Bone marrow derived cells, especially B lymphocytes, have been shown to function as tolerogenic antigenpresenting cells (APCs) both in vivo and in vitro. In addition, it is well established that immunoglobulins can function as potent tolerogenic carriers for associated epitopes. We have taken advantage of these properties to develop a gene therapy approach to induce unresponsiveness in a number of animal models for clinical diseases. In our system, we engineered target peptide-IgG constructs into retroviral vectors and transduced hematopoietic cells to create tolerogenic antigenpresenting cells. In this review, we discuss the strategies and mechanism of our gene therapy approach mediated by B cells, as well as by bone marrow cells, for tolerance acquisition in various mouse models for autoimmune disease and hemophilia A. Our results show that MHC class II and co-stimulatory molecules must be expressed on the tolerogenic antigen presenting cells for efficacy. This therapy requires regulatory T cells for both the induction and maintenance of tolerance. The putative role of epitopes provided by the IgG carrier in this process is emphasized. Studies in non-human primates and with human T cell clones in vitro are in progress to transition this approach to the clinic. The use of stem cells and B cell-delivered gene therapy in human clinical diseases may soon become a reality.
Keywords: Immune tolerance, B cells, immunoglobulin fusion proteins, regulatory T cells, Gene Therapy, Autoimmunity, Hemophilia, antigen-presenting cells, immunoglobulins, peptide-IgG, retroviral vectors, hematopoietic cells, regulatory T cells., bone marrow transplantation (BMT), gone amok, thymus, tolerogenic hapten-carrier conjugates., Fc receptors., bacteriophage protein, myeloma, tolerogenic, retroviral vector, anti-CTLA-4, [gamma interferon, lysosomal transferase;, autoimmune uveitis, experimental autoimmune encephalomyelitis, adjuvant arthritis, interphotoreceptor retinoid-binding protein, myelin basic protein, proteolipid protein, myelin oligodendro-cyte glycoprotein, encephalitogenic peptide,, lipopolysaccharide, glutamic acid decarboxy-lase, hyperglycemia, disulfide bonds, immunizations, CD40 liga-tion, tolerogenicity, mutagenesis, murine, busulfan
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