title: Long-term silencing of autoimmune diabetes and improved life expectancy by a soluble pHLA-DR4 chimera in a newly-humanized NOD/DR4/B7 mouse.
abstract: Several human MHC class II (HLA) molecules are strongly associated with high incidence of autoimmune diseases including type 1 diabetes (T1D). The HLA-humanized mice may thus represent valuable tools to test HLA-based vaccines and therapeutics for human autoimmune diseases. Herein, we have tested the therapeutic potential of a soluble HLA-DR4-GAD65 271-280 (hu DEF-GAD65) chimera of human use in a newly-generated NOD/DR4/B7 double transgenic (dTg) mouse that develops spontaneously an accelerated T1D regardless the gender. The NOD/DR4/B7 dTg mice generated by a two-step crossing protocol express the HLA-DR*0401 molecules on 20% of antigen presenting cells, the human B7 molecules in pancreas, and HLA-DR4/GAD65-specific T-cells in the blood. Some 75% of pre-diabetic NOD/DR4/B7 dTg mice treated with hu DEF-GAD65 chimera remained euglycemic and showed a stabilized pancreatic insulitis 6 months after treatment. The 25% non responders developing hyperglycemia survived 3-4 months longer than their untreated littermates. T1D prevention by this reagent occurred by a Th2/TR-1 polarization in the pancreas. This study strongly suggests that the use of soluble pHLA reagents to suppress/stabilize the T1D progression and to extend the life expectancy in the absence of side effects is an efficient and safe therapeutic approach.
authors: Department of Medicine; Division of Immunology; F. Edward Herbert School of Medicine; Uniformed Services University of the Health Sciences; Bethesda, MD USA.
authors: Luis
authors: L
authors: Pow Sang
authors: Naval Medical Research Center; Walter Reed Army Institute of Research; Infectious Diseases Directorate-Malaria Program; Silver Spring, MD USA.
authors: Sai
authors: S
authors: Majji
authors: Department of Medicine; Division of Immunology; F. Edward Herbert School of Medicine; Uniformed Services University of the Health Sciences; Bethesda, MD USA; Naval Medical Research Center; Walter Reed Army Institute of Research; Infectious Diseases Directorate-Malaria Program; Silver Spring, MD USA.
authors: Sofia
authors: S
authors: Casares
authors: Department of Medicine; Division of Immunology; F. Edward Herbert School of Medicine; Uniformed Services University of the Health Sciences; Bethesda, MD USA.
authors: Teodor D
authors: TD
authors: Brumeanu
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D004195:Disease Models, Animal; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008136:Longevity; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D010179:Pancreas / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000276:immunology*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000949:Histocompatibility Antigens Class II; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2
keywords: HLA-humanized NOD mouse; HLA-peptide chimera; T1D prevention and stabilization