| pubmed-article:18218852 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:18218852 | lifeskim:mentions | umls-concept:C0030705 | lld:lifeskim |
| pubmed-article:18218852 | lifeskim:mentions | umls-concept:C0521119 | lld:lifeskim |
| pubmed-article:18218852 | lifeskim:mentions | umls-concept:C0178719 | lld:lifeskim |
| pubmed-article:18218852 | lifeskim:mentions | umls-concept:C0037083 | lld:lifeskim |
| pubmed-article:18218852 | lifeskim:mentions | umls-concept:C1863236 | lld:lifeskim |
| pubmed-article:18218852 | lifeskim:mentions | umls-concept:C0542341 | lld:lifeskim |
| pubmed-article:18218852 | lifeskim:mentions | umls-concept:C0221099 | lld:lifeskim |
| pubmed-article:18218852 | lifeskim:mentions | umls-concept:C1710082 | lld:lifeskim |
| pubmed-article:18218852 | lifeskim:mentions | umls-concept:C0181586 | lld:lifeskim |
| pubmed-article:18218852 | lifeskim:mentions | umls-concept:C0205349 | lld:lifeskim |
| pubmed-article:18218852 | pubmed:issue | 8 | lld:pubmed |
| pubmed-article:18218852 | pubmed:dateCreated | 2008-4-9 | lld:pubmed |
| pubmed-article:18218852 | pubmed:databankReference | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:18218852 | pubmed:databankReference | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:18218852 | pubmed:abstractText | Mutations in the adenosine deaminase (ADA) gene are responsible for a form of severe combined immunodeficiency (SCID) caused by the lymphotoxic accumulation of ADA substrates, adenosine and 2'-deoxy-adenosine. The molecular mechanisms underlying T-cell dysfunction in humans remain to be elucidated. Here, we show that CD4(+) T cells from ADA-SCID patients have severely compromised TCR/CD28-driven proliferation and cytokine production, both at the transcriptional and protein levels. Such an impairment is associated with an intrinsically reduced ZAP-70 phosphorylation, Ca(2+) flux, and ERK1/2 signaling and to defective transcriptional events linked to CREB and NF-kappaB. Moreover, exposure to 2'-deoxy-adenosine results in a stronger inhibition of T-cell activation, mediated by the aberrant A(2A) adenosine receptor signaling engagement and PKA hyperactivation, or in a direct apoptotic effect at higher doses. Conversely, in T cells isolated from patients after gene therapy with retrovirally transduced hematopoietic stem/progenitor cells, the biochemical events after TCR triggering occur properly, leading to restored effector functions and normal sensitivity to apoptosis. Overall, our findings provide a better understanding of the pathogenesis of the immune defects associated with an altered purine metabolism and confirm that ADA gene transfer is an efficacious treatment for ADA-SCID. The trials in this study are enrolled at www.ClinicalTrials.gov as #NCT00598481 and #NCT0059978. | lld:pubmed |
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| pubmed-article:18218852 | pubmed:language | eng | lld:pubmed |
| pubmed-article:18218852 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:18218852 | pubmed:citationSubset | AIM | lld:pubmed |
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| pubmed-article:18218852 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:18218852 | pubmed:month | Apr | lld:pubmed |
| pubmed-article:18218852 | pubmed:issn | 0006-4971 | lld:pubmed |
| pubmed-article:18218852 | pubmed:author | pubmed-author:BordignonClau... | lld:pubmed |
| pubmed-article:18218852 | pubmed:author | pubmed-author:RoncaroloMari... | lld:pubmed |
| pubmed-article:18218852 | pubmed:author | pubmed-author:AiutiAlessand... | lld:pubmed |
| pubmed-article:18218852 | pubmed:author | pubmed-author:TabucchiAnton... | lld:pubmed |
| pubmed-article:18218852 | pubmed:author | pubmed-author:CarlucciFilip... | lld:pubmed |
| pubmed-article:18218852 | pubmed:author | pubmed-author:CattaneoFeder... | lld:pubmed |
| pubmed-article:18218852 | pubmed:author | pubmed-author:CassaniBarbar... | lld:pubmed |
| pubmed-article:18218852 | pubmed:author | pubmed-author:MiroloMassimi... | lld:pubmed |
| pubmed-article:18218852 | pubmed:author | pubmed-author:HershfieldMic... | lld:pubmed |
| pubmed-article:18218852 | pubmed:author | pubmed-author:BenninghoffUl... | lld:pubmed |
| pubmed-article:18218852 | pubmed:issnType | Print | lld:pubmed |
| pubmed-article:18218852 | pubmed:day | 15 | lld:pubmed |
| pubmed-article:18218852 | pubmed:volume | 111 | lld:pubmed |
| pubmed-article:18218852 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:18218852 | pubmed:authorsComplete | Y | lld:pubmed |
