Modulation of CD4+ T cells in autoimmune uveitis

Project: Research project

Description

DESCRIPTION: Autoimmune uveitis is an inflammatory disease mediated by autoreactive CD4+ T cells. The animal model of the disease, experimental autoimmune uveitis (EAU), can be triggered by immunization with several identified retinal antigens, including interphotoreceptor retinoid binding protein (IRBP). IRBP peptide 1-20 (IRBP 1-20) has been identified to be one of the major uveitogenic epitopes in a mouse model. The purpose of this study is to develop a novel strategy to selectively turn on or turn off T cells recognizing this epitope according to our choice. We hypothesize that co-expression of a covalent peptide/MHC class 11 molecule complex and an accessory molecule will allow activation or deletion of peptide-specific, uveitogenic CD4+ T cells in a T cell receptor (TCR) guided fashion. In this study, recombinant adenoviruses will be engineered to express a fusion protein of MHC class Il and IRBP 1 -20. The covalent IRB 1-20/class II complex expressed by the adenovirus on the surface of infected cells will serve as bait or molecule-capturing device, as it will selectively bind to TCRs recognizing this antigen. In addition, the same adenovirus will express either a co-stimulatory molecule (137-1) necessary for T cell activation or a death molecule (FasL) that will trigger T cell apoptosis. Therefore, only the T cells specifically bound to the covalent IRBPl-20/class 11 complex will be selectively activated or deleted, while the T cell population that does not recognize the antigen will be left untouched, remaining nalve or immune competent to other antigens. In Specific Aim 1, recombinant adenovirus co-expressing IRBPl-20/class II complex and 137-1 will be generated and characterized. IRBP 1-20-sPecific T cell activation and possible induction of EAU in adenovirusinfected mice will be defined. In Specific Aim 2, recombinant adenovirus co-expressing IRBP 1-20/class 11 complex and FasL will be generated and characterized. IRBPl-20-specific T cell deletion and possible reduction of EAU in mice infected by this FasL-expressing adenovirus will be defined. These studies will not only yield new insights for the underlying causes and pathogenesis of autoimmune uveitis, but may also lead to a more selective immunotherapy for the disease.
StatusFinished
Effective start/end date7/1/015/31/05

Funding

  • National Institutes of Health: $158,000.00
  • National Institutes of Health: $151,500.00
  • National Institutes of Health: $151,500.00

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Uveitis
Adenoviridae
T-Lymphocytes
Antigens
Peptides
Animal Disease Models
T-Lymphocyte Epitopes
Research Ethics Committees
T-Cell Antigen Receptor
Immunotherapy
Epitopes
Immunization
interstitial retinol-binding protein
Apoptosis
Equipment and Supplies
Population

ASJC

  • Medicine(all)