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Diabetes. 2016 Dec;65(12):3765-3775. Epub 2016 Sep 26.

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

Author information

1
Department of Pediatrics, University of Florida, Gainesville, FL hallemj@peds.ufl.edu.
2
Department of Pediatrics, University of California, San Francisco, San Francisco, CA.
3
Department of Pediatrics and Medicine, University of Colorado, Denver, CO.
4
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.
5
Department of Biomedical Engineering, University of Florida, Gainesville, FL.
6
Department of Health Outcomes and Policy, University of Florida, Gainesville, FL.
7
Department of Biostatistics, University of Florida, Gainesville, FL.
8
Department of Pediatrics, University of Florida, Gainesville, FL.

Abstract

Low-dose antithymocyte globulin (ATG) plus pegylated granulocyte colony-stimulating factor (G-CSF) preserves β-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 "nonresponders" (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+CD56hi 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.

PMID:
27669730
PMCID:
PMC5127248
DOI:
10.2337/db16-0823
[Indexed for MEDLINE]
Free PMC Article

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