • T cell tumor antigens: Specific antigen peptides were purified based on their activity to stimulate tumor specific T cell clones (derived from cancer patients). • Tumor inducing mutations as tumor antigens: Mutations that lead to cancer formation are distinctions that immune cells can use to recognize tumor cells. Many of these mutations have been proved to be tumor antigens. • B cell tumor antigens: Serum from cancer patients were used to clone tumor antigens from cDNA library prepared from tumor cells (SEREX). Many of these antigens identified from different approaches proved to be on the same tumor molecules. Viral antigens as tumor antigens Viruses and Cancer Formation Some persistent viruses (e.g. EBV) are known to induce human cancers. immunity is apparent in these cancers and other virus induced-cancers. Immunodeficiency predisposes patients to these tumors. Anti-tumor A peculiar bacterium, H. pylori was associated with the occurrence of human stomach cancer. As this bacterium does not transform human epithelial cells, the mechanism for cancer induction appears more complex than carcinogenic viruses. How Tumors Escape Immune Destruction Lack of MHC class I in a prostate carcinoma MHC class I loss in tumor cells makes them less susceptible to CTL but more vulnerable to NK killing. Immunosuppressive signal: suppressive cytokines, e.g. TGF- Lack of costimulation (e.g.B7): inducing antigen specific anergy Expression of suppressive signal: e.g. FasL, PD-L1inducing leukocyte cell death and immunosuppression, stimulation of CTLA-4 on CTL also inactivate the anti-tumor activity. How to Revive the Immune Responses: Breaking the Immunological Silence: Providing the Costimulation •B7 transfected tumor cells as cancer vaccine Adjuvants •Since 1920’s, certain substances were added to immunogens to increase desirable immune responses. •The biological effects are to be a depot for immunogen or induce cytokines. •A lot of interest and experiments are going on to use cytokines to increase responses to vaccines in the future. Cancer Vaccines •Coley used bacterial filtrate to stimulate immune system in order to reject tumors one century ago. •The idea of non-specific immune stimulation has attracted enormous amount of imagination and efforts from both the scientific community and general public. Little success was documented. •New strategies based on insights in immune response to tumors will be used to design approaches for “therapeutic vaccines”. •HSP-peptide purified from tumors as vaccines. •Dendritic cells as strong antigen presenting cells for tumor antigens. “Immunotherapy” for cancers •TIL (tumor infiltration lymphocytes) as an adaptive immunotherapy for cancers. •Graft versus tumor (good) and graft versus host disease (a complication of bone marrow transplantation) Immunodetection for Cancer Diagnosis Detection of metastasis at gross and cellular levels Serum tumor proteins: CEA, -fetal protein are embryonic proteins that are expressed in adult tumors. These markers become useful for tumor detection, progression or recurrence.