Journal
CLINICAL AND EXPERIMENTAL IMMUNOLOGY
Volume 183, Issue 3, Pages 350-357Publisher
WILEY
DOI: 10.1111/cei.12731
Keywords
clinical trial; granulocyte-colony stimulating factor; human; monotherapy; type 1 diabetes
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Funding
- JDRF [11-2007-825]
- NIH [DK078863]
- NIH (NCATS) grant [UL1 TR000064]
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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 (6mg administered subcutaneously every 2 weeks for 12 weeks) would promote regulatory T cell (T-reg) 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<001) but did not alter T-reg 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.
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