Prolonged Survival of Rat Liver Allografts Transfected With Fas-Ligand Expressing Plasmid

Xk, Li; Tamura, A.; Okuyama, Tadashi; Fujino, Masaie; Funeshima, N.; Enosawa, S.; Kaneda, Yoshihisa; Kita, Yusuke; Yamada, Makoto; Amemiya, H.; Suzuki, S.

doi:10.1097/00007890-199805131-00522

Cited by 27 publications

(37 citation statements)

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“…Enhanced or elevated expression of FasL on specific tissues or cells by a transgene technique is being extensively applied for gene therapy of tumors (34) (35), rheumatoid arthritis (36), autoimmune diseases (37,38), and regulation of rejection in transplantation (39 -41). Thus, significant prolongation of allogeneic grafts has been achieved by directly transducing FasL gene into donor tissue or organs before transplantation (39,40), or by cotransplanting FasL-transfected carrier cells (41). The studies we report suggest that DC transfected with FasL are capable of down-regulating T cell responses.…”

Section: Discussionmentioning

confidence: 83%

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

Min

Gorczynski

Huang

et al. 2000

The Journal of Immunology

224

141

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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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Section: Discussionmentioning

confidence: 83%

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

Min

Gorczynski

Huang

et al. 2000

The Journal of Immunology

224

141

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“…43,86 However, direct ectopic expression of FasL in the liver resulted in opposing outcomes depending on the percentage of cells expressing this molecule. 100 Expression of FasL in more than 11% of liver cells resulted in fulminant hepatitis, whereas lower expression was well tolerated. Importantly, transplantation of these livers into allogeneic recipients resulted in long-term graft survival.…”

Section: Endothelium Of Vascularized Organ Graftsmentioning

confidence: 99%

“…Importantly, transplantation of these livers into allogeneic recipients resulted in long-term graft survival. 100 Low levels of FasL expression in hepatocytes do not necessarily induce apoptosis since they express a series of antiapoptotic molecules and survival factors, such as Bcl-2, and Bcl-xL, 53 and metalloproteinases that cleave membranous FasL into soluble form having low or undetectable apoptotic activity. 37 The liver also secretes hepatocyte growth factor that up-regulates the expression of Bcl-xL.…”

Section: Endothelium Of Vascularized Organ Graftsmentioning

confidence: 99%

Induction of tolerance using Fas ligand: a double-edged immunomodulator

Askenasy

Yolcu

Yaniv

et al. 2005

Blood

109

103

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Fas/FasL system and immune homeostasisThe immune system functions in complex and dynamic microenvironments, where decisions pertaining to the survival and/or physical elimination of antigen-specific T-cell clones are critical to the establishment and maintenance of functional immunity. Activationinduced cell death (AICD) is the primary homeostatic mechanism used by the immune system to control T-cell responses, promote tolerance to self-antigens, and prevent autoimmunity. [1][2][3] Following activation, T cells express Fas and Fas ligand (FasL) and upon repeated antigenic stimulation become sensitive to Fas/FasLmediated autocrine and paracrine apoptosis (Figure 1). [4][5][6] These 2 modes of apoptotic cell death serve to control the pool size of antigen-activated T-cell clones and regulate immune responses. 7 All lymphocytes, including CD4 ϩ and CD8 ϩ T, B, and natural killer (NK) cells as well as dendritic cells, monocytes, macrophages, and neutrophils are subject to Fas/FasL-regulated immune homeostasis. [8][9][10][11] Dysregulation of Fas/FasL-mediated AICD is associated with a series of pathophysiologic conditions, including degenerative and autoimmune disorders. 12 Mouse strains that lack Fas (lpr) or express a defective FasL molecule (gld) suffer from severe lymphoproliferative disorders and autoimmunity, 12,13 arising from the absence of antigen-induced clonal T-cell deletion in the periphery. 14,15 Similarly, the autoimmune lymphoproliferative syndrome in humans, an inherited disorder of lymphocyte homeostasis, is associated with the lack of AICD due to defects in Fas, FasL, and effector caspases. 16 Fas is a 45-kDa, type I cell surface protein with an extracellular domain that binds to FasL and a cytoplasmic domain that transduces the death signal. 17 Apoptosis is executed by the engagement and coaggregation of FasL with the Fas receptor on the cell surface followed by a series of intracellular molecular interactions that coordinate the hierarchical activation of caspases and cell death (Figure 2). Oligomerization of Fas following FasL engagement leads to the recruitment of Fas-associated proteins having death domains and the initiator procaspase-8 via its death effector domain into a death-inducing signaling complex (DISC). [18][19][20] Procaspase-8 undergoes autoproteolysis in the DISC complex to generate an active caspase-8, which in turn initiates extrinsic apoptosis by converting inactive effector procaspases-3, -6, and -7 into active enzymes via transproteolysis and intrinsic apoptosis via cleavage of Bid, release of cytochrome c, and activation of caspase-9. 18,21 Executioner caspases cleave various vital cellular substrates, which leads to cell death.FasL is a 40-kDa, type II cell surface protein that is inducibly expressed in lymphocytes, particularly T cells, 22 and constitutively expressed in cells present in immune privileged organs, such as Sertoli cells of the testis and epithelial cells in the eye. 23,24 Inasmuch as FasL-mediated apoptosis is critical to peripheral T-cell homeostasis...

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“…Enforced expression of FasL has been shown to protect allografts from rejection in some cases (15,16) but not others (17). In the skin, tolerance induced by UV irradiation involves Fas/FasL (11,18) and a number of skin diseases are thought to involve FasL (19).…”

mentioning

confidence: 99%

Termination of Antigen-Specific Immunity by CD95 Ligand (Fas Ligand) and IL-10

Barreiro

Luker

Herndon

et al. 2004

The Journal of Immunology

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Following elimination of a foreign invader, the immune system must return to its normal quiescent levels. This process requires removal of reactive immune cells when they are no longer needed. We have explored the role of Fas/Fas ligand (FasL) in terminating immunity and demonstrate that mice defective in these proteins have prolonged immune responses. Studies demonstrate that termination of immunity occurs via the interaction of Fas+ lymphoid cells with FasL+ nonlymphoid cells at the site of Ag challenge. Our results also show that FasL is absent in quiescent tissue but is rapidly up-regulated during the local immune reaction. This occurs through the production of IL-10. Thus, FasL and IL-10 work in concert to eliminate inflammatory cells and control the duration of an immune response.

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Prolonged Survival of Rat Liver Allografts Transfected With Fas-Ligand Expressing Plasmid

Cited by 27 publications

References 0 publications

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

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

Induction of tolerance using Fas ligand: a double-edged immunomodulator

Termination of Antigen-Specific Immunity by CD95 Ligand (Fas Ligand) and IL-10

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