IL-17 in health and disease March 2014 PSO13-C051n
Originally Researchers Suggested That IL-12 and IL-4 drove Th Cell Differentiation Naïve CD4 + T cell Question: Which of these cell types is responsible for autoimmunity? IL-4 IL-12 Prevailing early hypothesis: Th-1 cells cause autoimmunity Th2 Mediates humoral immunity Th1 IL-12R Mediates cellular immunity BUT: Removal of IL-12 (and Th1 cells) may not prevent autoimmunity Mosmann T et al. The Journal of Immunology 1986; 136:2348:. Qian Y et al. Cell and Mol Immunology 2010; 7:328; Kaplan MH Immunity 1996;4:313-319 2
Animal Studies Showed That Removing IL-12 Does NOT Prevent Autoimmunity and Revealed a Role for IL- 23 1. IL-12 and IL-23 deficient mice are resistant to collagen-induced arthritis (CIA), an autoimmune disease model 1 2. IL-12p35 deficient mice were not resistant to autoimmune disease 1 3. The IL-12 p40 subunit is shared by IL-23, a heterodimer composed of p40 and p19 subunits 2 4. IL-23p19-deficient mice were protected from CIA 1 IL-12 (heterodimer composed of p35 and p40 subunits) IL-23 (heterodimer composed of p19 and p40 subunits) IL-23, and not IL-12, promotes a T cell population that drives autoimmune inflammation 1 1. Murphy C et al. The Journal of Experimental Medicine 2003; 198:1951; 2. Oppmann B et al. Immunity 2000;13:715; 3
IL-6 & IL-23 Stabilise Differentiation of Th-17 Cells 1. Following antigen presentation by dendritic cells and exposure to specific cytokines, naïve T-cells differentiate into Th1, Th2, or Th17 effector cells Thymocytes IL-12 Naïve CD4 + T cell IL-4 IL-12R 2. IL-23 promotes the development of an IL-17- producing CD4+ helper T-cell subset 3. Tregs suppress the differentiation and effector function of Th1 and Th2 cells. The effects of Tregs on Th17 cells are unknown Iwakura Y et al. J Clin Invest. 2006;116:1218-1222; Weaver C et al Immunity. 2006;24:677-688; Ivanov S and Linden A. Trends Pharmacol Sci. 2008;30:95-103 Th1 IL-23 IL-6 Th2 IL-4R IFN- ROR t IL-4 IL-5 IL-13 TGF- 1 IL-23 IL-10 TGF- 1 IL-23R Th17 Th IL-17? Treg CD25 IL-17F IL-6 TNF-α 4
IL-23 Stimulates Th-17 Cells and Other Immune Cells to Produce IL-4 Naïve CD4 + T cell IL-12 Cell differentiation Cytokine production IL-23 Th2 Th1 Th17 IL-22 IL-6 Other immune cells IL-17F TNF-α Proinflammatory activity on multiple cell types Iwakura Y et al. J Clin Invest. 2006;116:1218-1222. 5
is a Critical Proinflammatory Cytokine Interleukin Families 5 IL-1 Family IL-2 Family IL-6 Family IL-12 Family 6 IL-17 Family IL-1 IL-1α IL-Ra IL-18 IL-33 IL-2 IL-15 IL-21 IL-6 IL-11 Amino acid sequence Homology diagram * IL-23 IL-12 IL-27 IL-35 Is a homodimeric glycoprotein (35 kda) 1 Signalling bridges innate and adaptive immunity 2 Has important roles against extracellular pathogens 3 Promotes inflammatory pathology 1,4 IL-17F IL-17B IL-17D IL-17C IL-17E (aka IL-25) Representative interleukin families, not a complete list of families or members; IL-17 family list complete * Among the IL-17 family members, the IL-17F isoforms 1 and 2 have the highest degree of homology with (55% and 40%, respectively), followed by IL-17B (29%), IL-17D (25%), IL-17C (23%), and IL-17E (17%) 2 1. Ivanov S and Linden A. Trends Pharmacol Sci. 2008;30:95-103; 2. Kolls J, Linden A. Immunity. 2004;21:467-476; 3. Gaffen S. Nat Rev Immunology. 2009/9:556-567. 4. Blanco p et al. Cytokine and Growth Factor Reviews 2008; 19:41 5. Meager A and Wadhwa M Encyclopedia of Life Sciences John Wiley and Sons, Ltd, 2007; www.els.net 6. Vignali DA and Kuchroo VK. Nat Immunol. 2012;13:722-728. 6
