title: Soluble, dimeric HLA DR4-peptide chimeras: an approach for detection and immunoregulation of human type-1 diabetes.
abstract: Still there are no effective methods to predict or cure type 1 diabetes (T1D) in humans. Soluble, dimeric MHC class II-peptide (DEF) chimeras have potential for both early diagnosis and immunospecific therapy. DEF chimeras prevent and reverse diabetes in mice by stimulating antigen-specific type 1 T regulatory cell (Tr1)-like cells. We also showed that diabetes could be predicted by changes in the phenotype of autoreactive CD4 T cells in peripheral blood. Herein, we demonstrated that human DEF (HLA-DR*0401/Fcgamma1) chimeras expressing peptides of beta-cell antigens stimulate Tr1-like cells in blood of patients with T1D, non-diabetic relatives, and controls. Furthermore, the specific and stable binding of DEF chimeras to cognate TCR and CD4 coreceptor allowed quantification and phenotyping of autoreactive CD4 T cells in non-stimulated blood by FACS. Our results indicate that (1) autoreactive CD4 T cells to GAD65 autoantigen are commonly present in humans expressing diabetes-susceptible HLA-DR*0401 molecules; (2) these autoreactive T cells undergo avidity maturation upon encountering the self antigen early in life; (3) the disease is associated with an imbalance between autoreactive CD4+CD25+ and CD4+CD69+ T cells specific for GAD65. Based on this, we propose a model to explain the kinetics of autoreactive CD4 T cells in blood during the natural history of T1D.
authors.affiliation: Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Ioana
authors.initials: I
authors.lastname: Preda
authors.forename: Robert C
authors.initials: RC
authors.lastname: McEvoy
authors.forename: Marvin
authors.initials: M
authors.lastname: Lin
authors.forename: Constantin A
authors.initials: CA
authors.lastname: Bona
authors.forename: Robert
authors.initials: R
authors.lastname: Rapaport
authors.forename: Teodor D
authors.initials: TD
authors.lastname: Brumeanu
authors.forename: Sofia
authors.initials: S
authors.lastname: Casares
mesh_terms: D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000276:immunology* / Q000628:therapy; D019281:Dimerization; D005260:Female; D005434:Flow Cytometry; D005968:Glutamate Decarboxylase / Q000276:immunology*; D015804:HLA-DR4 Antigen / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D007527:Isoenzymes / Q000276:immunology*; D037181:Lectins, C-Type; D008297:Male; D008875:Middle Aged; D015375:Receptors, Interleukin-2 / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D005968:Glutamate Decarboxylase; D015804:HLA-DR4 Antigen; D007527:Isoenzymes; D037181:Lectins, C-Type; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D000099192:CD69 Antigens; C401141:glutamate decarboxylase 2