Mobilization without immune depletion fails to restore immunological tolerance or preserve beta cell function in recent onset type 1 diabetes

Clin Exp Immunol. 2016 Mar;183(3):350-7. doi: 10.1111/cei.12731. Epub 2015 Dec 7.

Abstract

Granulocyte colony-stimulating factor (G-CSF) has been used to restore immune competence following chemoablative cancer therapy and to promote immunological tolerance in certain settings of autoimmunity. Therefore, we tested the potential of G-CSF to impact type 1 diabetes (T1D) progression in patients with recent-onset disease [n = 14; n = 7 (placebo)] and assessed safety, efficacy and mechanistic effects on the immune system. We hypothesized that pegylated G-CSF (6 mg administered subcutaneously every 2 weeks for 12 weeks) would promote regulatory T cell (Treg) mobilization to a degree capable of restoring immunological tolerance, thus preventing further decline in C-peptide production. Although treatment was well tolerated, G-CSF monotherapy did not affect C-peptide production, glycated haemoglobin (HbA1c) or insulin dose. Mechanistically, G-CSF treatment increased circulating neutrophils during the 12-week course of therapy (P < 0·01) but did not alter Treg frequencies. No effects were observed for CD4(+) : CD8(+) T cell ratio or the ratio of naive : memory (CD45RA(+)/CD45RO(+)) CD4(+) T cells. As expected, manageable bone pain was common in subjects receiving G-CSF, but notably, no severe adverse events such as splenomegaly occurred. This study supports the continued exploration of G-CSF and other mobilizing agents in subjects with T1D, but only when combined with immunodepleting agents where synergistic mechanisms of action have previously demonstrated efficacy towards the preservation of C-peptide.

Keywords: clinical trial; granulocyte-colony stimulating factor; human; monotherapy; type 1 diabetes.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • C-Peptide / blood
  • CD4-CD8 Ratio
  • Child
  • Diabetes Mellitus, Type 1 / diagnosis
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / physiopathology
  • Disease Progression
  • Drug Administration Schedule
  • Female
  • Glycated Hemoglobin A / analysis
  • Granulocyte Colony-Stimulating Factor / administration & dosage*
  • Granulocyte Colony-Stimulating Factor / adverse effects
  • Granulocyte Colony-Stimulating Factor / blood
  • Granulocyte Colony-Stimulating Factor / therapeutic use
  • Humans
  • Immune Tolerance*
  • Insulin / therapeutic use
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / physiology*
  • Leukocyte Count
  • Lymphocyte Depletion
  • Male
  • Middle Aged
  • Neutrophils / drug effects
  • Neutrophils / physiology
  • Polyethylene Glycols / administration & dosage*
  • Polyethylene Glycols / adverse effects
  • Polyethylene Glycols / therapeutic use
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / adverse effects
  • Recombinant Proteins / therapeutic use
  • Splenomegaly
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • Young Adult

Substances

  • C-Peptide
  • Glycated Hemoglobin A
  • Insulin
  • Recombinant Proteins
  • Granulocyte Colony-Stimulating Factor
  • Polyethylene Glycols
  • pegylated granulocyte colony-stimulating factor