Advances in the Pathogenesis of IBD: Genetics Leads to Function Pathogenesis of IBD Environmental Factors Microbes Scott Plevy, MD Associate Professor of Medicine, Microbiology & Immunology UNC School of Medicine Replicated CD loci: NOD2 IBD5 IL23R ATG16L1 Barrier function Host factors Innate and adaptive immunity IBD Xavier RJ and Podolsky DK. Nature 2007;448:427-434. New Genes Highlight Host-Microbial Interactions Genetics CG Matthew, Nature Reviews Genetics 2008;9:10 ou Are Only 10% Human Environment = 10 12 to 10 13 Cells = 10 13 to 10 14 Intestinal Bacteria
Mouse Models of IBD and the Role of Commensal Enteric Bacteria No bacteria No immune activation Mice KO IL-10 KO TCR KO CD 3 26 TG SAMP1/it CD 45 RB hi SCID Rats HLA-B27 TG Indomethacin Non-human primate Cotton top tamarin Resident bacteria Macrophage and Th1 immune activation What Is the Mucosal Immune System? What happens when things go wrong? No colitis Colitis Normal Intestine vs. IBD Intestine Environmental Triggers (infection, bacterial products) Failure to down regulate Chronic uncontrolled inflammation = IBD Moderately inflamed Down regulate Normal gut Controlled inflammation Normal gut Controlled inflammation The Mucosal Immune System Anatomy Organized: Activation arm Diffuse: Effector arm Mucosa-Associated Lymphoid Tissue (MALT) Examples: - Nasal-associated lymphoid tissue (NALT) - tonsils, adenoids. - Gut-associated lymphoid tissue (GALT) - Peyer s patches. - Bronchus-associated lymphoid tissue (BALT)
How Do Cells Home to the Mucosal Immune System? Mucosal Zip Codes Adhesion and Recruitment Mucosal and Inflammatory Zip Codes Innate and Adaptive Immunity 0-6 Hours 1-5 Days 4 Integrins 4 1 4 7 Threat Detection Immediate Responses Longer-Term Mobilization TECK/CCR9 Innate Immunity Broad Action PRIME Adaptive Immunity Antigen-Specific Leukocyte VCAM-1 Pattern Recognition Receptors Cytokines And Chemokines ACTIVATE MODULATE Cytokines And Chemokines Vascular Endothelium MAdCAM-1 Release of anti-microbials Recruitment of cells Localized Inflammation KILL PATHOGENS CLEAR INFECTION Mahida. Rolfe N. Clinical Science 2004;1007:331-341. Innate Immunity Innate Immunity: Evolutionarily Conserved Innate immunity is the initial response to microbes that prevents infections and in some cases eliminates pathogens. Effector mechanisms of innate immunity are often used to eliminate microbes even during the adaptive response (the first AND the end effectors). Innate immunity stimulates and directs adaptive responses. Components of the innate immune response recognize structures unique to microbes and required for their survival (PAMPs). Receptors of innate system are germ-line encoded. Lemaitre et al. Cell. 1996;86:973-83
Defects in Innate Immunity in IBD Intestinal Barrier Defects Commensals Pathogens Intestinal epithelium Increased concentration of mucosal bacteria Increased intestinal permeability Decreased defensin expression NOD2 B cells IgA Cells of the Mucosal Immune System Neutrophil / Macrophage Defects Neutrophil Monocyte macrophage Abnormal neutrophil function Mutations of NOD2 Folwaczny C et al. Eur J Gastroenterol Hepatol 2003;15:621-626.
Cells of the Mucosal Immune System T cells Lamina Propria Peyer s Patch Intraepithelial Lymphocytes Oral Tolerance -Oral tolerance is the generation of systemic immune unresponsiveness by feeding of antigen. -Oral tolerance is likely a mechanism for prevention of harmful immune responses to harmless antigens such as foods. -Necessary to prevent excessive response to normal flora and food antigens. Oral tolerance as a treatment for experimental allergic encephalomyelitis. Induction of oral tolerance is being studied for use clinically.
Modulating the immune system Trafficking T cell Activation Cyclosporine Tacrolimus Cytokine regulation TNF- IL-1 IL-12 / 3 IFN Anti-integrins show clinical activity in IBD Natalizumab anti 4 4 1 4 7 rhumab Beta7 anti 7 E 7 Corticosteroids 6-MP/AZA Methotrexate (?) IL-4 4 / IL-13 IL-1Ra TGF IL-10 MLN0002 anti 4 7 Approved for treatment of MS and CD Clinical activity in Phase II UC In Phase I in UC Anti MAdCAM Activity in Phase 1 UC VCAM Confirmed cases of PML Broad expression CNS, peripheral B and T cells MAdCAM Gut-specific E-cadherin Mucosal Epithelium Intra-epithelial lymphocytes (Gut, skin, lung) 31 T-cell Response in Normal Mucosa Inflammatory T cells respond to foreign bacteria and antigens, breaching mucosal barrier Th1 Th2 Th17 Cytokines Regulatory T-cells maintain homeostasis by rapidly downregulating inflammatory response once the job is done T reg Tr1, Th3 Too much Th1, Th2 or too little T-cell regulation results in uncontrolled inflammation Plevy. Gastroenterol Clin N Am. 2002;31:77. Biology of Cytokines Cytokines are a group of low molecular weight regulatory proteins Secreted by leukocytes and a variety of other cells in response to stimuli Membrane-bound forms of some secreted cytokines exist Mediate effect by binding to cell-associated receptors on target cells Cytokines regulate the intensity and duration of the immune response Stimulate or inhibit activation, proliferation, and/or differentiation of various cells Regulate secretion of antibodies, other cytokines Roitt I, et al. Immunology. 5 th ed. 1998. Key Actions Attributed to TNF The IL-12/IL 12/323 Pathway is Important in Crohn s s Disease Pathogenesis Anti-p40 Ab IL-12 Anti-p40 Ab 3 p40 p35 p40 p19 IL-12R 12R 1 IL-12R 12R 2 IL-12R 12R 1 3R IL-12 and 3 share common p40 subunit and common 1 receptor IL-12 and 3 activate different subpopulations of T cells IL-12 p40 neutralizing antibodies are therapeutic in mouse colitis models and in human Crohn s disease (Mannon, et al. N Engl J Med 2004, and Sandborn DDW 2007) A specific polymorphism in 3R (Arg381Gln) is protective of Crohn s disease: OR 0.26 (0.15 0.43) Adapted from Trinchieri G. Nat Rev Immunol 2003;3:133-45. Duerr RH, et al. Science Express 2006.
T H 1/17 Cytokines in IBD Evidence from Animal Models T H 1/17 scid T reg Anti-3 Anti-TNF Newer Model of the Pathogenesis of IBD Th1/Th17 IL-12 3 TGF Retinoic acid EBI3 Th2 Crohn s Disease Treg Ulcerative Colitis Modulating the immune system Trafficking T cell Activation Cytokine regulation The Real Spectrum of IBD Antisense ICAM Anti- 4 7 Anti- 4 Small molecules CTLA4 Ig Anti-CD25 Anti-CD3 TNF- IL-1 IL-12 / 3 IFN IL-4 4 / IL-13 IL-1Ra TGF IL-10 Anti-TNF Anti-IL-12/23 UC Th2 IBDx panca IRGM IL23R IBD OmpC I2 ATG16L1 NOD2 CD ASCA CBir1 Th1/17