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 (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+CD56hinatural 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.
Department of Pediatrics, University of Florida, Gainesville, FL hallemj@peds.ufl.edu.
Michael J
MJ
Haller
Department of Pediatrics, University of California, San Francisco, San Francisco, CA.
Stephen E
SE
Gitelman
Department of Pediatrics and Medicine, University of Colorado, Denver, CO.
Peter A
PA
Gottlieb
Department of Pediatrics and Medicine, University of Colorado, Denver, CO.
Aaron W
AW
Michels
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.
Daniel J
DJ
Perry
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.
Andrew R
AR
Schultz
Department of Biomedical Engineering, University of Florida, Gainesville, FL.
Maigan A
MA
Hulme
Department of Health Outcomes and Policy, University of Florida, Gainesville, FL.
Jonathan J
JJ
Shuster
Department of Biostatistics, University of Florida, Gainesville, FL.
Baiming
B
Zou
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.
Clive H
CH
Wasserfall
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.
Amanda L
AL
Posgai
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.
Clayton E
CE
Mathews
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.
Todd M
TM
Brusko
Department of Pediatrics, University of Florida, Gainesville, FL.|Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.
Mark A
MA
Atkinson
Department of Pediatrics, University of Florida, Gainesville, FL.
Desmond A
DA
Schatz
D000293:Adolescent; D000328:Adult; D000961:Antilymphocyte Serum / Q000627:therapeutic use*; D019540:Area Under Curve; D002096:C-Peptide / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D019002:CD56 Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D054367:Receptors, CXCR3 / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism; D055815:Young Adult
D000961:Antilymphocyte Serum; D002096:C-Peptide; D019002:CD56 Antigen; C515187:CXCR3 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007155:Immunologic Factors; D054367:Receptors, CXCR3; D017452:Receptors, IgG; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D011092:Polyethylene Glycols; C423652:pegylated granulocyte colony-stimulating factor
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