PMID- 27669730
OWN - NLM
STAT- MEDLINE
DCOM- 20170531
LR  - 20220317
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 65
IP  - 12
DP  - 2016 Dec
TI  - Antithymocyte Globulin Plus G-CSF Combination Therapy Leads to Sustained 
      Immunomodulatory and Metabolic Effects in a Subset of Responders With Established 
      Type 1 Diabetes.
PG  - 3765-3775
AB  - Low-dose antithymocyte globulin (ATG) plus pegylated granulocyte 
      colony-stimulating factor (G-CSF) preserves beta-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.
CI  - (c) 2016 by the American Diabetes Association.
FAU - Haller, Michael J
AU  - Haller MJ
AD  - Department of Pediatrics, University of Florida, Gainesville, FL 
      hallemj@peds.ufl.edu.
FAU - Gitelman, Stephen E
AU  - Gitelman SE
AD  - Department of Pediatrics, University of California, San Francisco, San Francisco, 
      CA.
FAU - Gottlieb, Peter A
AU  - Gottlieb PA
AD  - Department of Pediatrics and Medicine, University of Colorado, Denver, CO.
FAU - Michels, Aaron W
AU  - Michels AW
AD  - Department of Pediatrics and Medicine, University of Colorado, Denver, CO.
FAU - Perry, Daniel J
AU  - Perry DJ
AD  - Department of Pathology, Immunology and Laboratory Medicine, University of 
      Florida, Gainesville, FL.
FAU - Schultz, Andrew R
AU  - Schultz AR
AD  - Department of Pathology, Immunology and Laboratory Medicine, University of 
      Florida, Gainesville, FL.
FAU - Hulme, Maigan A
AU  - Hulme MA
AD  - Department of Biomedical Engineering, University of Florida, Gainesville, FL.
FAU - Shuster, Jonathan J
AU  - Shuster JJ
AD  - Department of Health Outcomes and Policy, University of Florida, Gainesville, FL.
FAU - Zou, Baiming
AU  - Zou B
AD  - Department of Biostatistics, University of Florida, Gainesville, FL.
FAU - Wasserfall, Clive H
AU  - Wasserfall CH
AD  - Department of Pathology, Immunology and Laboratory Medicine, University of 
      Florida, Gainesville, FL.
FAU - Posgai, Amanda L
AU  - Posgai AL
AD  - Department of Pathology, Immunology and Laboratory Medicine, University of 
      Florida, Gainesville, FL.
FAU - Mathews, Clayton E
AU  - Mathews CE
AD  - Department of Pathology, Immunology and Laboratory Medicine, University of 
      Florida, Gainesville, FL.
FAU - Brusko, Todd M
AU  - Brusko TM
AD  - Department of Pathology, Immunology and Laboratory Medicine, University of 
      Florida, Gainesville, FL.
FAU - Atkinson, Mark A
AU  - Atkinson MA
AD  - Department of Pediatrics, University of Florida, Gainesville, FL.
AD  - Department of Pathology, Immunology and Laboratory Medicine, University of 
      Florida, Gainesville, FL.
FAU - Schatz, Desmond A
AU  - Schatz DA
AD  - Department of Pediatrics, University of Florida, Gainesville, FL.
LA  - eng
GR  - P01 AI042288/AI/NIAID NIH HHS/United States
GR  - P30 DK063720/DK/NIDDK NIH HHS/United States
GR  - UL1 TR000004/TR/NCATS NIH HHS/United States
GR  - UL1 TR001427/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20160926
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Antilymphocyte Serum)
RN  - 0 (C-Peptide)
RN  - 0 (CD56 Antigen)
RN  - 0 (CXCR3 protein, human)
RN  - 0 (FOXP3 protein, human)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Immunologic Factors)
RN  - 0 (Receptors, CXCR3)
RN  - 0 (Receptors, IgG)
RN  - 0 (Recombinant Proteins)
RN  - 143011-72-7 (Granulocyte Colony-Stimulating Factor)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - I4QL0KKG3K (pegylated granulocyte colony-stimulating factor)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Antilymphocyte Serum/*therapeutic use
MH  - Area Under Curve
MH  - C-Peptide/metabolism
MH  - CD4-Positive T-Lymphocytes/drug effects/metabolism
MH  - CD56 Antigen/metabolism
MH  - CD8-Positive T-Lymphocytes/drug effects/metabolism
MH  - Child
MH  - Diabetes Mellitus, Type 1/*drug therapy/metabolism
MH  - Female
MH  - Forkhead Transcription Factors/metabolism
MH  - Granulocyte Colony-Stimulating Factor/*therapeutic use
MH  - Humans
MH  - Immunologic Factors/therapeutic use
MH  - Killer Cells, Natural/drug effects/metabolism
MH  - Male
MH  - Middle Aged
MH  - Monocytes/drug effects/metabolism
MH  - Polyethylene Glycols/*therapeutic use
MH  - Receptors, CXCR3/metabolism
MH  - Receptors, IgG/metabolism
MH  - Recombinant Proteins/therapeutic use
MH  - T-Lymphocyte Subsets/drug effects/metabolism
MH  - T-Lymphocytes, Regulatory/drug effects/metabolism
MH  - Young Adult
PMC - PMC5127248
EDAT- 2016/09/28 06:00
MHDA- 2017/06/01 06:00
PMCR- 2017/12/01
CRDT- 2016/09/28 06:00
PHST- 2016/07/07 00:00 [received]
PHST- 2016/09/18 00:00 [accepted]
PHST- 2016/09/28 06:00 [pubmed]
PHST- 2017/06/01 06:00 [medline]
PHST- 2016/09/28 06:00 [entrez]
PHST- 2017/12/01 00:00 [pmc-release]
AID - db16-0823 [pii]
AID - 0823 [pii]
AID - 10.2337/db16-0823 [doi]
PST - ppublish
SO  - Diabetes. 2016 Dec;65(12):3765-3775. doi: 10.2337/db16-0823. Epub 2016 Sep 26.