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1968 QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. Rio Negro Nature 2009;426:266 Science 2010;327:928 Avanços científicos nas doenças inflamatórias intestinais: o que vai ajudar o paciente? Claudio Fiocchi Department of Pathobiology, Lerner Research Institute Department of Gastroenterology & Hepatology The Cleveland Clinic Foundation Cleveland, Ohio, USA CCF The clinical spectrum of inflammatory bowel diseases (IBD) Ulcerative colitis (UC) Crohn’s disease (CD) Other colitides and IBDIBD-like conditions Ulcerative colitis Inflamed Normal Crohn’s cobblestone mucosa Distribution of IBD: pre-World War II Distribution of IBD: 1950-1970 Distribution of IBD: 1970-1990 Distribution of IBD: 1990-present Childhood mortality due to infectious diarrhea Petri WA et al. J Clin Invest 2008:118:1277-1290 The hygiene hypothesis: the incidence of infectious diseases has decreased and of immune disorders has increased over the last fifty years % 100 % 300 Hepatitis A Tuberculosis 50 200 Rheumatic fever Asthma IDDM Crohn's disease Measles Multiple sclerosis 100 0 1955 65 75 85 95 Infectious diseases 1955 65 75 85 95 Immune disorders Bach J-F. N Engl J Med 2002; 347:911 Geography and social status Stress Microbes and enteric flora Drugs Permeability Diet Environmental factors Smoking Immune system Genes Appendectomy “Physiological” inflammation Pathological inflammation Normal IBD Psoriasis Depression Schizophrenia Strong genetic influence IQ Neurosis Diabetes Asthma Cardiac disease Cancer Multiple sclerosis Adapted from Chakravarti and Little, Nature 2003 Weak genetic influence Major genetic variations detected by GWAs in IBD Chr Gene Product function CD UC 1p31 IL IL--23 receptor Immune inflammatory response + + 5q33 IL IL--12b (p40) Immune inflammatory response + + 9p24 JAK2 Signaling molecules + + 17q21 STAT3 Transcription factor + + 18p11 PTPN2 T cell tyrosine phosphatase + - 9q32 TNFS15 Immune inflammatory response + - 6q27 CCR6 Chemokine receptor + - 3p21 MST1 Macrophage chemotaxis + - 2q37 ATG16L1 + - 5q33 IRGM Autophagosome pathway + - 16q12 NOD2/CARD15 Bacterial recognition + - 20q13 TNFRSF6B Inflammatory response, apoptosis + + 21q22 PSMG1 Proteasome-related protein + + 12q12 MUC19 Epithelial integrity - + 1q32 IL IL--10 Immunoregulation - + Autophagosome pathway All >50 genetic associations reported so far account for <30% of all IBD cases Disruption of the Paneth cell granule exocytosis pathway in mice and humans carrying Atg16L1 mutations WT Atg16L1HM* Murine ileum *HM: hypomorphic Normal Atg16L1 mutant Human ileum Cadwell K et al. Curr Topics Microbiol & Immunol. 2009;335:141 Morphological and functional abnormalities in macrophages and Paneth cells carrying autophagy gene mutations Cadwell K et al. Curr Topics Microbiol & Immunol. 2009;335:141 Modulation of autophagy by small molecules Rubinzstein D et al. Nat Rev Drug Discovery. 2007;6:304 Use of sirolimus (rapamycin) to treat refractory Crohn’s disease Massey D et al. Gut 2008;57:1294 Clinical predictive value of complex genetic signatures Gene expression signatures in breast cancer Gene expression signatures in IBD Children carrying 34 or more of the common CD risk alleles have a ~13-fold increased risk of developing CD, while children carrying 20 or more of the common UC risk alleles have a ~7-fold increased risk of developing UC Imielinski M et al. Nat Genetics 2009;41:1335 Sotiriou C, Pusztai L. NEJM 2009;360:790 Gut 2009;58:1612 Inflam Bowel Dis 2010 [Epub ahead of print] IBD: what will benefit the patient? Genetics • • Genetic screening • Creation of IBD, CD, and UC genetic signatures • Prediction of clinical course, response to therapy, and disease outcome • Potential for targeted gene therapy Identification of patient subsetsubset-specific genetic variations The enteric commensal flora 1014 resident microbes 109 probiotic Courtesy of F. Shanahan The Human Microbiome Project “Characterize the microbiome and the factors that influence the distribution and evolution of constituent microorganisms to understand the range of human genetic, physiological and pathological diversity” IBD: “Think in terms of interacting microbial communities rather than individual pathogenic organisms” Turnbaugh PT et al. Nature 2007; 449:804 Eckburg P & Relman D. Clin Infect Dis Nature 2007; 44:256 Microbial communities shape intestinal immune responses in health and disease Round JL & Mazmanian SR. Nat Rev Immunol 2009;9:313 Result of hosthost-bacterial interactions in the gastrointestinal tract Beneficial interaction Detrimental interaction Antibiotics Probiotics Prebiotics “Physiological” inflammation Pathological inflammation (IBD) Antimicrobial, immune and nonnon-immune functions of