Immune Responses Against Tumors and Transplants Cancerous cells lead to tissue damage - typifying true cancer (versus

benign). - continuously dividing cells - cells that require nutrients Acquire nutrients via: - vascular infiltration (increased blood supply) - metastasize (uncontrolled growth, invasion of surrounding tissue, and the ability for metastasis - 3 hallmarks of a malignant neoplasm) Malignancies - goal is to ENHANCE the immune response in order to effect treatment AGAINST the tumor Transplants - the goal is to MINIMIZE the immune response in order to reduce rejection of, and damage to, grafted tissues/organs How does the immune system recognize tumor cells as foreign? Immune surveillance by adaptive immunity - produce inhibitory effects on tumor growth. Tumor Antigens: Can occur on potentially any tissue. Sometimes antigenic molecules are simply mutated versions of normal self molecules, esp proteins - new versions are considered foreign Another source: induction of cancer through the activation of oncogenes (cancer-inducing genes that are present in the human genome); normal products - cellular growth factos that regulate and control both cellular growth and differentiation - at this stage 'proto-oncogenes' b/c does not lead to malignancies. They can contribute to cancer upon being activated (via enviro factor, viral infxn, mutation) causing malfunction and result in over-ride of apoptosis - cell continues to divide. Tumor Suppressor gene - normal fxn - suppress tumor formation. Mutation = malignancy. 'two hits' - both copies of the gene are affected by mutation. Some malignant cells cause the over stimulation of normal cell proteins - they become antigenic The expression of certain proteins/ gene products that would not normally be produced in that type of cell or tissue. (being where they do not belong may stim response against them). Presence of viral products on/in cells that have been infected with oncogenic viruses (virus that has the ability, upon infection to transform the infected cell into a malignant cell). Transform r/t

virus either inserting an oncogene in the hosts genome OR by activation of an already-existing oncogene in the host cell genome. Tumor Rejection by the Immune System **CD8 T-cells are the ones that have the primary responsibility of attacking and killing tumor cells. They specifically target tumor antigens. **Tumor antigens are typically displayed on MHC-I molecules on the tumor cells. Possible - dendritic cells or macrophages will ingest tumor cells, or tumor antigens, then present on their surfaces bound to MHC-I (this activates any CD8 cell that has a TCR specific for those presented molecules) *CD4 cells and antibodies that produce responses against tumor cells have been discovered in some ppl* Tumor Evasion of Immune Responses Tumor cells can d/c MHC-I molecule production which prevents any display of tumor antigens to CD8 cells. Failure to display MHC-I is seen as 'abnormal' or 'stressed' by NK cells (therefore phagocytosis). Produce cytokines that will suppress immune reactions. - TGF-beta (Tumor growth factor-beta) Activate pathways - CTLA-4; inhibits T-cell activity. CTLA-4 binds to B7 on APCs blocking cos-stim signals needed for activation of T-cells. Treatment of Malignancy using Immunity: 1. supply effector cells or molecules (such as t-cells or antibodies), that target tumors, to pts with those tumors 2. provide active immunity against tumor cells in pts with those tumors 3. engage the antitumor immune responses on the pts own immune system Immune Therapy Cannot be surgically removed - irradiation and use of chemotherapy. Harmful effects r/t insufficient differentiation between tumor cells and normal cells Monoclonal Antibody - An antibody produced by a single clone of cells. A monoclonal antibody is therefore a single pure type of antibody. Monoclonal antibodies can be made in large quantities in the laboratory and are a cornerstone of immunology - specially modified with cancerous cell itself in order to make the antibody-producing cell immortal. Are specific for one antigen (which is tumor specific). Amplification of T-cells - via removal of t-cells, exposure of cells to growth factor in vitro and re-injection back into the patient. The amplified population will contain a greater number of t-

cells w TCRs against tumor antigens increasing the likelihood of the pt producing an immune response of their own against the tumor cells. 'Vaccinate" with tumor antigens or tumor cells (causes tumor proteins to combine with adjuvant molecules [are non-antigenic] but promote enhanced expression of costimulator molecules and release cytokines by APCs) 'Pulsed' dendritic cells Tumors produced by oncogenic viruses - vaccinate against virus [hep B and HPV against Liver and Cervical cancers...not always possible to correctly id and isolate tumor specific antigens for the purposes of vaccine development. so Boost immune system directly - inject immune stimulating cytokines directly into the pt (locally or systemically)...IL2 (but high dose = toxic)...indirect - vaccinate w a tumor cell that is transfected w a plasmid containing the DNA to code for co stimulator/cytokine production; tumor cell WILL provide all co stimulation required to fully activate a t-cell response against itself. Immune responses against transplanted cells/tissues: immune SUPPRESSION that is required in order to permit the acceptance of transplanted cell/tissues. Rejection IS an immune reaction. Transplantation DONOR - individual providing the GRAFT RECIPIENT/HOST is the one in receipt of the graft Genetically identical - SYNGENEIC Same species - ALLOGENEIC diff species - XENOGENEIC >>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>> SYNGENEIC - will always be accepted ALLOGENEIC and XENOGENEIC will always be rejected due to the presence of ALLOANTIGENS and XENOANTIGENS, whicha re targeted by ALLOREACTIVE and XENOREACTIVE T-cells or antibodies Which antigens form the basis for the recognition of allogeneic transplants, or allografts? The primary source for allograft antigens are the MHC molecules present on all of the nucleated cells of graft tissue. MHC Alleles: There are 3 genes that determine the production of MHC-I molecules. E person receives one allele from each parent, for each gene...therefore each person has at least 6 alleles for MHC-II molecules.

TOTAL # of diff alleles for MHC - 350 diff for HLA-, 650 for HLA-B (both code for portions of MHC-I mole structure), 400 diff for DR (code for portions of MHC-II) and 90 diff for DQ (Code MHC-II). **nearly EVERY individual will possess MHC molecules that will be recognized as antigenic by another individual. REJECTION is based on MHC incompatibility. Could potentially produce rejection in a matter of 30 mins** Mechanism for recognition in the ability for TCRs to recognize MHC Other graft antigens: 'minor histcompatibility antigens'. most are normal cellular proteins. recognition of alleogenic MHC - graft dendritic cells themselves may display graft MHC, thus eliciting host immune responses against graft cells.