A Non-Cleavable Mutant of Fas Ligand Does Not Prevent Neutrophilic Destruction of Islet Transplants1

Kang, Sang Mo; Braat, D.; Schneider, Darren B.; O’Rourke, Robert W.; Lin, Zhonghua; Ascher, Nancy L.; Dichek, David A.; Baekkeskov, Steinunn; Stock, Peter G.

doi:10.1097/00007890-200005150-00014

Transplantation

2000

DOI: 10.1097/00007890-200005150-00014

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A Non-Cleavable Mutant of Fas Ligand Does Not Prevent Neutrophilic Destruction of Islet Transplants1

Sang Mo Kang

D. Braat²,

Darren B. Schneider

et al.

Abstract: Membrane-bound Fas ligand is fully capable of inducing a neutrophilic response to transplants, suggesting an activation by Fas ligand of neutrophil chemotactic factors.

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Cited by 37 publications

(1 citation statement)

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“…The initial observation that syngeneic myoblasts genetically engineered to express FasL when cotransplanted with allogeneic islets resulted in prolonged graft survival led to a series of studies using FasL for the induction of allotolerance. 2,4,3 Although some studies reported positive outcomes, 2,3,5 others demonstrated that FasL accelerated allograft rejection. 6,7 Importantly, all these studies used gene therapy and most were conducted with wild-type FasL, which is cleaved off the cell membrane into a soluble form by matrix metalloproteinases.…”

mentioning

confidence: 99%

Posttransplantation Systemic Immunomodulation with SA-FasL–Engineered Donor Splenocytes Has Robust Efficacy in Preventing Cardiac Allograft Rejection in Mice

Zhao¹,

Woodward²,

Shirwan³

et al. 2013

Transplantation Proceedings

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Apoptosis induced by the engagement of FasL with Fas receptor on the surface of lymphocytes is an important immune homeostatic mechanism that ensures tolerance to self-antigens under normal physiologic conditions. As such, FasL has been extensively tested as a tolerogenic molecule with the use of gene therapy in settings of autoimmunity and transplantation with conflicting outcomes. Although the mechanistic basis of these contradictory observations is largely unknown, the use of wild-type FasL and the means by which the gene was expressed may provide an explanation. To overcome these complications, we generated a chimeric FasL protein with streptavidin (SA-FasL) having potent apoptotic activity and displayed this molecule effectively and rapidly on biotinylated biologic membranes for immunomodulation. In the present study, we displayed SA-FasL on the surface of BALB/c splenocytes and injected 5 × 106 cells intraperitoneally into C57BL/6 recipients of BALB/c heart grafts on days 1, 3, and 5 after-transplantation. To control initial graft-reactive immune responses and facilitate FasL-mediated apoptosis, rapamycin was used as an immunosuppressant at 0.2 mg/kg daily for a total of 15 doses immediately after heart transplantation. All mice injected with SA-FasL–engineered donor splenocytes accepted their grafts during the 100-day observation period. In marked contrast, immunomodulation with control streptavidin protein-engineered BALB/c splenocytes had minimal effect on graft survival (mean survival, 21.4 ± 1.5 d). Taken together, these results establish posttransplantation systemic immunomodulation with SA-FasL–engineered donor splenocytes under transient cover of rapamycin as an effective regimen in preventing cardiac allograft rejection in rodents with important clinical implications.

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mentioning

confidence: 99%

Posttransplantation Systemic Immunomodulation with SA-FasL–Engineered Donor Splenocytes Has Robust Efficacy in Preventing Cardiac Allograft Rejection in Mice

Zhao¹,

Woodward²,

Shirwan³

et al. 2013

Transplantation Proceedings

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The dual role of Fas-ligand as an injury effector and defense strategy in diabetes and islet transplantation

et al. 2006

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The exact process that leads to the eruption of autoimmune reactions against beta cells and the evolution of diabetes is not fully understood. Macrophages and T cells may launch an initial immune reaction against the pancreatic islets of Langerhans, provoking inflammation and destructive insulitis. The information on the molecular mechanisms of the emergence of beta cell injury is controversial and points to possibly important roles for the perforin-granzyme, Fas-Fas-ligand (FasL) and tumor-necrosis-factor-mediated apoptotic pathways. FasL has several unique features that make it a potentially ideal immunomodulatory tool. Most important, FasL is selectively toxic to cytotoxic T cells and less harmful to regulatory T cells. This review discusses the intrinsic sensitivity of beta cells to FasL-mediated apoptosis, the conditions that underlie this beta cell sensitivity, and the feasibility of using FasL to arrest autoimmunity and prevent islet allograft rejection. In both the autoimmune and transplant settings, it is imperative to progress from the administration of nonspecific immunosuppressive therapy to the concept of beta-cell-specific immunomodulation. FasL evolves as a prime candidate for antigen-specific immunomodulation.

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Roles of CXC chemokines and macrophages in the recruitment of inflammatory cells and tumor rejection induced by Fas/Apo‐1 (CD95) ligand‐expressing tumor

Shimizu

Yoshimoto

Sato

et al. 2005

Intl Journal of Cancer

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A Non-Cleavable Mutant of Fas Ligand Does Not Prevent Neutrophilic Destruction of Islet Transplants1

Abstract: Membrane-bound Fas ligand is fully capable of inducing a neutrophilic response to transplants, suggesting an activation by Fas ligand of neutrophil chemotactic factors.

Cited by 37 publications

References 34 publications

Posttransplantation Systemic Immunomodulation with SA-FasL–Engineered Donor Splenocytes Has Robust Efficacy in Preventing Cardiac Allograft Rejection in Mice

Posttransplantation Systemic Immunomodulation with SA-FasL–Engineered Donor Splenocytes Has Robust Efficacy in Preventing Cardiac Allograft Rejection in Mice

The dual role of Fas-ligand as an injury effector and defense strategy in diabetes and islet transplantation

Roles of CXC chemokines and macrophages in the recruitment of inflammatory cells and tumor rejection induced by Fas/Apo‐1 (CD95) ligand‐expressing tumor

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