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Download Integrating model organisms to the study of human IBD
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Lauri Diehl, Sr. Scientist/Pathologist, Genentech December 5, 2014 Rodents are the model organisms of choice for IBD-related research Mouse most common used Inbred strains Ease of genetic manipulation Reagent availability Cost Housing space Spontaneous colitis occurs in several species Humane considerations Etiology? Reliance on murine models is controversial Virtually every major medical Despite some outstanding drugdevelopment successes, the mouse version of multiple sclerosis has been worryingly unreliable at screening human treatments. advance for both humans and animals has been achieved through biomedical research using animal models to study and find a cure for a disease and through animal testing to J. Rice prove the safety and efficacy of a new Nature Outlook April 2012 treatment. C. Everett Koop, M.D Former U.S. Surgeon General (Genomic) responses in corresponding mouse models correlate poorly with (acute inflammatory) human conditions… J. Seok et al, PNAS, 2013 How are mouse colitis models used? Basic scientific research Mucosal immunology IBD pathogenesis Anatomic and immunologic differences between human and mouse Preclinical efficacy testing Drives industry decision making Predictive value? Pharmacokinetics Biomarker studies Predictive and/or pharmacodynamic markers Earlier and more diverse hypothesis testing What is the best IBD model? Better question is “what do we need from this model?” Genetics Location of interest Lesion of interest Response to control Cell type of interest Molecule of interest Pathway of interest Experimental goals should drive model choice Many murine colitis/enteritis models exist Genetic (spontaneous or induced) Chemical Degree of characterization varies Pathway involvement Impact of local microflora environment Degree of technical difficulty varies may influence model selection inappropriately Published data should be approached with caution Commonly used “workhorse” intestinal inflammation models Chemical-induced colitis DSS colitis, TNBS colitis Rapid and reproducible induction of colitis Use widely available mouse strains Immune-mediated colitis models Transfer colitis, IL-10KO colitis May be more technically challenging and time consuming DSS colitis model is used to query acute disease manifestations Dextran sodium sulfate in drinking water Widely used for preclinical efficacy studies Suitable for genetically modified mice Study duration varies and may impact pathway involvement Has minimal T cell involvement Best suited for studying epithelial (short duration) or myeloid/innate immune (longer duration) effects Cox et al, 2012 Genetic considerations can be a basis for model selection More than 160 IBD susceptibility genes/loci identified with many shared between UC and Crohn’s Are models based on human genetics useful for preclinical efficacy or biomarker studies? IL-10 KO TL1A (TNSF15) Tg Jostins et al, Nature, 2012 IL-10KO colitis model Human IL-10 and IL-10R polymorphisms associated with very early onset IBD (dx at less than 6 years of age) Loss of function mutations Severe disease, colon only IL-10KO – spontaneous chronic colon inflammation Gradual onset, variable disease penetrance Mouse strain dependent 129/Sv > Balb/c > C57BL/6 Microflora dependent Amplified by NSAIDS Benefits and caveats as an IBD model? Pathway of interest represented? May need to validate in model Shah et al, Curr Allergy Asthma Rep, 2012 Model validation needs depend on scientific question General validation criteria Reproducibility IL-10 KO respond to anti-TNF Disease incidence IL-10KO often requires piroxicam tx Experimental observation Specific validation criteria Response to control treatment Treatment response in IL-10KO Anti-TNF therapy – variable Anti-p40 – highly effective Relationship to human response? Pathways of interest Anatomic localization of lesions Colon vs. intestine, mucosal vs. submucosal Especially for fibrosis questions Scheinin et al, Clin Exp Immunol, 2003 Does this look like Crohn’s disease? Does TNFdeltaARE model phenocopy CD? Chronic TNFa elevation Deletion of TNF AU-rich elements (ARE) ARE mediate TNFa transcript degradation Posttranscriptional regulatory mechanism Kontoyiannis et al, Immunity, 1999 Ileitis and arthritis Normal ileum Transmural inflammation, noncaseating granulomas, no submucosal fibrosis TNFa inhibition is protective TNFdeltaARE het Crohn’s disease Murine model of submucosal fibrosis would be valuable No animal model described which develops the morphologic features of human fibrostenotic disease Rat models described (not widely used) Mouse models preferred Chronic inflammation, no smooth muscle proliferation Mouse models have been described Chemical models – chronic DSS, chronic TNBS Infectious models – chronic Salmonella Chronic streptomycin tx required Presence of active infection is problematic Genetic models – TL1a transgenic Salmonella enterica Grassl et al, 2008 TL1A Transgenic mouse model TL1A interaction with DR3 increases IFN-g and IL-17 Polymorphism may predispose to fibrostenotic disease in Crohn’s patients Tg mice (T or myeloid cell overexpression) develop mild enteritis Ileal involvement and collagen deposition (“fibrosis”), no smooth muscle proliferation Is this suitable for specific questions? What validation would be needed? Aiba et al, Med Inflam, 2013 Barrett et al, Am J Path, 2012 Crohn’s disease Integrating model organisms to the study of human IBD Understanding the suitability of animal models is important when evaluating published data Successful integration of animal models into IBD research requires a clear understanding of the scientific question. There is no model which is suitable for every question and, for some questions, none of the established models may be ideal. We need to guide the discussion toward questions which can enable successful study decisions and make best use of scarce resources
