A Preclinical Consortium Approach for Assessing the Efficacy of Combined Anti-CD3 Plus IL-1 Blockade in Reversing New-Onset Autoimmune Diabetes in NOD Mice

Ronald G. Gill, Philippe P. Pagni, Tinalyn Kupfer, Clive H. Wasserfall, Songyan Deng, Amanda Posgai, Yulia Manenkova, Amira Bel Hani, Laura Straub, Philip Bernstein, Mark A. Atkinson, Kevan C. Herold, Matthias von Herrath, Teodora Staeva, Mario R. Ehlers, Gerald T. Nepom

There is an ongoing need develop strategic combinations of therapeutic agents to prevent type 1 diabetes (T1D) or to preserve islet beta cell mass in new-onset disease. While clinical trials using candidate therapeutics are commonly based on preclinical studies, there is growing concern regarding the reproducibility as well as the potential clinical translation of reported results using animal models of human disorders. In response, the NIH Immune Tolerance Network and JDRF established a multi-center consortium of academic institutions designed to assess the efficacy and inter-group reproducibility of clinically applicable immunotherapies for reversing new-onset disease in the non-obese diabetic (NOD) mouse model of T1D. Predicated on prior studies, this consortium conducted coordinated, prospective studies utilizing joint standard operating procedures, fixed study entry criteria, and common reagents to optimize combined anti-CD3 treatment plus IL-1 blockade to reverse new-onset disease in NOD mice. We did not find that IL-1 blockade with either anti-IL-1β monoclonal antibody (mAb) or IL-1trap provided additional benefit for reversing new-onset disease compared to anti-CD3 treatment alone. These results demonstrate the value of larger, multicenter preclinical studies for vetting and prioritizing therapeutics for future clinical use.