RRC ID 4752
Author Tanemura M, Saga A, Kawamoto K, Machida T, Deguchi T, Nishida T, Sawa Y, Doki Y, Mori M, Ito T.
Title Adenovirus-mediated gene expression of the human c-FLIP(L) gene protects pig islets against human CD8(+) cytotoxic T lymphocyte-mediated cytotoxicity.
Journal Transplant Proc
Abstract Cell-mediated immunity, especially of human CD8+ cytotoxic T lymphocytes (CTLs) is believed to have an important role in the long-term survival of pig islet xenografts. Protection against human CD8+ CTL cytotoxicity may reduce the direct damage to pig islets and enable long-term xenograft survival in pig-to-human islet xenotransplantation. We have previously reported that c-FLIP(S/L) genes, which are potent inhibitors of death receptor-mediated proapoptotic signals through binding competition with caspase-8 for recruitment to the Fas-associated via death domain (FADD), markedly suppress human CD8+ CTL-mediated xenocytotoxicity. In addition, the cytoprotective effects of c-FLIP(L) seem to be significantly stronger than those of c-FLIP(S). Accordingly, in the present study, expression of c-FLIP(L) was induced in intact pig islets by adenoviral transduction. Consequently, the cytoprotective capacity of the transgene in pig islets was examined in in vitro and in vivo exposure to human CD8+ CTLs. Cells from untransduced islets or mock islets were sensitive to CD8+ CTL-mediated lysis (59.3% +/- 15.9% and 64.0% +/- 8.9% cytotoxicity, respectively). In contrast, cells from pig islets transduced with the c-FLIP(L) gene were markedly protected from lysis (30.5% +/- 3.5%). Furthermore, prolonged xenograft survival was elicited from pig islets transduced with this molecule as assessed using an islet transplant model using the rat kidney capsule. Thus, these data indicate that intact pig islets can be transduced to express c-FLIP(L) with adenovirus. Pig islets expressing c-FLIP(L) are significantly resistant to human CTL killing and further exhibit beneficial effects to prolong xenograft survival.
Volume 41(1)
Pages 319-22
Published 2009-1-1
DOI 10.1016/j.transproceed.2008.10.030
PII S0041-1345(08)01453-X
PMID 19249545
MeSH Adenoviridae / genetics* Animals CASP8 and FADD-Like Apoptosis Regulating Protein / genetics* Cell Survival Gene Expression Regulation* Humans Immunohistochemistry Islets of Langerhans / cytology Islets of Langerhans / immunology* Islets of Langerhans Transplantation / immunology Rats Rats, Inbred Lew Swine T-Lymphocytes, Cytotoxic / immunology* Transfection Transplantation, Heterologous / immunology
IF 0.784
Times Cited 0
DNA material AxCAhFLIP (RDB02199)