Dendritic Cells Genetically Engineered to Express Fas Ligand Induce Donor-Specific Hyporesponsiveness and Prolong Allograft Survival

Department of Surgery and Multiorgan Transplant Program, Toronto Hospital Research Institute, University of Toronto, Ontario, Canada.
The Journal of Immunology (Impact Factor: 4.92). 02/2000; 164(1):161-7. DOI: 10.4049/jimmunol.164.1.161
Source: PubMed


Polarization of an immune response toward tolerance or immunity is dictated by the interactions between T cells and dendritic cells (DC), which in turn are modulated by the expression of distinct cell surface molecules, and the cytokine milieu in which these interactions are taking place. Genetic modification of DC with genes coding for specific immunoregulatory cell surface molecules and cytokines offers the potential of inhibiting immune responses by selectively targeting Ag-specific T cells. In this study, the immunomodulatory effects of transfecting murine bone marrow-derived DC with Fas ligand (FasL) were investigated. In this study, we show that FasL transfection of DC markedly augmented their capacity to induce apoptosis of Fas+ cells. FasL-transfected DC inhibited allogeneic MLR in vitro, and induced hyporesponsiveness to alloantigen in vivo. The induction of hyporesponsiveness was Ag specific and was dependent on the interaction between FasL on DC and Fas on T cells. Finally, we show that transfusion of FasL-DC significantly prolonged the survival of fully MHC-mismatched vascularized cardiac allografts. Our findings suggest that DC transduced with FasL may facilitate the development of Ag-specific unresponsiveness for the prevention of organ rejection. Moreover, they highlight the potential of genetically engineering DC to express other genes that affect immune responses.

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Available from: Reg Gorczynski, May 16, 2014
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    • "By binding the cell death receptor Fas (CD95), Fas ligand participates in the maintenance of peripheral T-cell tolerance and maintenance of immune privilege in certain organs. DCs expressing transgenic Fas ligand inhibited antigen-specific T-cell responsiveness, prolonging the survival of fully MHC-mismatched cardiac allografts in some studies [215, 216], but not in others [217, 218]. Mouse tolerogenic DCs generated with antisense ODN against the costimulatory molecules CD40, CD80, and CD86 remained costimulatory deficient in vivo, even after 3 weeks of injection [219]. "
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    • "Selective inducing apoptosis of antigen-specific T cells by APCs genetically modified to express death ligand (e.g., FasL and TRAIL) is an alternative way to downregulate antigen-specific T-cell responses. DCs genetically modified to express FasL can induce donor-specific T-cell hyporesponsiveness to alloantigen and facilitate allograft survival [41]. FasL-expressing DCs are also able to suppress collagen-reactive T cells and inhibit the progression of murine CIA after systemic injection [26]. "
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    • "first the cells were fixed with paraformaldehyde, then permeabilized with Triton X-100, and analyzed by flow cytometry. The FITC-conjugated AnnexinV and PI staining was used for determination of apoptosis /necrosis as previously described by Min et al. (2000). "
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