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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
3
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pubmed:dateCreated |
2003-8-13
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pubmed:abstractText |
Activation-induced cell death and cytokine deprivation are demonstrated by peripheral T cell populations at the conclusion of natural immune responses, and each of these processes is modulated by the immunosuppressive cytokine interleukin (IL)-10 in vitro. This study employs a clinically relevant in vivo model of IL-10 gene transfer with heterotopically transplanted cardiac allografts to determine the mechanisms of the effects of IL-10 on T cell survival. IL-10 protein overexpression within allografts 4-5 days after gene transfer augments apoptosis of CD4+ and CD8+ graft-infiltrating lymphocytes by 7.1-fold (P < 0.001) and 6.0-fold (P < 0.001), respectively. Graft-infiltrating T cells express 10-fold more proapoptotic Fas (P < 0.01) and 30-fold more Bax (P < 0.01) than controls. The fractions of activated caspase-8 (FADD-like IL-1beta-converting enzyme) and activated caspase-9 were increased 7- and 2.3-fold, respectively, in IL-10 gene-treated allografts at postoperative day 4-5. These changes in the Fas-Fas ligand pathway and Bcl-2 mitochondrial apoptosis regulation are enhanced by complete suppression of antiapoptotic FADD-like IL-1beta-converting enzyme inhibitory protein (FLIP) (from 30.5 to 0.0%, P < 0.01) and Bcl-xL (from 22.5 to 0.1%, P = 0.03) expression among these cells from the earliest days after gene transfer. Although changes in proteins of Fas- and Bcl-2-mediated apoptosis signaling occur, only the levels of Fas and FLIP correlate to the rate of apoptosis of graft-infiltrating CD3 lymphocytes and histological rejection scores. These results indicate that dichotomous apoptosis-regulatory pathways are affected by IL-10 gene therapy, but Fas-mediated mechanisms of activation-induced cell death more substantially contribute to the greater cell death of graft-infiltrating T cells after ex vivo IL-10 gene transfer.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD3,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD95,
http://linkedlifedata.com/resource/pubmed/chemical/BAX protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/BCL2L1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CASP8 and FADD-Like Apoptosis...,
http://linkedlifedata.com/resource/pubmed/chemical/CASP8 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CASP9 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CFLAR protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 8,
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 9,
http://linkedlifedata.com/resource/pubmed/chemical/Caspases,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-10,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-bcl-2,
http://linkedlifedata.com/resource/pubmed/chemical/bcl-2-Associated X Protein,
http://linkedlifedata.com/resource/pubmed/chemical/bcl-X Protein
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
0363-6135
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
285
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
H964-73
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:12915385-Animals,
pubmed-meshheading:12915385-Antigens, CD3,
pubmed-meshheading:12915385-Antigens, CD95,
pubmed-meshheading:12915385-Apoptosis,
pubmed-meshheading:12915385-CASP8 and FADD-Like Apoptosis Regulating Protein,
pubmed-meshheading:12915385-Carrier Proteins,
pubmed-meshheading:12915385-Caspase 8,
pubmed-meshheading:12915385-Caspase 9,
pubmed-meshheading:12915385-Caspases,
pubmed-meshheading:12915385-Gene Therapy,
pubmed-meshheading:12915385-Graft Rejection,
pubmed-meshheading:12915385-Graft Survival,
pubmed-meshheading:12915385-Heart Transplantation,
pubmed-meshheading:12915385-Humans,
pubmed-meshheading:12915385-Interleukin-10,
pubmed-meshheading:12915385-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:12915385-Male,
pubmed-meshheading:12915385-Proto-Oncogene Proteins,
pubmed-meshheading:12915385-Proto-Oncogene Proteins c-bcl-2,
pubmed-meshheading:12915385-Rabbits,
pubmed-meshheading:12915385-T-Lymphocytes,
pubmed-meshheading:12915385-Transplantation, Homologous,
pubmed-meshheading:12915385-Up-Regulation,
pubmed-meshheading:12915385-bcl-2-Associated X Protein,
pubmed-meshheading:12915385-bcl-X Protein
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pubmed:year |
2003
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pubmed:articleTitle |
Dual upregulation of Fas and Bax promotes alloreactive T cell apoptosis in IL-10 gene targeting of cardiac allografts.
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pubmed:affiliation |
Division of Cardiothoracic Surgery, Department of Surgery, UCLA Medical Center, David Geffen School of Medicine, University of California-Los Angeles, 10833 Leconte Avenue, Los Angeles, CA 90095-1679, USA.
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pubmed:publicationType |
Journal Article
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