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Lecture Notes (3/5) Vaccines and Tolerance 2016 3/18 C.K.Shieh § Routine vaccination for common infectious diseases changes the life of every human being in our world. In this lecture, we will discuss about the vaccines in use and the strategies that have been used to develop useful vaccines. In addition we will discuss about one of the complex and essential characters of acquired immunity, antigen-specific tolerance. Vaccination, the Most Successful Medical Practice Many diseases have disappeared (small pox) or become rare (measles, poliomyelitis) due to successful nationwide vaccination programs. Vaccination Schedule in Taiwan Not including: Human papilloma vaccine, pneumococcal vaccine. Including: HBV, BCG. (When compared with vaccination schedule in the US) Types of Vaccine Preparations • Live organisms • Non-living organism • Subcellular fragments • Toxoids • Recombinant proteins Live Vaccines Important ones: polio (Sabin), measles, mumps, rubella (MMR), BCG, Rota virus How a Live Attenuated Vaccine Is Prepared Continuous culture in the cell lines or animals. Adequate mutations accumulate in the live organism to attenuate its pathogenesis mechanisms. Killed Organisms as Vaccines More toxicity, low efficacy. Not often used now. Still in use in some countries: pertussis (bacteria), polio (virus) Vaccines Made From Subcellular Fragments Important ones: HBV surface proteins, Hib, meningococcus and pneumococcus capsule Toxoids Diphtheria, tetanus (DT) Recombinant viruses as vaccines Strategy for future vaccines Adjuvants for Vaccines Only Al(OH)3 (Alum) is used in humans, acting as a reservoir in the injection site and also as a pro-inflammatory stimulator (an inflammasome activator) at the same time. Other adjuvants to boost the favored immune responses are being developed. Non-specific Immunotherapy Cytokines and other immunostimulants Safety Problems For live vaccines: reverse mutation to pathogenic microbes; fatal infection for immunodeficient patients For killed vaccines: contamination, strong reactions… CNS effects for pertussis vaccine Intussusception for Rota virus vaccine Future Vaccines Vaccines prepared from recombinant, non-virulent viruses (e.g. vaccinia virus) Vaccines with immunomodulaing activities Vaccines make from anti-idiotype antibodies DNA Vaccines Bare DNA (DNA without protein coating) is a form of “future vaccines” that is stable and cheap. Bare DNA should enter the cells of hosts and be transcribed and translated. The produced proteins then become the immunogens. The approach has the theoretical advantage that it might induce stronger T cell responses than extracellular antigens. 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”. Regarding anti-idiotype antibodies as vaccines… 1. Balance of idiotype anti-idiotype network was believed to be an important basis for immune responses and homeostasis between the body and the immune system. Although this theory is no longer in the mainstream of immunology, some previous findings remain true. 2. As the binding surface (idiotope) of an antibody may be the complementary image of the original antigen, some anti-idiotope antibodies may bear similar antigenicity to the original antigens. They may thus be used as vaccines. This idea, however, remains more of theoretical interest than practical use. In some situation like production of high affinity antibody against carbohydrate antibody, anti-idiotype Ab as a surrogate vaccine appears more attractive. Immunological Tolerance 1. Tolerance is one of the central characters of the immune system (along with memory and specificity). 2. Location: Central tolerance and peripheral tolerance 3. Cell type: T cell tolerance and B cell tolerance 4. Mechanisms: deletion, anergy, immune deviation (ignorance), cell mediated immunoregulation 5. Lack of appropriate co-stimulation as a way an antigen-specific tolerance induction through different mechanisms. Central and Peripheral Immunological Tolerance 1. Theoretically, most endogenous antigens can tolerize the immune cells during their maturation in the “central” lymphoid organs. AIRE gene play an important role in inducing the expression of various genes in the thymus. 2. Exogenous antigens usually are encountered in the peripheral tissues. e.g. food antigens, air allergens Regulatory T cells regulate immune responses in an antigen specific manner through suppression at different levels. 1. Immunosuppressive cytokines: IL-10, TGF-, IL-35 etc. 2. IL-2 consumption 3. Direct cytolysis 4. Modulation of dendritic cells Regulatory T cells regulate immune responses in an antigen specific manner through suppression at different levels. 1. Anergy 2. Deletion 3. Receptor editing 4. Exclusion from sites for maturation