Tu136 - Immune Responses to Gut Bacteria Associated with Time to Diagnosis and Clinical Response to T-cell Directed Therapy for Type 1 Diabetes Prevention

Sean Oh, MSc. – Laboratory Research Project Coordinator, Genetics and Genome Biology, The Hospital for Sick Children; Christopher Yau, MSc. – PhD Candidate, Immunology, University of Toronto; Kevan Herold, MD – CNH Long Professor, Immunobiology and Internal Medicine, Yale University; Jayne Danska, PhD – Tanenbaum Chair in Molecular Medicine, Senior Scientist, Genetics and Genome Biology, Hospital for Sick Children Research Institute

Abstract Text: Immune-targeted therapies have demonstrated efficacy for treatment of several auto-inflammatory diseases. For example, a single treatment course with the T cell-specific anti-CD3 monoclonal antibody teplizumab delayed disease onset in participants at high risk for Type 1 Diabetes (T1D) in the TN-10 trial. However, heterogeneity in therapeutic responses observed in TN-10 and other immunotherapy trials identify the need to improve prediction of disease progression and treatment responses. The intestinal microbiome is a potential source of new biomarkers, but extensive bacterial sequencing studies have not identified either single, or consortia of species associated with future T1D diagnosis in at-risk cohorts. In contrast, we reported that antibody responses to gut commensal bacteria were associated with T1D diagnosis suggesting that immune reactivities to these microbes may help predict disease onset. Here, we examined anti-commensal antibody (ACAb) responses against cultured intestinal bacterial species in serum sampled from TN-10 participants before and after randomization into teplizumab or placebo treatment arms. We identified IgG2 responses to three taxonomically distinct species that were associated with time to T1D diagnosis and with treatment responses. These ACAb are the first biomarkers linking human intestinal bacteria with T1D progression. Measures of these ACAb responses before teplizumab treatment added value to known T1D risk factors in predictive models. Thus, ACAb responses may help identify individuals who will benefit from teplizumab, a drug recently approved by the U.S. FDA for use in delaying T1D onset.