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

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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127248/
https://www.ncbi.nlm.nih.gov/pubmed/27669730
http://dx.doi.org/10.2337/db16-0823
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author 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.
author_facet 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.
author_sort Haller, Michael J.
collection PubMed
description 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(+)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.
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spelling pubmed-51272482017-12-01 Antithymocyte Globulin Plus G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders With Established Type 1 Diabetes 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. Diabetes Pharmacology and Therapeutics 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(+)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. American Diabetes Association 2016-12 2016-09-26 /pmc/articles/PMC5127248/ /pubmed/27669730 http://dx.doi.org/10.2337/db16-0823 Text en © 2016 by the American Diabetes Association. http://www.diabetesjournals.org/content/licenseReaders 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.
spellingShingle Pharmacology and Therapeutics
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.
Antithymocyte Globulin Plus G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders With Established Type 1 Diabetes
title Antithymocyte Globulin Plus G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders With Established Type 1 Diabetes
title_full Antithymocyte Globulin Plus G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders With Established Type 1 Diabetes
title_fullStr Antithymocyte Globulin Plus G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders With Established Type 1 Diabetes
title_full_unstemmed Antithymocyte Globulin Plus G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders With Established Type 1 Diabetes
title_short Antithymocyte Globulin Plus G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders With Established Type 1 Diabetes
title_sort antithymocyte globulin plus g-csf combination therapy leads to sustained immunomodulatory and metabolic effects in a subset of responders with established type 1 diabetes
topic Pharmacology and Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127248/
https://www.ncbi.nlm.nih.gov/pubmed/27669730
http://dx.doi.org/10.2337/db16-0823
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