title: Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs.
abstract: Safe induction of autoantigen-specific long-term tolerance is the "holy grail" for the treatment of autoimmune diseases. In animal models of type 1 diabetes, oral or i.n. immunization with islet antigens induces Tregs that are capable of bystander suppression. However, such interventions are only effective early in the prediabetic phase. Here, we demonstrate that a novel combination treatment with anti-CD3epsilon-specific antibody and i.n. proinsulin peptide can reverse recent-onset diabetes in 2 murine diabetes models with much higher efficacy than with monotherapy with anti-CD3 or antigen alone. In vivo, expansion of CD25(+)Foxp3(+) and insulin-specific Tregs producing IL-10, TGF-beta, and IL-4 was strongly enhanced. These cells could transfer dominant tolerance to immunocompetent recent-onset diabetic recipients and suppressed heterologous autoaggressive CD8 responses. Thus, combining a systemic immune modulator with antigen-specific Treg induction is more efficacious in reverting diabetes. Since Tregs act site-specifically, this strategy should also be expected to reduce the potential for systemic side effects.
authors.affiliation: Department of Developmental Immunology-3, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
authors.forename: Damien
authors.initials: D
authors.lastname: Bresson
authors.forename: Lisa
authors.initials: L
authors.lastname: Togher
authors.forename: Evelyn
authors.initials: E
authors.lastname: Rodrigo
authors.forename: Yali
authors.initials: Y
authors.lastname: Chen
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
authors.forename: Kevan C
authors.initials: KC
authors.lastname: Herold
authors.forename: Matthias
authors.initials: M
authors.lastname: von Herrath
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage / Q000627:therapeutic use*; D017252:CD3 Complex / Q000737:chemistry* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control* / Q000628:therapy*; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D011384:Proinsulin / Q000008:administration & dosage / Q000627:therapeutic use*; D012074:Remission Induction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D001324:Autoantigens; D017252:CD3 Complex; C485468:Cd3e protein, mouse; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4; D011384:Proinsulin