Understanding clinical aspects of Crohn s disease and ulcerative colitis: Implications for the basic scientist

Transcription

1 Understanding clinical aspects of Crohn s disease and ulcerative colitis: Implications for the basic scientist Scott Plevy, MD Associate Professor of Medicine, Microbiology & Immunology UNC School of Medicine IBD in US: Overview 1,400,000 people with IBD 2,000,000 physician visits/ ,000 hospitalizations/2004 Long-term outlook Chronic, lifelong disease without medical cures Surgery for 50% to 80% of CD patients Surgery for 20% of UC patients Most people live normal, productive lives Decreased quality of life 1

2 Current Theories of Pathogenesis of IBD Genetic Predisposition Ulcerative Colitis Crohn s Disease IBD Immunologic Abnormalities Environmental Factors Research Armamentarium GWAS New genes Functional significance Animal models Characterization of immunologic pathways Microbiome Early, but increasingly important 2

3 Clinical observations best validate our experimental models Disease Location 3

4 Crohn s Disease Endoscopic Appearances Aphthous ulcers Stellate ulcers Longitudinal or serpiginous ulcers Cobble- stoning of mucosa Ulcerative Colitis 4

5 Variable phenotypes in IL-10-/- mice monoassociated with 2 commensal bacteria E. faecalis E. coli E. faecalis Kim SC et al. Gastroenterology 2005 Rutgeerts Endoscopic Scoring System Neoterminal Ileum I,1 I,3 I,4 5

6 Crohn s Disease: Role of Luminal Contents Ileocecal resection, 1 0 anastamosis, recurrence 85% Resection, 1 0 anastamosis, proximal diversion No recurrence Takedown of proximal ostomy recurrence <1 month Reinfusion of luminal contents inflammation within 1 week D Haens et. al, Gastroenterology, 1998; 114:262 A new model of postsurgical bowel inflammation and fibrosis following ileocecal resection in IL-10-/- mice Rigby, R J et al. Gut 2009;58:

7 Environmental Factors Environmental Triggers of IBD Altered mucosal barrier function and/or immunoregulation Altered microbiota Antibiotics Diet IBD Onset and Reactivation Acute infections NSAIDs Smoking Stress 7

8 Smoking is Protective Against UC: The Pittsburgh Experience Reguiero M et al. Inflamm Bowel Dis 2005 CO Ameliorates Colitis in IL-10 -/ - Mice Air CO Average Colitis Score * Air CO 0 Air (n=8) CO (n=12) Hegazi et al., J.Exp.Med.,2005 8

9 Tobacco Smoke Enemas Post-op op Recurrent Crohn s: Influence of Smoking * * * 267/ 584 pt Questionnaire RIR = Relative Incidence Rate Ryan WR. Am J Surg 2004:187:

10 Diet in IBD The first question patients ask is how should I change my diet? Diet provides luminal antigens, serves as substrate for bacterial metabolism and alters microbiota. Bowel bypass (surgical diversion, TPN, elemental or polymeric enteral feedings) decreases inflammation, which returns after restoration of regular diet or fecal flow. Deferoxamine Inhibits Intestinal Cytokines in TCRa-/- Mice 6000 Intestinal Cytokines (pg/ml) PBS DFX-50mg/kg 3xwk/3wks 0 IL-1b TNF IL-17 Hegazi R et al. DDW

11 Concurrence of Gut and Joint Inflammation Evidence from Animal Models T H 1/17 Anti-TNF Germ-free TNF-ARE SAMP1/YitFc HLA-B27 transgenic rodents T reg Clues about Common Pathogenesis from Reactive Arthritis Chronic spondyloarthropy after a gastrointestinal infection with enteroinvasive bacterial strains, such as Yersinia enterocolitica, Salmonella typhimurium and enteriditis, Shigella flexnerii, and Campylobacter jejuni. Shared genes Shared environmental triggers 11

12 Predicting Response to Therapeutics: Lessons from TNF blockade since inflammatory disease is a process than involves several agonists, only drugs which affect most or all of the agonists are likely to be of proven benefit. Drugs which affect one single mediator and/or block one single receptor are unlikely to be helpful. Rachmilewitz D. Gut. 1992;33:1301. Conclusions Learn from the clinic about questions we should be asking in the lab. Model our mice after humans, not the other way around. One mouse doesn t fit all. People trump mice. We can test hypotheses in people. Heterogeneity 12

13 UC The Real Spectrum of IBD IL23R IRGM IBDx ATG16L1 NOD2 IBD CD Th2 panca Treg OmpC ASCA agm-csf CBir1 Th1/17 13