Is Expressed by a Variety of Innate and Adaptive Immune Cells Macrophages 1 Mast cells 2 Neutrophils 2 T-cells 4 Cytotoxic (CD 8) Th17 cells 3 T-cells 4 Additional Immune Cells Expressing Innate Adaptive Natural killer cells 2 T-cells with natural killer like properties 3,4 Eosinophils 5 1. Onishi R, Gaffen S. Immunology. 2010;129:311-321; 2. Lin A et al. J Immunol. 2011;187:490-500; 3. Miossec P et al. N Engl J Med. 2009;361:888-898; 4. Weaver C et al. Annu Rev Immunol. 2007;25:821-852. 5. Shamri R et al Cell Tissue Res. 2011 343: 57 83 7
Effects Cells of Multiple Lineages Target-Cell Type Macrophage, dendritic cell Endothelial cell Fibroblast Osteoblast* Osteoclast* Chondrocyte Keratinocytes Products Released IL-1 TNF IL-6 CRP IL-6 Coagulation MMP IL-6 Chemokines Growth factors MMP RANKL MMP Osteo- clastogenesis RANKL MMP MMP IL-6 Chemokines Ki67 (proliferation) * Effects of on osteoblast/osteoclast interactions are not completely understood. TNF, tumour necrosis factor; CRP, C-reactive protein; MMP, matrix metalloproteinase; RANKL, receptor-activated nuclear factor κb ligand. Adapted from: Miossec P et al. N Engl J Med. 2009;361:888-898; Onishi R, Gaffen S. Immunology. 2010;129:311-321; Kotake S et al. J Bone Miner Metab. September 2011; Chrircozzi A et al J Invest Dermatol. 2011; de Oliveira VL et al PLOS ONE 2012 8
Signalling Induces Diverse Inflammatory Mediators Inflammation Neutrophil and T cell migration Growth factors Chemokines IL-17RC IL-17RA Proinflammatory cytokines SEFIR Act1 Expression of proinflammatory genes TRAF6 TAK1 Cytoplasm mrna NF-kB and Nucleus other transcription factors Ivanov S, Lindén A. Trends Pharmacol Sci. 2009;30:95-103; Gaffen S. Nature Rev Immol 2009;9:556-566. May M. Nat Immunol. 2011;12:813-815. 9
Is Directly Associated With Autoimmunity in Animal Models Preclinical evidence suggests that removing IL-17 signalling prevents or dampens autoimmune disease Mice lacking the receptor for IL-17 (IL-17RA -/- ) are partially protected from the clinical symptoms of arthritis 1 Mice deficient in ( -/- ) are protected from collagen induced arthritis (CIA) compared with normal mice 2 Mice treated with anti- antibodies after onset of CIA had significantly reduced disease severity compared with mice treated with control serum 3 Mice treated with anti- antibodies had reduced clinical symptoms of experimental autoimmune encephalitis (EAE) and ameliorated disease course 4 Rats treated with IL-17R/IgG1 fusion protein have reduced joint inflammation and bone erosion from adjuvant induced arthritis 5 1. Sadik C et al. PLoS One 2011;6: e26342. 2. Nakae S et al. The Journal of Immunology 2003; 171:6173. 3. Lubberts E. et al. Arthritis and Rheumatism 2004;50:650. 4. Hofstetter H et al. Cellular Immunology 2005;237:123. 5. Bush K et al. Arthritis and Rheumatism 2002:46:802. 10
Induces Hallmarks of Psoriasis Golden JB et al Cytokine 2013;62:193-201;. Patel M et al Derm Ther 2012;2: 16;. Fischer-Stabauer M et al Eur J Derm2012;22:781-784
IL-17 Can Be Targeted, Regardless of Source, Without Affecting Other Cytokines in Immunity IL-4 Naïve CD4 + T cell IL-12 Cell differentiation Cytokine production IL-23 Th2 Th1 Th17 IL-22 IL-6 Other immune cells IL-17F TNF-α Proinflammatory activity on multiple cell types Iwakura Y et al. J Clin Invest. 2006;116:1218-1222; Miossec P and Kolls Nature Rev Immunology 2012;11:763. 12
Summary The balance of cytokine regulates lymphocyte differentiation IL-23 stabilises differentiation of Th17 cells IL-23 stimulates Th17 and other immune cells to produce bridges innate and adaptive immunity and promotes inflammatory pathology by acting on a range of effector cells Dysregulated IL-17 activity induces several hallmarks of psoriasis IL-17 represents a rational therapeutic target 13