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Blood, 15 April 2008, Vol. 111, No. 8, pp. 4209-4219. Prepublished online as a Blood First Edition Paper on January 24, 2008; DOI 10.1182/blood-2007-05-092429. This Article Full Text Full Text (PDF) Supplemental Material and Figures All Versions of this Article: blood-2007-05-092429v1 111/8/4209    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Cassani, B. Articles by Aiuti, A. Search for Related Content PubMed PubMed Citation Articles by Cassani, B. Articles by Aiuti, A. Related Collections Immunobiology Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients Barbara Cassani1, Massimiliano Mirolo1, Federica Cattaneo1, Ulrike Benninghoff1, Michael Hershfield2, Filippo Carlucci3, Antonella Tabucchi3, Claudio Bordignon4, Maria Grazia Roncarolo1,4, and Alessandro Aiuti1 1 San Raffaele Telethon Institute for Gene Therapy, Milan, Italy; 2 Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC; 3 Department of Medicina Interna, Scienze Endocrino Metaboliche e Biochimica, University of Siena, Siena, Italy; and 4 Vita-Salute San Raffaele University, Milan, Italy 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, Ca2+ flux, and ERK1/2 signaling and to defective transcriptional events linked to CREB and NF-B. Moreover, exposure to 2'-deoxy-adenosine results in a stronger inhibition of T-cell activation, mediated by the aberrant A2A 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 [ClinicalTrials.gov] and #NCT0059978. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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