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

作者：Haller M J^*; Atkinson M A; Wasserfall C H; Brusko T M; Mathews C E; Hulme M; Cintron M; Shuster J; McGrail K; Posgai A; Schatz D

来源：Clinical and Experimental Immunology, 2016, 183(3): 350-357.

DOI：10.1111/cei.12731

• clinical trial
• granulocyte-colony stimulating factor
• human
• monotherapy
• type 1 diabetes

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.

• 出版日期2016-3