L#21 & #22: Autoimmunity and Cancer and Transplant Immunology
L#21 & #22: Autoimmunity and Cancer and Transplant Immunology 0530
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This 4 page Class Notes was uploaded by Denise Croote on Saturday January 23, 2016. The Class Notes belongs to 0530 at Brown University taught by Dr. Richard Bungiro in Fall 2013. Since its upload, it has received 23 views. For similar materials see Principles of Immunology in Biology at Brown University.
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Date Created: 01/23/16
Lecture Twenty One: Autoimmunity An attack on self that results from failure to distinguish between self and non-self Mediated by auto-antibodies or self reactive T cells Tolerance is a state of non-responsiveness to a self antigens Toleragens are antigens that induce tolerance Factors that promote Tolerance: o High Ag dose o Ag persistence o Absence of adjuvants o Lack of inflammatory stimuli o Low levels of co-stimulation Central tolerance is where self reactive B cells are deleted in the bone marrow and self reactive T cells are deleted in the thymus Peripheral tolerance is where self reactive B cells are anergized or deleted and is usually mediated by T regulatory cells Sequestration is a non tolerogenic mechanism by which certain antigens are isolated in tissues, prevent contact with lymphocytes Experiments have shown that B cells reactive to self antigen will either be deleted or undergo receptor editing, introducing anti-self antigen into the periphery induces anergy T Regulatory Cells o Selected in the thymus for their intermediate affinity o 5-7% of the CD4 T cells in the periphery o Suppressive mechanism is unknown but shown to involve CTLA4 and IL10 o Pathogens may induce T regs as a survival strategy Autoimmune responses can directly cause cell death or damage via antibodies (ADCC or C’ activation) or cell mediated (DTH or CTLs) Autoimmunity can lead to the production of auto-antibodies which can act on hormone receptors and either mimic the actions of the hormones and stimulate the receptor or block the receptor and antagonize the actions on the hormones Diseases are most common in 40 -60 year old women, it could be because damages have accumulated all of their life or it could be because of the hormone changes that occur around this time COMMON DISEASES: o Hashimoto’s Thyroiditis – autoantibodies and Th1 cells go after thyroid proteins and cause inflammation and hypothyroidism o Pernicious Anemia – autoantibodies block vitamin B uptake interfering with RBC production o Hemolytic Anemia – autoantibodies to RBC or drugs that bind to RBCs induce phagocytosis or C’ activation o Goodpasture’s Syndrome – autoantibodies bind to membranes in kidney and lungs leading to inflammation, IgG completely saturates kidney secretions o Insulin Dependent Diabetes - autoantibodies and Th1 cells mediated the destruction of insulin producing beta cells resulting in unregulated blood sugar levels o Grave’s Disease – autoantibodies bind to TSH receptor on thyroid and stimulate is causing overproduction of thyroid hormones (hyperthyroisism) o Myasthenia Gravis – autoantibodies to Ach block Ach binding to activate muscles resulting in weakness and fatigue o Systemic Lupus – autoantibodies against DNA, histones, RBCs, platelets, clotting factors leads to immune complexes and complement activation o Multiple Sclerosis – autoreactive T cells mediate inflammatory lesions along the myelin sheaths of nerves causing neurological damages, weakness, and paralysis, scraping off the insulation of the nerves makes it difficult for them to fire o Rheumatoid Arthritis – autoantibodies bind to IgG to form immune complexes that deposit in the joints and activate complement Factors thought to induce Autoimmunity o CD4 T cells o Certain MHC alleles are more common among individuals with autoimmune diseases o Certain TCR variable regions are more common in mice with autoimmunity What can cause autoimmunity? o Failure of tolerance promoting mechanisms to develop like…. Fas mutations decreasing apoptosis AIRE mutations decreasing central tolerance Foxp3 mutations decreasing Tregs o Release of sequestered Ags due to injury or infection o Cytokine imbalances o Molecular mimicry – certain epitopes on pathogens can be found elsewhere in the body How to treat autoimmunity? o Most therapies are aimed at replacing the damages organ o Use of immunosuppressive drugs o Remove the autoantibodies from the blood, but this is only temporary because they will regenerate o New experimental approaches: antibodies directed against the MHC, TCR, CD4 o Introducing a worm infection to increase the Th2 response so that the Th1 (autoimmune) response decreases Lecture Twenty Two: Cancer Immunology Characteristics of a Cancer Cell o Provide their own growth signals o Avoid cell death o Ignore growth inhibitory signals and replicate without limits o Produce their own new blood vessels to sustain growth Immuno-surveillance theory states that the immune systems is able to recognize and eliminate malignant cells and cancer develops when these malignant cells can circumvent the immune response Immunodeficient mice (lacking perforin for lysis for example) and immunodeficient humans have an increased risk of cancer Some tumors develop as a result of infectious pathogens, for example leukemia can be caused by Epstein Barr virus Some tumors develop as a result of inflammation, for example Hepatitis B infection can lead to hepatocellular carcinoma During apoptosis cells move phosphotidylseme from the inside of the cell to the outside of the cell, which serves as a “I’m dying come eat me signal” Tumors can subvert the Immune Response by: o Cancer cells are often very close to self cells and their difference could go unnoticed, resulting in tolerogenic cell activation o Tumors create their own special blood vessels and T cells are unable to leave the circulation to