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Inflammation

Innate immediate amnesic. Acquired specificity memory. Inflammation. IL-18 IL-15 IL-12, IL-23, IL-27. IFN g IL-17. TNF a IL-1. minutes. hours. days. A model for innate sessions?. Raulet 2004. Innate Immunity.

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Inflammation

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  1. Innate immediate amnesic Acquired specificity memory Inflammation IL-18 IL-15 IL-12, IL-23, IL-27 IFNg IL-17 TNFa IL-1 minutes hours days

  2. A model for innate sessions? Raulet 2004

  3. Innate Immunity • Initial response to microbes to prevent infection with elimination of danger • often stimulates adaptive responses • components also important in adaptive

  4. Problem? • limit to number of genes organism can encodeHUMAN------30-40K(majority nothing to do with immunity) [1014-1018 B and T cell receptors] • innate immune receptors?-----hundreds

  5. Adaptive Immunity • trillions of clones of B and T cells. • each with unique antigen receptor. • somatically created by gene rearrangement. • time lapse for maturation. • “acquired immunity” i.e. memory.

  6. Recognition receptors in innate immunity

  7. Janeway, NEJM, 2000

  8. Akira (2001)

  9. Strategy of Host? Microbes are heterogeneous and can mutate ---- On highly conserved structures present in large groups of microorganisms. FOCUS PAMPS ---- Pathogen - associated molecular patterns

  10. Common features of PAMPS produced only by the microorganismLPS--bacteria--alerts host--immune response usually essential for microorganism survival or pathogenicity invariant structures shared by entire classes of pathogens ----- LPS

  11. Effect of PAMP recognition • activation of innate effector mechanisms phagocytosis antimicrobial peptide synthesis induction of NO in macrophages • induction of inflammatory effector cytokines and chemokines • induction of co-stimulatory molecules on surface of APC (B7.1 + B7.2)

  12. Effect of LPS Recognition • stimulation of cytokine production(IL-1, TNF, IL-12). • induces acute phase response. • enhances microbicidal function of macrophages and other cells. • promotes development and growth of Th cells.

  13. Macrophage release of TNFa in response to LPS challenge provides local protective effects Increased: blood flow vascular permeability stickiness local clot cells to draining l/nRESOLUTION

  14. excessive release of TNFa in response to systemic LPS challenge causes: shock disseminated clotting uncontrolled bleeding multiple organ failureDEATH

  15. Receptors on macrophages activated by pathogen • various receptors • Stimulates phagocytosis and uptake • destruction of pathogen • inflammatory response

  16. Signalling Receptors-TLRs • activate intracellular signalling via NFkB • variety of effector genes activated • family of homologous proteins • extracellular leucine-rich repeat (LRR) • cytoplasmic domain for signalling • cytoplasmic domain homologous to that of IL-1 receptor family

  17. Human TLR • 2 5 6 10 (13) ?? known TLRs • ligands now well known • mediate innate immunity • TLR4 LPS binding • TLR2 lipoprotein and peptidoglycan X X X

  18. Family clustering of TLR Akira (2003)

  19. Cellular expression of TLR R&D systems

  20. How was TLR4 discovered ? • lps gene of lps-hyporesponsive mouse C3H/Hej • Proline to histidine mutation in signalling domain of TLR4 • Specific gene deletion followed

  21. TLR specificity Akira (2004)

  22. Janeway, NEJM, 2000

  23. Effects of TLR engagement • TNFa • IL-12 • Microbial killing • iNOS • IL-1b, IL-6, IL-8 • DC reprogramming for Th1/Th2 Akira (2001)

  24. Adaptor molecules • Now at least 5 • MyD88 • Mal- MyD88 adaptor-like(TIRAP) TIR domain containing adaptor protein • TRIF TIR domain-containing adaptor inducing IFN-b(TICAM-1) TIR-containing adaptor molecule-1 • TRAM TRIF-related adaptor molecule • SARM sterile a and HEAT–Armadillo motifs

  25. Does innate receptor dysfunction cause disease? mutations----inactive-- immunodeficiencies ? mutations---- active-- inflammatory conditions ? e.g. autoimmunity.arthritis, asthma, allergy

