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rdf:type |
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lifeskim:mentions |
umls-concept:C0018133,
umls-concept:C0021079,
umls-concept:C0021080,
umls-concept:C0024400,
umls-concept:C0026336,
umls-concept:C0039194,
umls-concept:C0040732,
umls-concept:C0085358,
umls-concept:C0205314,
umls-concept:C0332206,
umls-concept:C0442537,
umls-concept:C0679622,
umls-concept:C1155046,
umls-concept:C1332717,
umls-concept:C1413244,
umls-concept:C1705182,
umls-concept:C1706438,
umls-concept:C2698600
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pubmed:issue |
24
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pubmed:dateCreated |
2010-12-14
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pubmed:abstractText |
We have developed a major histocompatibility complex-defined primate model of graft-versus-host disease (GVHD) and have determined the effect that CD28/CD40-directed costimulation blockade and sirolimus have on this disease. Severe GVHD developed after haploidentical transplantation without prophylaxis, characterized by rapid clinical decline and widespread T-cell infiltration and organ damage. Mechanistic analysis showed activation and possible counter-regulation, with rapid T-cell expansion and accumulation of CD8(+) and CD4(+) granzyme B(+) effector cells and FoxP3(pos)/CD27(high)/CD25(pos)/CD127(low) CD4(+) T cells. CD8(+) cells down-regulated CD127 and BCl-2 and up-regulated Ki-67, consistent with a highly activated, proliferative profile. A cytokine storm also occurred, with GVHD-specific secretion of interleukin-1 receptor antagonist (IL-1Ra), IL-18, and CCL4. Costimulation Blockade and Sirolimus (CoBS) resulted in striking protection against GVHD. At the 30-day primary endpoint, CoBS-treated recipients showed 100% survival compared with no survival in untreated recipients. CoBS treatment resulted in survival, increasing from 11.6 to 62 days (P < .01) with blunting of T-cell expansion and activation. Some CoBS-treated animals did eventually develop GVHD, with both clinical and histopathologic evidence of smoldering disease. The reservoir of CoBS-resistant breakthrough immune activation included secretion of interferon-?, IL-2, monocyte chemotactic protein-1, and IL-12/IL-23 and proliferation of cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin-resistant CD28(-) CD8(+) T cells, suggesting adjuvant treatments targeting this subpopulation will be needed for full disease control.
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pubmed:grant |
http://linkedlifedata.com/resource/pubmed/grant/,
http://linkedlifedata.com/resource/pubmed/grant/1 R01 HL095791-01A1,
http://linkedlifedata.com/resource/pubmed/grant/1R01 RR18144-01,
http://linkedlifedata.com/resource/pubmed/grant/2P01 AI044644,
http://linkedlifedata.com/resource/pubmed/grant/2R01 HL56067,
http://linkedlifedata.com/resource/pubmed/grant/2U19 AI051731,
http://linkedlifedata.com/resource/pubmed/grant/2U24 RR018109,
http://linkedlifedata.com/resource/pubmed/grant/5K08 AI065822,
http://linkedlifedata.com/resource/pubmed/grant/P01AI 056299,
http://linkedlifedata.com/resource/pubmed/grant/R01 HL 63452,
http://linkedlifedata.com/resource/pubmed/grant/R01 HL095791-02,
http://linkedlifedata.com/resource/pubmed/grant/R01AI 34495,
http://linkedlifedata.com/resource/pubmed/grant/RR00165
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
1528-0020
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pubmed:author |
pubmed-author:AndersonDaniel CDC,
pubmed-author:BeusJonathanJ,
pubmed-author:BlazarBruce RBR,
pubmed-author:CrenshawTimothyT,
pubmed-author:CrockerIanI,
pubmed-author:ElderEricE,
pubmed-author:GarciaAnapatriciaA,
pubmed-author:HambyKellyK,
pubmed-author:HoranJohnJ,
pubmed-author:KeanLeslie SLS,
pubmed-author:LarsenChristian PCP,
pubmed-author:MillerWeston PWP,
pubmed-author:Panoskaltsis-MortariAngelaA,
pubmed-author:PenedoM Cecilia TMC,
pubmed-author:SenSharonS,
pubmed-author:SharmaPrachiP,
pubmed-author:SinghKarnailK,
pubmed-author:SongMingqingM,
pubmed-author:SrinivasanSwethaS,
pubmed-author:StemporaLindaL,
pubmed-author:StrobertElizabethE,
pubmed-author:TaylorDeaneD,
pubmed-author:TurnerAlexaA,
pubmed-author:WardTheaT,
pubmed-author:WheelerCalebC
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pubmed:issnType |
Electronic
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pubmed:day |
9
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pubmed:volume |
116
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5403-18
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pubmed:dateRevised |
2011-2-3
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pubmed:meshHeading |
pubmed-meshheading:20833977-Animals,
pubmed-meshheading:20833977-Antigens, CD28,
pubmed-meshheading:20833977-CD8-Positive T-Lymphocytes,
pubmed-meshheading:20833977-Cell Proliferation,
pubmed-meshheading:20833977-Graft vs Host Disease,
pubmed-meshheading:20833977-Haplotypes,
pubmed-meshheading:20833977-Hematopoietic Stem Cell Transplantation,
pubmed-meshheading:20833977-Immunosuppression,
pubmed-meshheading:20833977-Lymphocyte Activation,
pubmed-meshheading:20833977-Macaca mulatta,
pubmed-meshheading:20833977-Sirolimus
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pubmed:year |
2010
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pubmed:articleTitle |
GVHD after haploidentical transplantation: a novel, MHC-defined rhesus macaque model identifies CD28- CD8+ T cells as a reservoir of breakthrough T-cell proliferation during costimulation blockade and sirolimus-based immunosuppression.
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pubmed:affiliation |
Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, and Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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