Document Detail


DNA vaccination with an insulin construct and a chimeric protein binding to both CTLA4 and CD40 ameliorates type 1 diabetes in NOD mice.
MedLine Citation:
PMID:  16107864     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Y Chang; S Yap; X Ge; J Piganelli; S Bertera; N Giannokakis; C Mathews; G Prud'homme; M Trucco
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Gene therapy     Volume:  12     ISSN:  0969-7128     ISO Abbreviation:  Gene Ther.     Publication Date:  2005 Dec 
Date Detail:
Created Date:  2005-11-18     Completed Date:  2006-02-09     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  9421525     Medline TA:  Gene Ther     Country:  England    
Other Details:
Languages:  eng     Pagination:  1679-85     Citation Subset:  IM    
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.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD
Antigens, CD40 / genetics*,  immunology
Antigens, Differentiation / genetics*,  immunology
COS Cells
Cercopithecus aethiops
DNA / administration & dosage*
Diabetes Mellitus, Type 1 / immunology,  therapy*
Enzyme-Linked Immunosorbent Assay / methods
Female
Gene Expression
Gene Therapy / methods*
Genetic Engineering
Immune Tolerance
Injections, Intramuscular
Insulin
Mice
Mice, Inbred NOD
Proinsulin / analysis,  genetics*,  immunology
Protein Precursors / analysis,  genetics*,  immunology
Reverse Transcriptase Polymerase Chain Reaction
Transgenes
Chemical
Reg. No./Substance:
0/Antigens, CD; 0/Antigens, CD40; 0/Antigens, Differentiation; 0/Protein Precursors; 0/cytotoxic T-lymphocyte antigen 4; 11061-68-0/Insulin; 61116-24-3/preproinsulin; 9007-49-2/DNA; 9035-68-1/Proinsulin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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