Caspase-8 polymorphisms result in reduced Alemtuzumab-induced T-cell apoptosis and worse survival after transplantation View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-02

AUTHORS

B E Shaw, F Lee, S Krishnamurthy, J L Byrne, C Seedhouse, N P Mayor, H Maldonado-Torres, A Saudemont, S G E Marsh, J A Madrigal, N H Russell

ABSTRACT

Allo-SCT using unrelated donors is a curative treatment for patients with hematological disorders. The best donor is one matched for 10/10 HLA alleles, however studies have shown an additional survival benefit when considering other genetic factors. It has been shown that a six-nucleotide insertion/deletion polymorphism in the CASP8 gene promoter results in reduced susceptibility of T lymphocytes to undergo apoptosis. In 186 SCT recipients, we found a significantly better OS in those who received a transplant from a WT/WT donor compared with donors with a deletion (3 years: 52 vs 34%; P=0.03; multivariate analysis; RR 0.61; 95% CI 0.38-0.98, P=0.04). This was more marked when both the patient and the donor had a deletion (3 years OS: 62% compared with 36%, P=0.01). As the majority of these patients received Alemtuzumab during conditioning, we went on to analyze the in vitro effect of the polymorphism on Alemtuzumab-induced apoptosis. We showed statistically significantly higher percentages of apoptotic naïve CD4 (P<0.0005) and CD8 (P<0.0005) T cells in WT/WT donors in comparison with donors with a deletion. These data imply an unrecognized role for the CASP8 promoter polymorphism on survival following unrelated SCT particularly in the context of T-cell depletion with Alemtuzumab. More... »

PAGES

237

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/bmt.2014.238

DOI

http://dx.doi.org/10.1038/bmt.2014.238

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1000455793

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/25347010


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