92-OR: Defining Type 1 Diabetes Endtypes

To explore T1D heterogeneity, the existence of endotypes, and their possible differential responses to immunotherapy administered at clinical onset, we studied 566 TrialNet clinical trial participants (MMF-DZB, anti-CD20; GAD-alum; CTLA4-Ig; Canakinumab; ATG-GCSF). A bioassay, where participant serum is used to induce transcription in healthy mononuclear cells, and unsupervised cluster analyses were used to identify 2 major groups (Gp1 and Gp2).Proportional analyses of subjects <18 years found Gp1 enriched with participants <14 years old (p=0.03); further Gp1 placebo arm participants exhibited a more rapid C-peptide rate of decline (<-0.15, p=0.02). Pathway analysis of transcriptomic data predicted inflammatory bias in Gp1, that was confirmed by detection of elevated plasma IFNγ, TNFα, and IL-6 levels (p<0.01), and higher memory T-cell abundances. When assessing response to therapy, Gp1 anti-CD20-treated participants exhibited a higher mean C-peptide compared to placebos at 6, 12 and 24 months post-onset (meta-p=0.002 vs 0.27 in Gp2) and a greater delay in the post-onset decline of baseline stimulated C-peptide (11.2 vs 5.4 months). In contrast, Gp2 CTLA4-Ig-treated participants exhibited a higher mean C-peptide compared to placebos at 6, 12, 18 and 24 months (meta p=2e-4 vs. 0.24 in Gp1) and a greater delay in the decline of baseline stimulated C-peptide (8.7 vs 5.8 months). Both Gp1 and Gp2 benefited from ATG treatment, respectively showing 9.5 and 6.7 month delays in the decline in baseline stimulated C-peptide compared to their corresponding placebos. Weighted correlation network analyses of transcriptomic data suggested that varying degrees of immunomodulation occurred in all 6 trials, including those not showing overall efficacy. In line with that observation, Gp2 canakinumab-treated participants showed a 3.4-month delay in the decline in baseline stimulated C-peptide compared to placebos. These data support the existence of two T1D endotypes that exhibit distinct immune phenotypes and therapeutic responsiveness.