Antithymocyte Globulin Plus G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders With Established Type 1 Diabetes

作者：Haller Michael J^*; Gitelman Stephen E; Gottlieb Peter A; Michels Aaron W; Perry Daniel J; Schultz Andrew R; Hulme Maigan A; Shuster Jonathan J; Zou Baiming; Wasserfall Clive H; Posgai Amanda L; Mathews Clayton E; Brusko Todd M; Atkinson Mark A; Schatz Desmond A

来源：Diabetes, 2016, 65(12): 3765-3775.

DOI：10.2337/db16-0823

Low-dose antithymocyte globulin (ATG) plus pegylated granulocyte colony-stimulating factor (G-CSF) preserves beta-cell function for at least 12 months in type 1 diabetes. Herein, we describe metabolic and immunological parameters 24 months following treatment. Patients with established type 1 diabetes (duration 4-24 months) were randomized to ATG and pegylated G-CSF (ATG+G-CSF) (N = 17) or placebo (N = 8). Primary outcomes included C-peptide area under the curve (AUC) following a 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 (0.49 nmol/L/min) versus placebo (0.29 nmol/L/min). Subjects treated with ATG(+)G-CSF demonstrated reduced CD4(+) T cells and CD4(+)/CD8(+) T-cell ratio and increased CD16(+)CD56(hi) natural killer cells (NK), CD4(+) effector memory T cells (Tem), CD4(+)PD-1(+) central memory T 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 immunological responders was identified. A phase II study of ATG+G-CSF in patients with new-onset type 1 diabetes is ongoing and may support ATG+G-CSF as a prevention strategy in high-risk subjects.

• 出版日期2016-12