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- W2085457657 abstract "824 Dendritic cells (DCs) are professional antigen-presenting cells that play critical roles in the initiation and modulation of immune responses, and may determine the balance between tolerance and immunity. Blockade of the B7-CD28 costimulatory pathway by CTLA4-Ig fusion protein administration can prevent the rejection of experimental organ allografts, and promote tolerance induction. Genetic engineering of DC to express CTLA4-Ig is an attractive approach to immunosuppressive therapy. DC migrate to interact with donor-reactive T cells in the lymphoid tissue microenviroment, and thus there is minimization of the systemic effects of the immunosuppressive gene product. Retroviral gene transfer may be preferable to use of adenoviral vectors as the former permit permanent transgene expression and are not immunogenic. Our Aims here was to transduce mouse bone marrow (BM)-derived DC progenitors to express CTLA4-Ig, using a non-immunogenic retroviral vector, and to assess the impact of transgene expression on DC phenotype and allostimulatory activity. Methods: DC progenitors (p) propagated from the bone marrow of C57/BL6 (H2b) mice in granulocyte-macrophage colony-stimulating factor (GM-CSF) + IL-4 were transduced by the centrifugal enhancement method, using retroviral supernatant obtained from the BOSC 23 ecotropic packaging cell line infected with DFG-CTLA4-Ig-Zeo. Viral titer was quantified by cloning of the Zeocin resistance gene (Zeo) after infecting NIH3T3 fibroblasts. To determine transduction efficiency, DC were transduced with MFG-enhanced green fluorescence protein (EGFP) as a marker gene. Transgene and key cell surface antigen expression (MHC and costimulation molecules) were examined by flow cytometry. DC function was assessed by the ability of the transduced cells to induce allogeneic (C3H;H2k) T cell proliferation in primary mixed leukocyte reactions (MLR). Results: Retroviral transfer of the marker gene EGFP to DC was achieved with a maximum transduction efficiency of 50%, and showed no effect on the allostimulatory function of the cells. The titer of the CTLA4-Ig retroviral supernatant was 4 × 106 CFU/ml. In comparison to EGFP-transduced DC as controls, CTLA4-Ig transduced cells showed no change in surface expression of MHC class II, or costimulatory molecules. However, CTLA4-Ig-transduced DC exhibited markedly reduced ability to stimulate naive allogeneic T cell proliferation. Conclusion: The lack of immunogenicity of retroviral vectors, and the use of replicating (immature) DC progenitors may optimize the potential of genetically-engineered DC for the therapy of organ allograft rejection. Retroviral delivery of CTLA4-Ig to DC markedly impairs their alloantigen-presenting cell function, and offers potential for in vivo inhibition of alloimmune reactivity. (Supported by NIH-AI-41011)" @default.
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- W2085457657 date "1999-04-01" @default.
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- W2085457657 title "RETROVIRAL DELIVERY OF CTLA4-Ig INTO MYELOID DENDRITIC CELLS MARKEDLY INHIBITS THEIR ALLOSTIMULATORY ACTIVITY" @default.
- W2085457657 doi "https://doi.org/10.1097/00007890-199904150-00848" @default.
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