defensins T-cell, monocyte, mast cell chemotaxis Mast cell Epithelial cell degranulation proliferation Dendritic cell recruitment and maturation Neovascularization, wound closure CpG (TLR9) Bacteria MDP (NOD2) LPS (TLR4) Selsted ME & Oulette AJ, Nat Immunol 2005;5:551 LTA α-defensins, sPLA2, lysozyme, TNF-α, α, matrilysin, CRIP Reduced Paneth cell α-defensins and antimicrobial activity in Nod2 mutated ileal Crohn’s disease HD5 Controls CD ileitis Controls CD ileitis Controls CD ileitis Is there a role for defensin supplementation in IBD therapy? Wehkamp J et al. PNAS 2005; 102:18129 B. fragilis PSA*-mediated prevention of experimental colitis *PSA: polysaccharide A Mechanism of action: induction of ILIL-10 10-producing Treg cells Mazmanian S et al. Nature 2008;453:620 Different frequency (%) of various serologic markers in CD and UC Antibody Controls CD UC ASCA 5 5555-65 5 pANCA <5 1010-25 5050-65 Anti-OmpC <5 3838-50 2 Anti-I2 <5 54 2 Anti-pancreas <5 3030-40 4 Beaven SW and Abreu MT. Curr Opinion Gastroenterol 2004;20:318 Clinical predictive value of combined serologic and genetic parameters Inflam Bowel Dis 2010 [Epub ahead of print] Inflam Bowel Dis 2010 [Epub ahead of print] IBD: what will benefit the patient? Gut flora • Identification of IBDIBD-promoting microbial communities (microbial signatures) • Identification of bacteriabacteria-derived homeostatic or protective molecules • Identification of microbial signatures predictive of disease course and clinical outcome • Complementation of antimicrobial therapy with natural antimicrobials (defensins, etc.) T cell differentiation pathways: one--way, twoone two-way, or going around traffic? Traditional one-way rigid view Novel two-way flexible view O’ Shea H & Paul W. Science 2010;327:1098 Distinct properties of CD and UC mucosal T cells CD: Th1/17 UC: Th2/17 Proliferation Higher Lower ILIL-2Rα expression Higher Lower Cytotoxicity Higher Lower ILIL-2, IFNIFN-γ production Higher Lower ILIL-12 and ILIL-18 production Higher Lower ILIL-4-mediated suppression No Yes Fas ligand expression Lower Higher Bax expression Decreased Normal Telomerase activity Increased Decreased Apoptosis Resistant Susceptible Survivin expression Increased Normal Induction of in vivo T cell apoptosis by azathioprine therapy in IBD patients Tiede I et al. J Clin Invest 2003;111:1133 Antibodies against T cell activation molecules and receptors Antibodies against molecules in the IL-12/IL-23 pathway Antibodies against cell adhesion molecules Antibodies against chemokine receptors Rutgeerts P et al. Gastroenterology, 2009;136:1182 Impact of environmental factors on T cell subset balance Environmental toxins Cytokines Th17 T reg AHR Hormones Th17 T reg Inflammation autoimmunity AHR: aryl hydrocarbon receptor Stevens EA & Bradfield CA. Nature 2008:453:46 Defective innate immunity in Crohn’s disease: impaired erythema, swelling and blood flow upon E. coli injection Control Control Crohn’s disease Marks DJB et al., Lancet 2006;367:668 Altered conditioning of mucosal dendritic in infection & inflammation Tolerogenic DC Immunogenic DC Coombes JL & Powrie F. Nat Rev Immunol 2008;8:435 Regulation of intestinal inflammation by mucosal DCs Food Flora Tolerogenic Immunogenic (Regulatory) (inflammatory) DC DC Host response Physiologic / controlled inflammation IL IL--10 Vitamin D3 Probiotics Corticosteroids Mycophenolate Estrogen Tracolimus Rapamycin Chloroquine Pathologic / uncontrolled inflammation (IBD) Potential therapeutic value of stem cell transplantation Therapeutic targeting of innate immunity with TLR agonists and antagonists X X X X X X X X X X X X X Liew FY et al. Nat Rev Immunol, 2005;5:446 Kinases as therapeutic targets for IBD Canonical Non--canonical Non * Dominguez C et al., Curr Opin Drug Disc Devel 2005;8:421 Gaestel M et al. Nat Rev Drugs 2009;8:480 Damage--associated molecular patterns (DAMPs) Damage PAMPs DAMPs Rubartelli A & Lotze M. Trends Immunol 2007;28:429 EPIGENETICS Definition and relevance to IBD • The study of changes in gene function that are stable and heritable (or potentially heritable) and do not entail changes in DNA sequence • The adaptation of chromosomal regions allowing to perpetuate a local activation state, whether of short or long duration, and whether inherited or not • In IBD an epigenetic stimulus could be environmental, infectious, inflammatory, or immune Maternal factors Genetics In utero nutrition Courtesy of A. Beaudet Toxins Diet Epigenotype (birth) Toxins,drugs Aging Health Epigenotype (adult) Illness IBD Wilson AG. J Periodontol 2008;79:1514 Inflammatory stimuli-induced transcription and chromatin remodelling IL-1β β LPS TNF-α α Inactive promoter: condensed chromatin Ac Ac Histone-coded enzymatically modified (Acetylated) promoter Ac Ac Ac Remodeled & accessible promoter: decondensed chromatin Active promoter H3 H4 Ac Pol II Ac gene transcription Courtesy of E. Stylianou Histone deacetylase inhibitors (HDACi) expand and increase the activity of Tregs Reddy P & Zou W. Nature 2007;13:1281 / Tao et al. Nature 2007;13:1307 Inhibition of HDAC9 increases Treg function and prevents murine colitis De Zoeten E et al. Gastroenterology 2010;138:583 IBD: what will benefit the patient? Immune response • Identification of IBDIBD-specific immune signatures (Th1, Th2, Th17, ThX, etc.) • Blockade of IBD subtypesubtype-specific inflammatory pathways • • Therapeutic modulation of epigenetic changes • Selective deactivation or reconstitution of innate and adaptive immune pathways Cell based therapies (tolerogenic DCs, stem cells, etc.) Angiogenesis blockade as biological therapy for IBD ATN-161 decreases vascular density and improves colitis in experimental IBD ATN-163 ATN-161 15 60 * 40 20 0 10 * 5 0 ATN-163 Danese S et al. Gut 2007;56:855 Histological score Vascular density 80 ATN-161 ATN-163 ATN-161 Impaired lymphatic flow in IBD Inflamed mucosa Increased blood flow Decreased lymphatic flow Lymphatic flow Blood flow OUT IN Leukocytes Courtesy of Dr. S. Danese Fibrostenotic Crohn’s disease Antifibrotic activity of the protein kinase inhibitor imatinib mesylate TGF--β TGF Potential antifibrotic agents Soluble TGFβRII fragments TGFβ antibodies TGFβRII kinase inhibitors TGFβ mRNA inhibitors PKCδ inhibitors Angiotensin inhibitors Rosenbloom J et al. Ann Inter Med 2010; 152:159 IBD: what will benefit the patient? Tissue response • Appreciation of the contribution of the chronic tissue reaction • Prevention of stimulation of nonnon-immune cells by bacterial products • Angiogenesis blockade • Stimulation of lymphatic flow • Blockade of selective propro-fibrogenic pathways Lifetime evolution of IBD ? Unknown ultimate outcome Remission recurrences medications hospitalizations operations cancer, etc. Life before IBD Clinical disease Microscopic disease Abnormal permeability Response / no response to therapy Therapy Diagnosis Immunoregulatory imbalance Birth: Exposure to environment Conception: Genetic susceptibility Triggering event Life after IBD Priming event Early disease Life with IBD Late disease 2.5 5 2.0 IL IL--12 p40 (ng/ml) 6 4 3 2 1 20 15 1.5 10 1.0 5 0.5 0 0 0 Pre Early Late Pre Early Late 300 IL IL--13 (pg/ml) IL IL--4 (pg/ml) Disease activity index Time--dependent immune response in experimental IBD Time 200 100 0 Pre Early Late Pre Early Late 300 200 100 0 Pre Early Late Spencer D et al. Gastroenterology 2002;122:94 Top-down (early Top(early combined immunosuppression) immunosuppression) vs step--up ((conventional step conventional management): management): induction of remission * * * D’Haens G et al. Lancet 371:660; 2008 IBD: what will benefit the patients? Timing of disease • Appreciate the evolution of IBD over time • Understand and differentiate mechanisms of early and late IBD • Customize therapy according to the stage of disease evolution Functional networks among components of IBD pathogenesis Environment Genes Microbes Immunity Environment Genes Microbes Immunity Environment Genes Microbes Immunity Environment Genes Microbes Immunity Volume 10, Number 4, April 2009 Systems biology: complex solutions for complex diseases Gardy JL, et al. Trends Immunol 2009;30:249 Evolution of IBD therapy: from empirical to pathophysiologypathophysiology-based Year Agent 1940’s 1950’s 1960’s 1970’s 1980’s Sulfasalazine ACTH, cortisone Azathioprine 5-ASA 6-MP Metronidazole Elemental diets Cyclosporine Budenoside Methotrexate Antibiotics Biologicals Probiotics, prebiotics Leukapheresis Combination therapies 1990’s (early) 1990’s (late) 2000’s Specificity of action No No No No No No No Yes No No No Yes No No Yes, No Combination of innate and adaptive immunity modulation in experimental IBD LL-mIL10 treatment Healthy control IL-10-/- colitis DSS colitis No treatment Steidler L, et al. Science 2000;298:1352 IBD: what will benefit the patient? Complexity of disease • Recognize and accept the complexity of mechanisms of IBD • Integrate data from multiple disease pathways • Start using system biology approaches for diagnosis and therapy • Routine use of bioinformatics Scientific advances in IBD: what will benefit the patient? • All disciplines investigating “IBD science” at the bench will eventually help clinical practice • How much each discipline may contribute will vary according to the underlying pathogenesis of each type of IBD • A possible “cure” for IBD can only be expected from highly integrated, complementary, and pathophysiologypathophysiologybased therapies CCF QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.