title: Immune therapy and β-cell death in type 1 diabetes.
abstract: Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing β-cells. The killing of β-cells is not currently measurable; β-cell functional studies routinely used are affected by environmental factors such as glucose and cannot distinguish death from dysfunction. Moreover, it is not known whether immune therapies affect killing. We developed an assay to identify β-cell death by measuring relative levels of unmethylated INS DNA in serum and used it to measure β-cell death in a clinical trial of teplizumab. We studied 43 patients with recent-onset T1D, 13 nondiabetic subjects, and 37 patients with T1D treated with FcR nonbinding anti-CD3 monoclonal antibody (teplizumab) or placebo. Patients with recent-onset T1D had higher rates of β-cell death versus nondiabetic control subjects, but patients with long-standing T1D had lower levels. When patients with recent-onset T1D were treated with teplizumab, β-cell function was preserved (P < 0.05) and the rates of β-cell were reduced significantly (P < 0.05). We conclude that there are higher rates of β-cell death in patients with recent-onset T1D compared with nondiabetic subjects. Improvement in C-peptide responses with immune intervention is associated with decreased β-cell death.
authors: Departments of Immunobiology and Internal Medicine and Surgery, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Jasmin
authors: J
authors: Lebastchi
authors: Songyan
authors: S
authors: Deng
authors: Amir H
authors: AH
authors: Lebastchi
authors: Isabel
authors: I
authors: Beshar
authors: Stephen
authors: S
authors: Gitelman
authors: Steven
authors: S
authors: Willi
authors: Peter
authors: P
authors: Gottlieb
authors: Eitan M
authors: EM
authors: Akirav
authors: Jeffrey A
authors: JA
authors: Bluestone
authors: Kevan C
authors: KC
authors: Herold
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D002096:C-Peptide / Q000097:blood; D017252:CD3 Complex / Q000737:chemistry; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D019175:DNA Methylation; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007155:Immunologic Factors / Q000627:therapeutic use*; D007167:Immunotherapy; D007328:Insulin / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D019518:Postprandial Period; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D002096:C-Peptide; D017252:CD3 Complex; D007004:Hypoglycemic Agents; D007155:Immunologic Factors; D007328:Insulin; C502540:teplizumab