Improved outcome of hematopoietic SCT in patients with homozygous gene variant of Toll-like receptor 9

Abstract

Toll-like receptor 9 (TLR9) is part of the innate immune system, which is activated by CpG oligonucleotides (ODNs) and produces potent Th1-type innate and adaptive immune responses. It is reported that TLR9 gene variants, T1486C and T1237C, are associated with a reduced TLR9 expression compared with the wild-type gene. In two cohort analyses, we evaluated the influence of these gene variants on the outcome of transplant in 413 patients and donors. A retrospective analysis of the first cohort (n=293) showed that the homozygous CC gene variant of TLR9 (1486) compared with TC/TT gene variants was significantly associated with a markedly improved 5-year TRM (11.7 versus 36.4%, P<0.003), 5-year OS (86.1 vs 48.3%, P<0.001) and a lower relapse rate (13.2 vs 33.3%, P<0.007), whereas the occurrence of acute GVHD was not different. A prospectively performed analysis of the second cohort (n=120) and multivariate analyses confirmed the influence of the CC gene variant on these end points. Compared with patients with TC/TT gene at position 1486 of TLR9, patients with the homozygous CC gene variant had a lower TLR9 mRNA expression and a delayed T-cell immune reconstitution after transplant, which might prevent them from overwhelming immune responses as sepsis or systemic inflammatory response syndrome (SIRS) associated with an increased TRM. In vitro studies using CpG-rich ODNs showed an upregulation of TLR9 expression in cell lines with CC gene variant, but not in cell lines with wild-type gene.