Abstract

Low-dose anti-thymocyte globulin (ATG) + pegylated granulocyte-colony stimulating factor (G-CSF) preserves beta cell function for at least 12-months in type 1 diabetes (T1D). Herein, we describe metabolic and immunologic parameters 24-months following treatment. Patients with established T1D (duration 4-24 months) were randomized to ATG and peg-G-CSF (N=17) or placebo (N=8). Primary outcomes included AUC C-peptide following mixed-meal tolerance test (MMTT) and flow cytometry. “Responders” (12-month C-peptide ≥ baseline), “Super-responders” (24-month C-peptide ≥ baseline), and “Non-responders” (12-month C-peptide < baseline) were evaluated for biomarkers of outcome. At 24-months, MMTT-stimulated AUC C-peptide was not significantly different in ATG+G-CSF (0.49nmol/L/min) versus placebo (0.29nmol/L/min). ATG+G-CSF-treated subjects demonstrated reduced CD4⁺ T-cells and CD4⁺/CD8⁺ T-cell ratio and increased CD16⁺CD56^hi natural killer cells (NK), CD4⁺ T-effector memory cells (Tem), CD4⁺PD-1⁺ T-central memory cells (Tcm), Tcm PD-1 expression, and neutrophils. FOXP3⁺Helios⁺ regulatory T-cells (Treg) were elevated in ATG+G-CSF subjects at 6, 12, and 18 but not 24-months. Immunophenotyping identified differential HLA-DR expression on monocytes and NK, and altered CXCR3 and PD-1 expression on T-cell subsets. As such, a group of metabolic and immunologic responders was identified. A phase-II study of ATG+G-CSF in new-onset T1D patients is ongoing and may support ATG+G-CSF as a prevention strategy in high-risk subjects.