attack the infected cell o Cancer cells can inhibit T cells Express inhibitory ligands for T cells Cancer contains cells that inhibit T cells (like T regs) on contact and with cytokines Have factors that inhibit T cell function (like inhibiting granzyme formation so that granzymes can’t lyse the tumor cells) How do you activate the immune response to fight the cancer? o Give antibodies that block inhibitory receptor signals o Give antibodies that induce activation of T cells o Give antibodies that deplete T regs o Activate the patients lymphocytes outside the body and infuse the activated cells back into the body o Infuse lymphocytes from other individuals o Apply inflammatory mediators to return the blood vessels to normal so that the T cells can exit the circulation and attack the cancerous area Cancer Vaccines – the best vaccine would have to be specific to an antigen that is expressed on the tumor cell and not in other tissues and that is important to the growth and development of the tumor o Possible antigens: Tumor Associated Proteins: normal proteins that are hugely over-expressed in the tumor cells but are also expressed in other tissues at certain stages of differentiation Tumor Specific Antigens: antigens only expressed in the tumor or mutated self proteins Tumor cells have lots of variation, killing just some of the cells won’t do any good, need to kill the cells with proteins that have been universally up-regulated on the cells Methods of vaccination o Directly inject a apoptotic tumor cell o Inject isolated tumor antigens o Inject peptides that have shown to be presented by HLA antigens expressed by the patient o Injection of antigens usually requires co-injection of adjuvants to get a response Vaccinations is not very successful because by that point the cancer has usually already caused a substantial amount of damage Process of Adoptive Cell Transfer involves taking a patient’s dendritic cells, expanding them in vitro with cytokines, loading them with antigens, and injecting them back into the patient (limited success) New attempts to transfer immune cells: o Lymphokine activated killer cells (LAK) – cells that are able to kill a wide range of tumor targets. The only problem is that they require high levels of IL2 stimulation in vivo and high levels of IL2 can cause capillary leakage o Tumor infiltration lymphocytes (TIL) – these take the tumor tissue and dissociate it o Cancer specific T cells are better at expanding in vitro than in vivo Chimeric Antigen Receptors – collect patient T cells and insert CAR into all of the T cells. CAR is a tumor antigen specific antibody variable region with a CD3 signaling domain. When injected into the patient, antibody portion of CAR binds tumor antigen and CD3 signals the T cell to activate Transplant Immunology Vocabulary o Autologous – from the same individual o Syngeneic – from another member of the same inbred strain o Allogeneic – from a different strain or individual of the SAME species o Xenogeneic – from a different species Strong T cell response to allogeneic MHC and HLA disparities causes transplant rejections To treat, a patient is given a high dose of chemotherapy/radiation to eliminate the tumor cells and then injected with a source of HSC cells to restablish the HSC system o Commonly injected with bone marrow, mobilized peripheral blood mononuclear cells, or cord blood o Graft vs. Host Disease is when allogeneic T lymphocytes present in the stem cells of the donor begin to attack the host. Is significant of a decreased graft vs tumor (GVT) relapse rate. o Cellular immunotherapy involves infusing a large number of haploidentical WBCs into the patient with the tumor, results in a rapid elimination of the donor cells Types of Rejection responses o Hyperacute – rejection occurs within minutes and is caused by preformed antibodies o Acute – rejection occurs within days or weeks and is caused by cellular immune responses o Chronic – rejection occurs over months or years and is caused by fibroblasts and increased collagen production Triggers for Transplant Rejection: o Disparity at HLA antigens – alloreactivity (MHC) o Disparity at non HLA antigens Minor Histocompatibility antigens – cytoplasmic proteins with different alleles coding for amino acid polymorphisms that can be recognized as foreign. Peptides from these proteins are presented by MHC molecules and trigger responses when stimulating cells from another individual o Immunological History of the recipient/donor Presence of antibodies and anticarbohydrates from other infections Presence of anti-HLA alloantibodies from pregnancy, transplant, or other infusions The presence of these preformed antibodies can trigger hyperrejection T cell responses to viruses in the past can increase alloreactivity Tolerance induction has worked in mice but is harder to induce in humans because we all have different histories and will react to the transplant differently Whether or not the patient in on immunosuppressive drugs can affect transplant rejection The balance of donor to recipient cells also affects the amount of rejection o Surgeon damage – damage signals are released when the surgeon makes the incisions and damages the tissue around the transplant area, level of damage can affect how much the immune response is triggered Ways to overcome transplant rejection(blocking the immune response) o Inhibit lymphocyte proliferation with mitotic inhibitors o Inhibit costimulation by blocking CD28 function and CD40 function (CTLA4 can do this) o Inducing immunoregulatory cells (like Tregs ) Summary: o With cancer you DON’T want to suppress the immune system because then the cancer will grow o With transplant you WANT to suppress the immune system so rejection will not occur With HSC transplants you worry about the DONOR attacking the HOST With organ transplants you worry about the HOST attacking the DONOR
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