title: Mucosal administration of CD3-specific monoclonal antibody inhibits diabetes in NOD mice and in a preclinical mouse model transgenic for the CD3 epsilon chain.
abstract: CD3-specific monoclonal antibody (mAb) treats autoimmune disease in animal models and has shown promise in clinical trials of type 1 diabetes. Whereas intravenous administration of CD3-specific mAb acts primarily by transient depletion of activated effector T cells, oral CD3-specific mAb acts primarily by the induction Tregs. We investigated whether oral CD3-specific mAb inhibits disease in non obese diabetic (NOD) mice that spontaneously develop autoimmune diabetes, closely resembling human type 1 diabetes. We found that oral CD3-specific mAb treatment delayed onset and reduced incidence of diabetes in NOD mice, inducing changes in both effector and regulatory T cell compartments. The therapeutic effect was associated with decreased T cell proliferation, decreased IFNγ and IL-17 production, and increased TGF-β and IL-10 production in vitro. In vivo transfer experiments demonstrated that oral CD3-specific mAb decreased diabetogenicity of effector T cells and increased the function of regulatory T cells. Oral OKT3, a monoclonal antibody specific for human CD3 had equivalent effects in transgenic NOD mice expressing the human CD3 epsilon chain which serves as a preclinical model for testing human CD3-specific mAb. These results suggest that oral CD3-specific mAb has the potential for treating autoimmune diabetes in humans.
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Chantal
authors.initials: C
authors.lastname: Kuhn
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rafael M
authors.initials: RM
authors.lastname: Rezende
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andre Pires
authors.initials: AP
authors.lastname: da Cunha
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Université Paris Descartes, Sorbonne Paris Cité, F-75475 Paris, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Valette
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Quintana
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, F-75475 Paris, France; INSERM U1151, CNRS UMR 8253, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Lucienne
authors.initials: L
authors.lastname: Chatenoud
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: hweiner@rics.bwh.harvard.edu.
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
mesh_terms: D058956:Administration, Mucosal; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D017252:CD3 Complex / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D007108:Immune Tolerance; D018928:Immunity, Mucosal; D016753:Interleukin-10 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D020011:Protective Agents / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D020011:Protective Agents; D016212:Transforming Growth Factor beta; D016753:Interleukin-10
keywords: Autoimmune diabetes; CD3 monoclonal antibody; Immunotherapy; Mucosal tolerance; NOD; Treg