Utility of adenoviral-mediated Fas ligand gene transfer to modulate islet allograft survival

Thomas A. Judge, Niraj M Desai, Z. Yang, S. Rostami, L. Alonso, H. Zhang, Y. Chen, J. F. Markman, R. P. DeMateo, C. F. Barker, A. Naji, Laurence A. Turka

Research output: Contribution to journalArticle

Abstract

Background. One of the best-defined mechanisms for the induction of apoptosis involves signaling via the cell surface molecule Fas, after binding of Fas ligand. Expression of Fas ligand is tightly regulated, being expressed primarily by T cells after activation, where it serves as a self-regulatory mechanism for immune responses. Fas ligand has also been found to be expressed constitutively at sites of immune privilege such as the testes and the anterior chamber of the eye. Recently, co-transplantation of Fas ligand- transfected myoblasts in association with islet cell allografts was shown to prolong islet allograft survival but only rarely led to indefinite graft survival. Graft rejection was associated with loss of Fas ligand on the myoblasts, suggesting that direct expression of the transgene on the islets might be more effective. Methods. A replication-defective adenoviral construct containing murine Fas ligand (Ad/MFL) was prepared by homologous recombination. NIH 3T3 cells, rodent splenocytes, and murine islets were infected with Ad/MFL and examined in vitro for functional murine Fas ligand expression. Survival of Ad/MFL-infected islets was subsequently evaluated in vivo in both syngeneic and allogeneic islet transplantation models. Results. Cell lines and islet allografts transfected with Ad/MFL expressed a functional Fas ligand, capable of inducing apoptosis (confirmed by three distinct assays for DNA fragmentation) in Fas+ targets, but not in Fas- controls. Furthermore, Ad/MFL was able to modify allogeneic immune responses in vitro, as addition of this virus, but not a control adenovirus, significantly reduced proliferation in a mixed lymphocyte reaction. Surprisingly, however, transplantation of islet allografts transfected with Ad/MFL resulted in long-term allograft survival in only 1 of 30 recipients. Moreover, adenoviral-mediated Fas ligand gene transfer was complicated by transient, dose-dependent islet dysfunction, perhaps contributing to the lack of long-term engraftment. Conclusion. These data suggest that adenoviral- mediated Fas ligand expression may impair normal islet function in vivo, and indicate that alternative strategies for Fas ligand transgene delivery may be required in this setting.

Original languageEnglish (US)
Pages (from-to)426-434
Number of pages9
JournalTransplantation
Volume66
Issue number4
DOIs
StatePublished - Aug 27 1998
Externally publishedYes

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Fas Ligand Protein
Allografts
Genes
Islets of Langerhans Transplantation
Myoblasts
Transgenes
Apoptosis
NIH 3T3 Cells
Mixed Lymphocyte Culture Test
Homologous Recombination
Homologous Transplantation
Graft Rejection
Anterior Chamber
DNA Fragmentation
Graft Survival
Islets of Langerhans
Adenoviridae

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Utility of adenoviral-mediated Fas ligand gene transfer to modulate islet allograft survival. / Judge, Thomas A.; Desai, Niraj M; Yang, Z.; Rostami, S.; Alonso, L.; Zhang, H.; Chen, Y.; Markman, J. F.; DeMateo, R. P.; Barker, C. F.; Naji, A.; Turka, Laurence A.

In: Transplantation, Vol. 66, No. 4, 27.08.1998, p. 426-434.

Research output: Contribution to journalArticle

Judge, TA, Desai, NM, Yang, Z, Rostami, S, Alonso, L, Zhang, H, Chen, Y, Markman, JF, DeMateo, RP, Barker, CF, Naji, A & Turka, LA 1998, 'Utility of adenoviral-mediated Fas ligand gene transfer to modulate islet allograft survival', Transplantation, vol. 66, no. 4, pp. 426-434. https://doi.org/10.1097/00007890-199808270-00003
Judge, Thomas A. ; Desai, Niraj M ; Yang, Z. ; Rostami, S. ; Alonso, L. ; Zhang, H. ; Chen, Y. ; Markman, J. F. ; DeMateo, R. P. ; Barker, C. F. ; Naji, A. ; Turka, Laurence A. / Utility of adenoviral-mediated Fas ligand gene transfer to modulate islet allograft survival. In: Transplantation. 1998 ; Vol. 66, No. 4. pp. 426-434.
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AU - Desai, Niraj M

AU - Yang, Z.

AU - Rostami, S.

AU - Alonso, L.

AU - Zhang, H.

AU - Chen, Y.

AU - Markman, J. F.

AU - DeMateo, R. P.

AU - Barker, C. F.

AU - Naji, A.

AU - Turka, Laurence A.

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