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Original Research
Anti-Thymocyte Globulin + G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders with Established Type 1 Diabetes
Michael J. Haller, Stephen E. Gitelman, Peter A. Gottlieb, Aaron W. Michels, Daniel J. Perry, Andrew R. Schultz, Maigan A. Hulme, Jonathan J. Shuster, Baiming Zou, Clive H. Wasserfall, Amanda Posgai, Clayton E. Mathews, Todd M. Brusko, Mark A. Atkinson and Desmond A. Schatz
Diabetes 2016 Sep; db160823. https://doi.org/10.2337/db16-0823
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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+CD56hi 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.

  • Received July 7, 2016.
  • Accepted September 17, 2016.
  • © 2016 by the American Diabetes Association.
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Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

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Anti-Thymocyte Globulin + G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders with Established Type 1 Diabetes
Michael J. Haller, Stephen E. Gitelman, Peter A. Gottlieb, Aaron W. Michels, Daniel J. Perry, Andrew R. Schultz, Maigan A. Hulme, Jonathan J. Shuster, Baiming Zou, Clive H. Wasserfall, Amanda Posgai, Clayton E. Mathews, Todd M. Brusko, Mark A. Atkinson, Desmond A. Schatz
Diabetes Sep 2016, db160823; DOI: 10.2337/db16-0823

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Anti-Thymocyte Globulin + G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders with Established Type 1 Diabetes
Michael J. Haller, Stephen E. Gitelman, Peter A. Gottlieb, Aaron W. Michels, Daniel J. Perry, Andrew R. Schultz, Maigan A. Hulme, Jonathan J. Shuster, Baiming Zou, Clive H. Wasserfall, Amanda Posgai, Clayton E. Mathews, Todd M. Brusko, Mark A. Atkinson, Desmond A. Schatz
Diabetes Sep 2016, db160823; DOI: 10.2337/db16-0823
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