Immunologic and Microbial Mechanisms of Inflammatory Bowel Diseases Therapy Failure

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Abstract

Project Summary Candidate: Simon M Gray, MD, PhD is a fellowship-trained board-eligible Gastroenterologist committed to im- proving the lives of patients with inflammatory bowel diseases (IBD) by understanding the causes of IBD. As a Clinical Instructor of Medicine at the University of North Carolina at Chapel Hill, he is focused on developing strategies to maintain durable IBD remission by understanding triggering events and preventing IBD therapy failure. The specific training objectives of this K08 are to develop expertise in 1) bioinformatic analysis of micro- bial metagenomics and host transcriptomics datasets and 2) statistical modeling of complex datasets. This train- ing will be led by an expert team of 5 mentors/advisors, including R. Balfour Sartor, MD and Timothy Hand, PhD. Environment: UNC-Chapel provides the ideal environment for the proposed research. The NIDDK P30-funded Center for Gastrointestinal Biology and Disease is a community of scientists with synergistic interests and skills in mucosal immunology, gut microbes, and multi-omics that provides a rich reservoir of mentors and advisors who will guide Dr Gray to accomplish the proposed research. UNC hosts the NIH National Gnotobiotic Rodent Resource Center, which is a critical resource for Dr Gray’s germ-free mouse studies. UNC has demonstrated its strong commitment to Dr Gray’s career by providing salary and project support to develop his research program. Research: Over 50% of IBD patients who achieve remission with immune-targeting drugs suffer therapy failure within 3 years despite maintaining therapeutic drug levels. I have developed a first-of-kind pre-clinical mouse model of experimental colitis remission and relapse to study the causes and mechanisms of IBD therapy failure. This model is clinically relevant because it integrates key features of human IBD (human microbes, FDA IBD therapy, a trigger-diet to elicit relapse) in colitis-prone Il-10-/- mice that mirror human IBD. IBD is caused by abnormal CD4+ T-cell mediated immune responses to gut microbes. IBD flares are strongly associated with the pathogenic gut bacterium C difficile. I use human IBD patient derived stool with or without C difficile to induce colitis in ex-germ-free Il-10-/- mice. This replicates clinically relevant disease because I found that 23% of my IBD patients are colonized with C difficile. After developing colitis, Il-10-/- mice achieve disease remission when treated with anti-IL-12/23 monoclonal antibodies, a 1st line FDA-approved human IBD therapy, even with the presence of toxigenic C difficile. Critically, feeding these mice in remission a diet associated with human IBD flares triggers recurrent gut inflammation despite continuing anti-IL12/23 IBD therapy. This therapy failure is associated with a >10-fold expansion of C difficile in the gut. I hypothesize that diet triggers C. difficile to induce chronic gut inflammation, despite anti-IL12/23 blockade, by shifting mucosal immune responses to uninhibited (non-IL12/23) inflammatory pathways driven by expanded CD4+ T cell clones reactive to dominant resident bac- terial antigens. Aim 1 will define the role of C difficile in therapy failure, aim 2 will identify the non-IL12/23 immune pathway(s) mediating therapy failure, and aim 3 will identify the CD4+ T cells expanded in IBD therapy failure.