Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients.
Journal Article (Clinical Trial;Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Cassani, B; Mirolo, M; Cattaneo, F; Benninghoff, U; Hershfield, M; Carlucci, F; Tabucchi, A; Bordignon, C; Roncarolo, MG; Aiuti, A
Published Date
- April 15, 2008
Published In
Volume / Issue
- 111 / 8
Start / End Page
- 4209 - 4219
PubMed ID
- 18218852
Pubmed Central ID
- PMC2288726
International Standard Serial Number (ISSN)
- 0006-4971
Digital Object Identifier (DOI)
- 10.1182/blood-2007-05-092429
Language
- eng
Conference Location
- United States