Faculty Collaboration Database

Caspase-8 polymorphisms result in reduced Alemtuzumab-induced T-cell apoptosis and worse survival after transplantation. Bone Marrow Transplant 2015 Feb;50(2):237-43

Date

10/28/2014

Pubmed ID

25347010

DOI

10.1038/bmt.2014.238

Scopus ID

2-s2.0-84922410096 (requires institutional sign-in at Scopus site)   2 Citations

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.

Author List

Shaw BE, Lee F, Krishnamurthy S, Byrne JL, Seedhouse C, Mayor NP, Maldonado-Torres H, Saudemont A, Marsh SG, Madrigal JA, Russell NH

Author

Bronwen E. Shaw MBChB, PhD Center Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Aged
Alemtuzumab
Allografts
Antibodies, Monoclonal, Humanized
Antineoplastic Agents
Apoptosis
Caspase 8
Child
Child, Preschool
Female
Hematologic Neoplasms
Humans
Lymphocyte Depletion
Male
Middle Aged
Polymorphism, Genetic
Stem Cell Transplantation
T-Lymphocytes
Transplantation Conditioning