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CYTOKINES

CYTOKINES. Cytokines are important because:. Master regulators of the immune system Therapeutic reagents. Cytokine Nomenclature. Monokines - cytokines produced by moncytes Lymphokines - cytokines produced by activated T cells

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CYTOKINES

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  1. CYTOKINES

  2. Cytokines are important because: • Master regulators of the immune system • Therapeutic reagents

  3. Cytokine Nomenclature • Monokines - cytokines produced by moncytes • Lymphokines - cytokines produced by activated T cells • Interleukins - cytokines produced by leukocytes which act leukocytes • Interferons - cytokines important in controlling viral infections and augmenting immune responses • Colony-Stimulating Factors - cytokines important in the maturation of leukocytes • Chemokines - cytokines important in directed migration of leukocytes during immune responses • Growth Factors - cytokines involved in stem cell differentiation and other functions

  4. Cytokine Functions Are: • PLEIOTROPIC • REDUNDANT • SYNERGISTIC • ANTAGONISTIC

  5. CYTOKINE PROPERTIES • Low molecular weight proteins or glycoproteins • Synthesized in active and inactive forms • Secretion is brief and self-limiting • Active at very low concentrations • Signal cells by binding to specific receptors on target cells

  6. Cytokine Receptors • Each cytokine has a receptor • Receptors are grouped into 5 families • Cytokine receptors are often multi-chain complexes • Signaling through receptors requires multiple events

  7. IL-8 and chemokines IL-2 IL-1 TNF-a, b IFN-a, b, g

  8. Cognate receptor subunit Signaling receptor subunit Cytokine Receptor Subfamilies

  9. -Chain Cognate receptor b-Chain Signaling receptor JAK P P P P P STATs P P P Transcription Generalized Cytokine Signaling Mechanism Nuclear membrane

  10. Cytokine Effects on Target Cells are: • AUTOCRINE - • PARACRINE - • ENDOCRINE -

  11. Hematopoietic Cytokines in the Immune System

  12. Cytokines are critical for lymphocyte development

  13. T Cell Maturation and Cytokines • Dependent on IL-2 for activation, growth and proliferation after Ag binding • Differentiation to helper T cell subsets (Th1 and Th2) depends on cytokines • Th1 cells produce cytokines that aid cell-mediated immunity (IFN-g, IL-2 , others) • Th2 cells produce cytokines that aid antibody production (IL-4, IL-5, others)

  14. B Cell Maturation and Cytokines • Dependent on multiple cytokines for activation, growth and proliferation after Ag binding • IL-6 is a major growth factor for B cells • Multiple cytokines are involved in isotype switching (e.g., TGF-b for IgA, IL-4 for IgE)

  15. Cytokines in Host Defense Viral Infections • Viruses infect by binding to a “receptor” and are internalized • Take-over host machinery, replicate DNA or RNA • Viral genetic material is recognized as foreign by TLRs (TLR3 - dsRNA, TLR8 - ssRNA) • Viral TLR binding leads to production of “Interferons” - anti-viral cytokines critical to clearing viral infections

  16. Viral Responsive TLRs ssRNA

  17. INTERFERONS Two Major Interferons:Types I and II Type I: produced by all cells (IFN-a/b) Type II: produced by act. T cells (IFN-g) • Functions: • innate immunity - viral clearance • adaptive immunity - lymphocyte activation/maturation

  18. Interferon anti-viral mechanisms • Induce the expression of MHC molecules - Allows Ag presentation to cytotoxic T cells - Loss of MHC expression allows targeting by NK cells • Shut down infected host cells - production of 2-5 (A) synthase -> activates RNAse L -> degrades mRNA - PKR inactivates eIF-2 (a translation factor) -> blocks protein synthesis

  19. Cytokines in Host Defense Bacterial Infections • Bacteria infect by a number of routes - ingested, inhaled, through cuts • Take over a niche and replicate rapidly • Bacterial PAMPS are recognized as foreign by TLRs (TLR4 - LPS, TLR5 - flagellin) • Bacterial PAMP binding to TLRs leads to production of pro-inflammatory cytokines and the acute phase response, critical to clearing bacterial infections

  20. Bacterial PAMP Responsive TLRs

  21. ACUTE PHASE RESPONSE • A well orchestrated sequence of events to mobilize a metabolic response of the organism to: • Eliminate invading pathogens • Prevent on-going tissue damage • Activate repair processes Mediated by “pro-inflammatory” cytokines including TNF-a, IL-1, IL-6, IL-8 and IFN-g

  22. Tumor Necrosis Factor-a (TNF-a) Interleukin 6 (IL-6) Interleukin 1 (IL-1) • Production induced by LPS and other PAMPS, made by MØ, fibroblasts, others • Activates myeloid cells, epithelium, endothelium • Induce production of multiple cytokines • Initiates acute phase response (fever) • Induces adhesion molecule expression • Toxic at high levels (septicemia)

  23. Acute Phase Proteins • Host Defense Proteins • Proteinase Inhibitors • Anti-oxidants CRP, complement, fibrinogen C1 inhibitor, a1-proteinase inhibitor Haptoglobin, ceruloplasmin

  24. Chemokines • Multiple families of small molecular weight cytokines (at least 60 at present time) • Classified based on different cysteine motifs • Involved in multiple immune functions including inflammation, cell recruitment, lymphocyte trafficking, lymphoid organ development and wound healing • Expressed in primary and secondary lymphoid organs

  25. Clinical Applications of Cytokines • Some of your patients will be receiving cytokine therapy for non-dental/optometry conditions • Cytokine-specific therapies are in use for some dental/optometry conditions

  26. Cytokine Therapy • Interferon-a therapy for chronic myeloid leukemia - disease remission • Soluble TNF-a receptor (Infliximab) - therapy for rheumatoid arthritis • Interferon-b therapy for multiple sclerosis - effective in about 30% of patients • Procrit (erythropoietin) to boost RBC levels in patients undergoing chemotherapy

  27. Cytokine Therapy for the Eye • Anti-TNF-a antibody in refractory posterior uveitis - restored visual acuity • Nerve growth factor heals corneal ulcers refractory to conventional therapy - no side effects • Interferon-a treatment of Bechet’s disease reduces retinal inflammation, improves visual acuity

  28. Cytokine Therapy for the Oral Cavity • Thalidomide (anti-TNF-a) therapy for orofacial granulomatosis - clinical resolution • Soluble TNF-a receptor therapy prevents root resorption in a rat model system • Interferon-a therapy combined with surgery clinically resolves aggressive oral giant cell tumors

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