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rdf:type |
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lifeskim:mentions |
umls-concept:C0035820,
umls-concept:C0039194,
umls-concept:C0085358,
umls-concept:C0205160,
umls-concept:C0871261,
umls-concept:C0936012,
umls-concept:C1332714,
umls-concept:C1332717,
umls-concept:C1413244,
umls-concept:C1515655,
umls-concept:C1704259,
umls-concept:C1704632,
umls-concept:C1705987,
umls-concept:C1706438,
umls-concept:C1706817,
umls-concept:C2698600,
umls-concept:C2911692
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pubmed:issue |
11
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pubmed:dateCreated |
2005-5-20
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pubmed:abstractText |
Negative costimulatory signals mediated via cell surface molecules such as CTLA-4 and programmed death 1 (PD-1) play a critical role in down-modulating immune responses and maintaining peripheral tolerance. However, their role in alloimmune responses remains unclear. This study examined the role of these inhibitory pathways in regulating CD28-dependent and CD28-independent CD4 and CD8 alloreactive T cells in vivo. CTLA-4 blockade accelerated graft rejection in C57BL/6 wild-type recipients and in a proportion of CD4(-/-) but not CD8(-/-) recipients of BALB/c hearts. The same treatment led to prompt rejection in CD28(-/-) and a smaller proportion of CD4(-/-)CD28(-/-) mice with no effect in CD8(-/-)CD28(-/-) recipients. These results indicate that the CTLA-4:B7 pathway provides a negative signal to alloreactive CD8(+) T cells, particularly in the presence of CD28 costimulation. In contrast, PD-1 blockade led to accelerated rejection of heart allografts only in CD28(-/-) and CD8(-/-)CD28(-/-) recipients. Interestingly, PD-1 ligand (PD-L1) blockade led to accelerated rejection in wild-type mice and in all recipients lacking CD28 costimulation. This effect was accompanied by expansion of IFN-gamma-producing alloreactive T cells and enhanced generation of effector T cells in rejecting allograft recipients. Thus, the PD-1:PD-L1 pathway down-regulates alloreactive CD4 T cells, particularly in the absence of CD28 costimulation. The differential effects of PD-1 vs PD-L1 blockade support the possible existence of a new receptor other than PD-1 for negative signaling through PD-L1. Furthermore, PD-1:PD-L1 pathway can regulate alloimmune responses independent of an intact CD28/CTLA-4:B7 pathway. Harnessing physiological mechanisms that regulate alloimmunity should lead to development of novel strategies to induce durable and reproducible transplantation tolerance.
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pubmed:grant |
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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 |
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Blocking,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD274,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD28,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD4,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD8,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD80,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD86,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, Differentiation,
http://linkedlifedata.com/resource/pubmed/chemical/CTLA-4 Antigen,
http://linkedlifedata.com/resource/pubmed/chemical/Cd274 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Cd86 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Ctla4 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/PD-1 antigen, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Pdcd1lg2 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Programmed Cell Death 1 Ligand 2...
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
0022-1767
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pubmed:author |
pubmed-author:AuchinclossHughHJr,
pubmed-author:AzumaMiyukiM,
pubmed-author:ClarksonMichael RMR,
pubmed-author:ItoToshiroT,
pubmed-author:JurewiczMollie MMM,
pubmed-author:NajafianNaderN,
pubmed-author:SayeghMohamed HMH,
pubmed-author:SharpeArlene HAH,
pubmed-author:UenoTakuyaT,
pubmed-author:YagitaHideoH,
pubmed-author:YuanXueliX
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
174
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
6648-56
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:15905503-Animals,
pubmed-meshheading:15905503-Antibodies, Blocking,
pubmed-meshheading:15905503-Antigens, CD,
pubmed-meshheading:15905503-Antigens, CD274,
pubmed-meshheading:15905503-Antigens, CD28,
pubmed-meshheading:15905503-Antigens, CD4,
pubmed-meshheading:15905503-Antigens, CD8,
pubmed-meshheading:15905503-Antigens, CD80,
pubmed-meshheading:15905503-Antigens, CD86,
pubmed-meshheading:15905503-Antigens, Differentiation,
pubmed-meshheading:15905503-CD4-Positive T-Lymphocytes,
pubmed-meshheading:15905503-CD8-Positive T-Lymphocytes,
pubmed-meshheading:15905503-CTLA-4 Antigen,
pubmed-meshheading:15905503-Down-Regulation,
pubmed-meshheading:15905503-Graft Rejection,
pubmed-meshheading:15905503-Heart Transplantation,
pubmed-meshheading:15905503-Membrane Glycoproteins,
pubmed-meshheading:15905503-Mice,
pubmed-meshheading:15905503-Mice, Inbred BALB C,
pubmed-meshheading:15905503-Mice, Inbred C57BL,
pubmed-meshheading:15905503-Mice, Knockout,
pubmed-meshheading:15905503-Mice, Mutant Strains,
pubmed-meshheading:15905503-Peptides,
pubmed-meshheading:15905503-Programmed Cell Death 1 Ligand 2 Protein,
pubmed-meshheading:15905503-Signal Transduction
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pubmed:year |
2005
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pubmed:articleTitle |
Analysis of the role of negative T cell costimulatory pathways in CD4 and CD8 T cell-mediated alloimmune responses in vivo.
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pubmed:affiliation |
Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, MA 02115, USA.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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