  26. TLRs and disease • Increasedgram –ve infections • TLR2 mutationincreased TB/leprosy Cook (2004)

  27. TLRs and disease • NOT ALL BAD! • reduced atherosclerosis • Reduced airway hyperreactivity • Reduced IL-6,VCAM Cook (2004)

  28. synovial membrane FLS TLR 2 _ _ + + TLR 4 _ _ + + b-actin _ _ 2 3 4 5 + + 1 – unstimulated + TNFa/IL-1b 1-5 = synovial membrane samples TLR expression in synovial membrane and FLS

  29. O’Neill, Immunology Today, 1999

  30. IL-1 and its superfamily R&D Systems

  31. adhesion molecule angiogenesis antigen : HLADR endothelial cell IL-12 chemokines ECM ? neutrophil T1 cell IL-21? IL-22? ± IL-15 IL-18 IL-17 IFN-g ROI / RNI enzyme degranulation cell contact macrophage ? chondrocyte FLS TNF-a IL-1b IL-10 IL-11 TGF-b MMP MMP GAG release NO Cellular and cytokine interactions in the immunopathogenesis of RA

  32. IL-12 • heterodimeric cytokine • produced by phagocytic cells in response to bacterial products • induces cytokine production from NK cells (IFNg) • growth factor for NK cells • promote phagocytic cell function and inflammation • (crucial in adaptive response for Th1 generation) • What about IL-23 and IL-27?

  33. IL-15 X • newish oldish cytokine • produced by activated monocytes • uses components of IL-2R • similar activities as IL-2 • stimulates NK cell proliferation, cytotoxicity and cytokine production • promotes NK cell survival

  34. T lymphocyte • activation / proliferation • cytokine production Th/c1 & Th/c2 • cytotoxicity • chemokinesis • cytoskeletal rearrangement • adhesion molecule expression • apoptosis • NK cell • cytotoxicity • cytokine production • reduced apoptosis • lineage development • Macrophage • dose dependent effect on activation • membrane expression of IL-15 • B lymphocyte • Ig production • proliferation IL-15 IL-15 • Osteoclast • maturation • calcitonin receptor • Neutrophil • activation • cytoskeletal rearrangement • cytokine release • reduced apoptosis • Possible effects on: • dendritic cell • endothelial cell • fibroblast like synoviocyte

  35. IL-15 T cell Receptor IL-15 IL-2/IL-15Rb gc IL-15Ra syk JAK-3 JAK-1 STAT5 STAT3 Proliferation/Differentiation

  36. Mean Clinical Score p<0.001 Day (Post challenge) Recombinant sIL-15R inhibited development of CIA HSA IL-15Ra Ruchatz et al J Immunol 1999

  37. IL-15 as a target? • Pro-inflammatory innate response cytokine • Present and active in RA tissues • Inhibition reduces rodent arthritis models • Proof of concept required in human studies • Fully human, IgG1, anti-IL-15 antibody • (Genmab; HuMax-IL15)

  38. Encouraging short term efficacy for anti-IL-15 • ACR20 in more than 60 % of patients in repeat dose • ACR70 achieved in all cohorts with repeat dose • No safety or tolerability issues • Phase II, multi-centre, RDBPCT ongoing • Candidate innate response cytokine targeting offers potential • ?synergy • ?multiple targets

  39. IL-18 X • newish cytokine • originally called IGIF • macrophages, osteoblasts, keratinocytes and many others • pro-IL-18 cleaved to active by ICE • Increases NK cell cytotoxicity • augments IL-6, GM-CSF and especially IFNg • promotes angiogenesis • promotes Th1 (and Th2 responses)

  40. neutrophil T cell NK cell macrophage cytokine release ROI / RNI granule release maturation activation cytokine release cytokine release NO production cognate interactions cytokine release cytotoxicity IL-18 osteoclast chondrocyte endothelial cell inhibits maturation (via GM-CSF) MMP expression GAG release NO production FLS angiogenesis adhesion molecule MMP expression Pleiotropic effects of IL-18 in inflammation?

  41. IL-18 as a potential target in inflammatory arthritis

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