title: DNA vaccination with an insulin construct and a chimeric protein binding to both CTLA4 and CD40 ameliorates type 1 diabetes in NOD mice.
abstract: Type 1 diabetes (T1D), a T-cell-mediated autoimmune disease, could be attributed to many defects in nonobese diabetic (NOD) mice, including deficient expressions of costimulatory molecules that impair antigen presentation. Thus, this deficient antigen presentation may result in a reduced ability to induce a tolerogenic response through negative selection/regulation of autoreactive T cells. Improperly activated T cells seem to be able to induce autoimmune responses causing diabetes. To re-establish tolerance to autoantigens by modulating costimulation, we constructed and tested a new type of DNA vaccine encoding a membrane-bound preproinsulin (mbPPI) and a chimeric gene vector encoding mutant B7.1/CD40L (mB7.1/CD40L) fusion protein. This mutant B7.1 binds CTLA4 but not CD28. We report that young NOD mice immunized with mbPPI along with mB7.1/CD40L DNA vectors significantly reduced diabetes incidence while treatment with CTLA4/IgG1 exacerbated diabetes. In conclusion, the combination of mbPPI and mB7.1/CD40L was able to protect against autoimmunity and diabetes in NOD mice possibly by promoting a more efficient presentation of autoantigen PPI and inducing specific tolerance to PPI by negatively regulating autoreactive T cells.
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh, School of Medicine, Rangos Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chang
authors.forename: S
authors.initials: S
authors.lastname: Yap
authors.forename: X
authors.initials: X
authors.lastname: Ge
authors.forename: J
authors.initials: J
authors.lastname: Piganelli
authors.forename: S
authors.initials: S
authors.lastname: Bertera
authors.forename: N
authors.initials: N
authors.lastname: Giannokakis
authors.forename: C
authors.initials: C
authors.lastname: Mathews
authors.forename: G
authors.initials: G
authors.lastname: Prud'homme
authors.forename: M
authors.initials: M
authors.lastname: Trucco
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics* / Q000276:immunology; D019013:CD40 Antigens / Q000235:genetics* / Q000276:immunology; D019556:COS Cells; D060908:CTLA-4 Antigen; D002522:Chlorocebus aethiops; D004247:DNA / Q000008:administration & dosage*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000628:therapy*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D015870:Gene Expression; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D007108:Immune Tolerance; D007273:Injections, Intramuscular; D007328:Insulin; D051379:Mice; D016688:Mice, Inbred NOD; D011384:Proinsulin / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D011498:Protein Precursors / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007328:Insulin; D011498:Protein Precursors; C013737:preproinsulin; D004247:DNA; D011384:Proinsulin