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+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.






Haller MJ,Gitelman SE,Gottlieb PA,Michels AW,Perry DJ,Schultz AR,Hulme MA,Shuster JJ,Zou B,Wasserfall CH,Posgai AL,Mathews CE,Brusko TM,Atkinson MA,Schatz DA




Has Abstract


2016-12-01 00:00:00
















  • In vivo cytotoxicity of insulin-specific CD8+ T-cells in HLA-A*0201 transgenic NOD mice.

    abstract:OBJECTIVE:CD8(+) T-cells specific for islet antigens are essential for the development of type 1 diabetes in the NOD mouse model of the disease. Such T-cells can also be detected in the blood of type 1 diabetic patients, suggesting their importance in the pathogenesis of the human disease as well. The development of pe...


    pub_type: 杂志文章


    authors: Jarchum I,Baker JC,Yamada T,Takaki T,Marron MP,Serreze DV,DiLorenzo TP

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  • Unaltered class II histocompatibility antigens and pathogenesis of IDDM in BB rats.

    abstract::The BB rat spontaneously develops insulin-dependent diabetes mellitus (IDDM) as an autoimmune abnormality involving the class II molecules of the major histocompatibility complex (MHC). The rat MHC (RT1 complex) encodes two class II loci, RT1.B and RT1.D. The possibility that variant or unique class II MHC molecules m...


    pub_type: 杂志文章


    authors: Holowachuk EW,Greer MK

    更新日期:1989-02-01 00:00:00

  • Effect of exogenous phospholipase A2 on insulin secretion from perifused rat islets.

    abstract::Treatment of isolated, perifused rat islets with exogenous PLA2 in amounts ranging from 1 to 1000 mU/ml caused a dose-dependent increase in the rate of insulin secretion. This effect of PLA2 was rapid and seen in the absence of added exogenous fuel. It differed from glucose-induced insulin release in temporal pattern:...


    pub_type: 杂志文章


    authors: Zawalich W,Zawalich K

    更新日期:1985-05-01 00:00:00

  • Combination therapy with glucagon-like peptide-1 and gastrin restores normoglycemia in diabetic NOD mice.

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  • Autosomal-dominant mode of inheritance of a melanocortin-4 receptor mutation in a patient with severe early-onset obesity is due to a dominant-negative effect caused by receptor dimerization.

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    authors: Hamilton-Wessler M,Bergman RN,Halter JB,Watanabe RM,Donovan CM

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    pub_type: 杂志文章,随机对照试验


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    pub_type: 杂志文章


    authors: Virji MA,Steffes MW,Estensen RD

    更新日期:1984-02-01 00:00:00

  • Reduction of diabetes-induced oxidative stress, fibrotic cytokine expression, and renal dysfunction in protein kinase Cbeta-null mice.

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    authors: Walsh MF,Pek SB

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    pub_type: 杂志文章,评审


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