title: Autoantigen-specific regulatory T cells induced in patients with type 1 diabetes mellitus by insulin B-chain immunotherapy.
abstract: There is a growing body of evidence to suggest that the autoimmunity observed in type 1 diabetes mellitus (T1DM) is the result of an imbalance between autoaggressive and regulatory cell subsets. Therapeutics that supplement or enhance the existing regulatory subset are therefore a much sought after goal in this indication. Here, we report the results of a double blind, placebo controlled, phase I clinical trial of a novel antigen-specific therapeutic in 12 subjects with recently diagnosed T1DM. Our primary objective was to test its safety. The study drug, human insulin B-chain in incomplete Freund's adjuvant (IFA) was administered as a single intramuscular injection, with subjects followed for 2 years. All subjects completed therapy and all follow-up visits. The therapy was generally safe and well-tolerated. Mixed meal stimulated C-peptide responses, measured every 6 months, showed no statistical differences between arms. All patients vaccinated with the autoantigen, but none who received placebo, developed robust insulin-specific humoral and T cell responses. Up to two years following the single injection, in peripheral blood from subjects in the experimental arm, but not the control arm, insulin B-chain-specific CD4+ T cells could be isolated and cloned that showed phenotypic and functional characteristics of regulatory T cells. The induction of a lasting, robust immune response generating autoantigen-specific regulatory T cells provides strong justification for further testing of this therapy in type 1 diabetes. (clinicaltrials.gov identifier NCT00057499).
authors.affiliation: Joslin Diabetes Center, Boston, MA 02215, USA. torban@joslin.harvard.edu <torban@joslin.harvard.edu>
authors.forename: Tihamer
authors.initials: T
authors.lastname: Orban
authors.forename: Klara
authors.initials: K
authors.lastname: Farkas
authors.forename: Heyam
authors.initials: H
authors.lastname: Jalahej
authors.forename: Janos
authors.initials: J
authors.lastname: Kis
authors.forename: Andras
authors.initials: A
authors.lastname: Treszl
authors.forename: Ben
authors.initials: B
authors.lastname: Falk
authors.forename: Helena
authors.initials: H
authors.lastname: Reijonen
authors.forename: Joseph
authors.initials: J
authors.lastname: Wolfsdorf
authors.forename: Alyne
authors.initials: A
authors.lastname: Ricker
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Matthews
authors.forename: Nadio
authors.initials: N
authors.lastname: Tchao
authors.forename: Peter
authors.initials: P
authors.lastname: Sayre
authors.forename: Pete
authors.initials: P
authors.lastname: Bianchine
mesh_terms: D000293:Adolescent; D000328:Adult; D001324:Autoantigens / Q000008:administration & dosage* / Q000627:therapeutic use; D015551:Autoimmunity / Q000187:drug effects; D049109:Cell Proliferation; D002999:Clone Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000628:therapy; D004311:Double-Blind Method; D006801:Humans; D007167:Immunotherapy; D007328:Insulin / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome; D014611:Vaccination; D055815:Young Adult
chemical_list: D001324:Autoantigens; D007328:Insulin