Editor’s summary
The U.S. FDA recently approved the immune-targeted therapy teplizumab as the first disease-modifying therapy for delaying onset of type 1 diabetes (T1D) in at-risk individuals. Examining participant data from the TrialNet 10 trial that supported this decision, Xie et al. now report that IgG2 antibodies against three gut microbial commensals are associated with the teplizumab response and with time to T1D diagnosis. They also found evidence of these relationships in an independent clinical trial, suggesting that anticommensal immune responses may play a role in T1D progression and may additionally be useful to identify individuals who will benefit from treatment in this setting. —Catherine Charneski
Abstract
Immune-targeted therapies have efficacy for treatment of autoinflammatory diseases. For example, treatment with the T cell–specific anti-CD3 antibody teplizumab delayed disease onset in participants at high risk for type 1 diabetes (T1D) in the TrialNet 10 (TN-10) trial. However, heterogeneity in therapeutic responses in TN-10 and other immunotherapy trials identifies gaps in understanding disease progression and treatment responses. The intestinal microbiome is a potential source of biomarkers associated with future T1D diagnosis and responses to immunotherapy. We previously reported that antibody responses to gut commensal bacteria were associated with T1D diagnosis, suggesting that certain antimicrobial immune responses may help predict disease onset. Here, we investigated anticommensal antibody (ACAb) responses against a panel of taxonomically diverse intestinal bacteria species in sera from TN-10 participants before and after teplizumab or placebo treatment. We identified IgG2 responses to three species that were associated with time to T1D diagnosis and with teplizumab treatment responses that delayed disease onset. These antibody responses link human intestinal bacteria with T1D progression, adding predictive value to known T1D risk factors. ACAb analysis provides a new approach to elucidate heterogeneity in responses to immunotherapy and identify individuals who may benefit from teplizumab, recently approved by the U.S. Food and Drug Administration for delaying T1D onset.
