1. 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
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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, and Schatz, Desmond A
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Immunology ,Immunotherapy ,Prevention ,Diabetes ,Clinical Research ,Clinical Trials and Supportive Activities ,2.1 Biological and endogenous factors ,Metabolic and endocrine ,Good Health and Well Being ,Adolescent ,Adult ,Antilymphocyte Serum ,Area Under Curve ,C-Peptide ,CD4-Positive T-Lymphocytes ,CD56 Antigen ,CD8-Positive T-Lymphocytes ,Child ,Diabetes Mellitus ,Type 1 ,Female ,Forkhead Transcription Factors ,Granulocyte Colony-Stimulating Factor ,Humans ,Immunologic Factors ,Killer Cells ,Natural ,Male ,Middle Aged ,Monocytes ,Polyethylene Glycols ,Receptors ,CXCR3 ,Receptors ,IgG ,Recombinant Proteins ,T-Lymphocyte Subsets ,T-Lymphocytes ,Regulatory ,Young Adult ,Medical and Health Sciences ,Endocrinology & Metabolism ,Biomedical and clinical sciences - 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.
- Published
- 2016