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Regulation of the immune response

Regulation of the immune response. Jan Żeromski 2013/2014. POINTS TO BE DISCUSSED. Regulation by antigen and antigen-presenting cell Regulation by antibody The role of T cells (Treg) and NK T cells The role of telomeres Idiotypes and idiotypic network Neuroendocrine mechanisms

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Regulation of the immune response

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  1. Regulation of the immune response Jan Żeromski 2013/2014

  2. POINTS TO BE DISCUSSED • Regulation by antigen and antigen-presenting cell • Regulation by antibody • The role of T cells (Treg) and NK T cells • The role of telomeres • Idiotypes and idiotypic network • Neuroendocrine mechanisms • Genetic aspects in immune regulation • Immune regulation vs immune modulation - vaccines

  3. REGULATION BY ANTIGEN • Chemical nature of Ag-polysaccharides vs.proteins • Soluble vs.intracellular Ags • Large doses vs. small doses of Ag • Competition between antigens and peptides • The route of administration of Ag • The role of adjuvants

  4. THE SIGNIFICANCE OF ANTIGEN-PRESENTING CELL • Professional vs. non-professional APC • CD40L on T cell- CD40 on APC interaction • CD28 |CTLA4 | vs. CD80 and CD86 The level of expression of MHC on APC

  5. THE SIGNIFICANCE OF ANTIGEN-PRESENTING CELL 2 • The extent of cytokines secreted by APC • Cross-presentation (cross-priming) of viral Ags by APC to Tc (CD8+) cells via MHC-I • APC killing by cytotoxic T cells

  6. IMMUNE RESPONSE: STIMULATORY AND INHIBITORY CYTOKINES • Interleukin-2 (IL-2) • IL-1 • IL-4 • IL-5 • IL-6 • IL-12 • IL-18 • Interferon gamma (IFN- ) • IL-4 • IL-10 • IL-11 • IL-13 • Transforming growth factor beta (TGF-) • IFN-/ • IFN-

  7. REGULATION BY T LYMPHOCYTES • CTLA-4, instead of CD28, on T cells, binds B7 (on APC) – inhibition of activation • Fratricide – mutual killing of T cells by Fas- FasL system • T cell suicide – by the same token • Prevention of induction of autoimmunity by CD4+ CD25+Treg cells

  8. FEATURES OF Treg CELLS • Quantity: 5-10 % of CD4+ T cells in the blood • Surface markers: CD25, CD103, Foxp3 GITR,(glucocorticoid-induced TNF receptor) • Cytokine expression/secretion:IL-10, IFN-, TGF- • Suppression mechanism: contact with activated target CD8+ / CD4+ T cells, secretion of cytoki- nes (IL-10, TGF-) and non-specific inhibition („bystander effect”)

  9. Regulation of cell senescence by telomere shortening • Telomeres – repeats of the DNA sequence (GGGTTA) and protein located at the end of chromosomes – up to 2000 copies per cell • Provide stabilization and protect chromosomal ends from damage; regulate cell replication • At every cell division they shorten by 50-100 bp

  10. Regulation of cell senescence by telomere shortening -2 • When telomeres become too short, chromosome gets unstable and DNA damage can occur. To prevent damaged cells being replicated such cells: - die by apoptosis, - Enter cell arrest, known as cellular senescence. • T cells in elderly people have significantly shorter telomeres than young ones, • People with some premature ageing syndromes have short telomeres and usually have low life expectancy

  11. IDIOTYPIC REGULATION OF IMMUNE RESPONSES (IR) • Idiotype = the sum of idiotopes, variable determinants in a given antibody molecule or TCR • There are public and private idiotopes: -public: those found on other cells private: unique for given cell or cell clone

  12. IDIOTYPIC REGULATION OF IMMUNE RESPONSES (IR) • Anti-idiotypic antibodies may block antigen binding and thus regulate immune response • These antibodies are present in small amounts within immunoglobulin pool of all humans and participate in normal both, humoral and cellular IR

  13. JERNE’S IDIOTYPIC NETWORK (NOBEL PRIZE IN 1984) • Idiotypic determinants are immunogenic • Anti – idiotypic antibodies are formed following formation anti - antigen antibody • Anti-idiotypic Ab induce anti-anti-idiotypic response • This leads to gradual fading of immune response against given antigen

  14. B cells, Tcells and NK cells express receptors that contain immuno-receptor tyrosine based inhibitory motifs (ITIMs), apart from ITAMs (activating ones).

