title: Mobilization without immune depletion fails to restore immunological tolerance or preserve beta cell function in recent onset type 1 diabetes.
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.
authors.affiliation: Departments of Pediatric Endocrinology, University of Florida, Gainesville, FL, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Haller
authors.affiliation: Departments of Pediatric Endocrinology, University of Florida, Gainesville, FL, USA.|Immunology, Pathology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Atkinson
authors.affiliation: Immunology, Pathology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Wasserfall
authors.affiliation: Immunology, Pathology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Brusko
authors.affiliation: Immunology, Pathology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Mathews
authors.affiliation: Biomedical Engineering, University of Florida, Gainesville, FL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hulme
authors.affiliation: Departments of Pediatric Endocrinology, University of Florida, Gainesville, FL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cintron
authors.affiliation: Health Outcomes and Policy, University of Florida, Gainesville, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Shuster
authors.affiliation: Immunology, Pathology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: K
authors.initials: K
authors.lastname: McGrail
authors.affiliation: Immunology, Pathology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Posgai
authors.affiliation: Departments of Pediatric Endocrinology, University of Florida, Gainesville, FL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Schatz
mesh_terms: D000293:Adolescent; D000328:Adult; D002096:C-Peptide / Q000097:blood; D016516:CD4-CD8 Ratio; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D006801:Humans; D007108:Immune Tolerance; D007328:Insulin / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D007958:Leukocyte Count; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D013163:Splenomegaly; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D055815:Young Adult
chemical_list: D002096:C-Peptide; D006442:Glycated Hemoglobin; D016179:Granulocyte Colony-Stimulating Factor; D007328:Insulin; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; C423652:pegylated granulocyte colony-stimulating factor
keywords: clinical trial; granulocyte-colony stimulating factor; human; monotherapy; type 1 diabetes