Targeting antigen-specific T cells by genetically engineered antigen presenting cells. A strategy for specific immunotherapy of autoimmune disease.

  • Wu J
  • Wu B
  • Guarnieri F
 et al. 
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Abstract

We describe a strategy for specific immunotherapy of autoimmune disease based on targeting the antigen-specific T cells in an experimental model of myasthenia gravis. To address the problem of heterogeneity of the T cell repertoire, we have genetically engineered antigen presenting cells (APCs) to process and present epitopes of the autoantigen, acetylcholine receptor (AChR), to the entire spectrum of AChR-specific syngeneic T cells. APCs derived from BALB/c mice were stably transfected with cDNA for the key immunogenic domain of the AChR alpha-subunit, flanked by sequences of the lysosome-associated membrane protein (LAMP) that direct APCs to process and present the antigen via the MHC Class II pathway. Transfected APCs strongly stimulated AChR-specific T cells from BALB/c mice. Fas ligand, or antibody to Fas, abrogated the T cell response, by inducing apoptosis of the APC-stimulated T cells. The new results of this investigation are (1) that autoreactive T cells can be effectively targeted by autologous APCs that are engineered to present the relevant autoantigen, and (2) that these specifically targeted and activated T cells can be profoundly inhibited by agents that trigger the Fas-mediated apoptosis pathway. The present findings suggest that engineering APCs for simultaneous presentation of the autoantigen and delivery of FasL will provide a powerful strategy for the elimination of autoreactive T cells.

Author-supplied keywords

  • Animals
  • Antibodies
  • Antibodies: pharmacology
  • Antigen-Presenting Cells
  • Antigen-Presenting Cells: physiology
  • Antigens, CD95
  • Antigens, CD95: immunology
  • Autoimmune Diseases
  • Autoimmune Diseases: therapy
  • Epitopes
  • Fas Ligand Protein
  • Female
  • Gene Targeting
  • Gene Targeting: methods
  • Genetic Engineering
  • Immunotherapy
  • Immunotherapy: methods
  • Membrane Glycoproteins
  • Membrane Glycoproteins: pharmacology
  • Mice
  • Mice, Inbred BALB C
  • T-Lymphocytes
  • T-Lymphocytes: drug effects
  • T-Lymphocytes: immunology

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Authors

  • J M Wu

  • B Wu

  • F Guarnieri

  • J T August

  • D B Drachman

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