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

Summary 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 (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  < 0·01) 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.