1. Mucosal administration of CD3-specific monoclonal antibody inhibits diabetes in NOD mice and in a preclinical mouse model transgenic for the CD3 epsilon chain
- Author
-
Fabrice Valette, Chantal Kuhn, Francisco J. Quintana, Rafael M. Rezende, Lucienne Chatenoud, Howard L. Weiner, and Andre Pires da Cunha
- Subjects
0301 basic medicine ,CD3 Complex ,medicine.drug_class ,Regulatory T cell ,medicine.medical_treatment ,CD3 ,Immunology ,Mice, Transgenic ,Nod ,Lymphocyte Activation ,Protective Agents ,Monoclonal antibody ,T-Lymphocytes, Regulatory ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Mice, Inbred NOD ,Transforming Growth Factor beta ,In vivo ,Immune Tolerance ,medicine ,Administration, Mucosal ,Animals ,Immunology and Allergy ,Immunity, Mucosal ,NOD mice ,Autoimmune disease ,biology ,Antibodies, Monoclonal ,Immunotherapy ,medicine.disease ,Interleukin-10 ,Disease Models, Animal ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,Female ,030215 immunology - 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.
- Published
- 2017