  15. NEUROENDOCRINE MODULATION OF IMMUNE RESPONSES • Most lymphoid tissues possess sympathetic innervation • Lymphocytes express receptors for a variety of hormones, neurotransmitters and neuropeptides

  16. NEUROENDOCRINE MODULATION OF IMMUNE RESPONSES -2 • Examples include steroids, catecholamines, enkephalins, endorphins and others • When released in vivo during stress, most of them are immunosuppressive

  17. NEUROENDOCRINE MODULATION OF IMMUNE RESPONSES - 3 • On the other hand, IL-1 and IL-6 cytokines act as stimulants of adrenal corticosteroid production • Both IL-1 and IL-6 are synthesized by neurons and glial cells and, in addition by cells in pituitary and adrenal glands

  18. GENETIC CONTROL OF IMMUNE RESPONSES • Strains of mice with different MHC haplotypes vary in their ability to mount immune response to given antigens • Peptide-binding groove of APC is formed by the most polymorphic residues in MHC molecules (encoded by different alleles) • Thus, MHC dependent aminoacid sequences of the groove determine the accuracy of peptide binding and in turn, antigen presentation

  19. CLINICAL IMPLICATIONS OF GENETIC CONTROL OF IR • MHC-linked genes control the response to several infections • Certain HLA haplotypes confer protection from malaria (Plasmodium falciparum) • Susceptibility to autoimmune diseases is influenced by MHC-linked genes

  20. CLINICAL IMPLICATIONS OF GENETIC CONTROL OF IR (2) • Linkage disequilibrium denotes grouping of some genes that increase risk of particular disease(example:HLA-DR3/DR4 -diabetes) • Non-MHC-linked genes also affect susceptibility to several diseases

  21. IMMUNE MODULATION – MANIPULATION OF THE IMMUNE RESPONSE • Vaccination – passive and active • Application of cytokines • Application of monoclonal antibodies • Suppression by glucocorticoids and other immunosuppressive drugs • Infusion of immune cells • Gene therapy related to the immune system

  22. FEATURES OF GOOD VACCINE Safe to use (live vaccines bear potential risk) Induce the right type of immunity Is affordable by the population concerned Easy to produce and store

  23. ADVANTAGES OF LIVE ATTENUATED VACCINES Preserve immunogenicity of virulent agent, especially conformational antigens involved in antibody production Mimic natural infection better than inactive vaccines Usually stimulate multiple components of the immune system including T cell and mucosal immunity mediated by IgA Herd immunity

  24. DISADVANTAGES OF LIVE ATTENUATED VACCINES • May contain adventitious agents • Can revert to virulence by mutation or interserotypic recombination • Can cause serious ilness in immunosupressed individuals • Stringent storage instructions for vaccine efficacy and safety

  25. THERAPEUTIC MODULATION OF IMMUNE RESPONSES • Non-specific immunization (BCG, bacterial lysates, cytokines) • Passive immunization: direct infusion of antibodies • Active immunization = vaccination: • live attenuated organisms(measles,mumps) • non-living organisms or subcellular fragments(pertussis, polio) • recombinant DNA-based (hepatitis B) • Edible transgenic plants (HBs in lettuce)

  26. NEW APPROACHES FOR BETTER VACCINES • Inactivated vaccines • Recombinant proteins produced in yeast, bacteria, cell culture or plants • Synthetic peptides • Anti-idiotypic vaccines • Nucleic acid vaccines • Novel adjuvants • Novel carriers

  27. ADJUVANTS, IMMUNOSTIMULANTS, PROBIOTICS • Adjuvants – organic and inorganic compounds enhancing immune response while applied together with an antigen (Freunds a. ) • Immunostimulants – microbial compounds that enhance general immune response(ribomunyl) • Probiotics – living microorganisms exerting favourable effect on patient’s health (Lactobacillus)

  28. Immunomodulation by monoclonal antibodies • Advantages structural stability unlimited supply of reagent, high specificity • Disadvantages: risk of sensitization for foreign protein (murine or rat Ig), potential hazard of anafilactic shock, difficult accesibility, high cost

  29. Modifications of monoclonal antibodies Mabs • Chimeric Mabs –-Variable parts from mice, constant regions (C) human (75% human sequences) • Humanized Mabs – hypervariable regions from mice, C regions from man (95% human sequences) • Human Mabs – human Ig gene expresion in various biological carriers (bacteriofages, transgenic animals, bacteria and even plants – „plantibodies”) • Minibodies – miniaturised Mabs (have better penetration) • Bispecific Mabs – specificity for 2 antigens

  30. Examples of Mabs currently used in therapy • Infliximab /anti TNF/ rheumatoid arthritis |RA|, Crohn disease • Rytuksymab /Anti CD20/ RA, B cell leukemias /lymphomas • Efalizumab /anti CD11a/ psoriasis • Trastuzumab /HER 2/neu/ breast carcinoma • Cetuksymab /EGFR/ large bowel carcinoma

  31. Next lecture: IMMUNOLOGY OF TRANSPLANTATION THIS IS ENOUGH! THANK YOU FOR ENDURANCE!

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