W105 - Insulin-Reactive T Cells Are Not Deleted in Participants with Early Stage T1D Treated with Oral Insulin

Aaron Michels – University of Colorado; Maki Nakayama – University of Colorado; Alice Wiedeman – Benaroya Research Institute; Hai Nguyen – Benaroya Research Institute; Eddie James – Benaroya Research Institute; Xiaomin Wen – Benaroya Research Institute; William Kwok – Benaroya Research Institute; Maria Redondo – Baylor College of Medicine; Andrea Steck – University of Colorado; Liping Yu – University of Colorado; Brian Bundy – University of South Florida; Susan Geyer – Mayo Clinic; Peter Gottlieb – University of Colorado; TrialNet Oral Insulin Study Group – TrialNet

Abstract Text: Oral insulin (OI) given for 6 months daily (67.5 mg, n=49), but not biweekly (500 mg, n=36, p=0.0066), reduced islet autoantibody levels at 12 months in early stage T1D, suggesting immune modulation. Since T cells regulate autoantibody production, we evaluated insulin-reactive T cells before and during treatment. Insulin-specific CD4 and CD8 T cell frequencies were assessed using Class II tetramer and Class I multimers in HLA-DR*0401(n=31) and HLA-A2 (n=30) participants, respectively, at enrollment, baseline and 3 months. Insulin-specific T cells were reproducibly identified in >80% of samples. No significant changes in T cell frequency were detected following 3 months of treatment. Yet, increased CD4 insulin-specific T cell frequency from baseline to 3 month correlated with reduced insulin autoantibody levels at 6 months in daily OI treated participants (n=15, r=0.51), suggesting linkage between insulin-specific T cells and antibody levels. No change in insulin-specific CD8 T cell frequency was confirmed across participants (n=42) with a range of HLA using tetramer in a CyTOF panel, and a CXCR3+tbet+ memory phenotype, which was enriched in islet-specific cells, also showed no change. By comparison, insulin peptide-reactive CD8 T cell responses detected by IFN-γ ELISPOT were similar at baseline between the groups but lower at 6 and 12 months in daily OI participants (n=18) compared to biweekly treatment (n=16, p< 0.01 at both timepoints). Thus, insulin-reactive CD4 and CD8 T cells can be detected in early stage T1D and are not depleted, suggesting that daily OI may functionally alter T cell responses.