Antithymocyte Globulin Plus G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders With Established Type 1 Diabetes
| Autor: | Daniel J. Perry, Maigan A. Hulme, Andrew R Schultz, Baiming Zou, Todd M. Brusko, Aaron W. Michels, Desmond A. Schatz, Amanda L. Posgai, Mark A. Atkinson, Stephen E. Gitelman, Peter A. Gottlieb, Clive Wasserfall, Jonathan J. Shuster, Clayton E. Mathews, Michael J. Haller |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
CD4-Positive T-Lymphocytes Male Endocrinology Diabetes and Metabolism T-Lymphocytes CD8-Positive T-Lymphocytes CXCR3 T-Lymphocytes Regulatory Medical and Health Sciences Monocytes Polyethylene Glycols Immunophenotyping T-Lymphocyte Subsets Granulocyte Colony-Stimulating Factor Receptors Killer Cells Child C-Peptide Area under the curve FOXP3 Forkhead Transcription Factors Middle Aged Regulatory Recombinant Proteins CD56 Antigen 3. Good health Killer Cells Natural Area Under Curve Natural Female Type 1 Adult medicine.medical_specialty Receptors CXCR3 Combination therapy Adolescent IgG Biology 03 medical and health sciences Young Adult Endocrinology & Metabolism Diabetes mellitus Internal medicine Internal Medicine medicine Diabetes Mellitus Humans Immunologic Factors Antilymphocyte Serum Type 1 diabetes Receptors IgG medicine.disease Pharmacology and Therapeutics 030104 developmental biology Endocrinology Diabetes Mellitus Type 1 CD8 |
| Zdroj: | Diabetes, vol 65, iss 12 Diabetes |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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