Abstract
Hematopoietic stem cell transplantation (HSCT) is a highly advanced technique that offers a potential cure for an increasing number of life-threatening diseases. Enormous progress achieved in the last decade, including the refinement of donor selection and advancements in patient supportive care, had significantly improved transplant outcomes; however, invasive infections, graft-vs.-host disease (GVHD) and other serious complications still represent a major source of morbidity and mortality in HSCT recipients. The damage of anatomical barriers due to pre-transplant conditioning, a severely damaged immune function and a profound disruption in the composition of gut microbial commensals (gut microbiota) are alterations inherent to the transplant procedure that are directly implicated in the development of invasive infections and other HSCT complications. Although HLA-matching represents the most important genetic predictor of transplant outcomes, genetic variants in non-HLA genes, especially single nucleotide polymorphisms (SNPs) of genes encoding proteins associated with the immune response to tissue injury and pathogen infection have also been proposed as additional risk factors implicated in the occurrence of HSCT complications. Furthermore, although the microbiota composition is affected by several factors, recent evidence suggests that certain host genetic variants are associated with an altered composition of the gut microbiome and may, therefore, predispose some individuals to invasive infectious complications. This article summarizes the current understanding of the influence that genetic variants in non-HLA genes have on the development of infectious complications in HSCT recipients.
Highlights
Hematopoietic stem cell transplantation (HSCT) recipients often suffer severe alterations in their microbiota composition, and it has become evident that dysbiosis, especially that of the gut microbiota, is involved in the development of transplant complications, including acute graft-vs.-host disease (GVHD) and invasive bloodstream infections (BSI)
The human microbiota is essentially determined by environmental factors, convincing evidence indicates that genetics help regulate the microbiota composition
Of particular interest is the finding that several immunity-related risk alleles, such as nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants, have been shown to alter the microbiome composition in association with Enterobacteriaceae family enrichment in the gut microbiota (Knights et al, 2014), which may explain the link between NOD2 variants and severe infectious complications in HSCT (Holler et al, 2004; Hildebrandt et al, 2008; Jaskula et al, 2014; Grube et al, 2015)
Summary
Hematopoietic stem cell transplantation (HSCTs) involves the intravenous infusion of hematopoietic stem and progenitor cells (HSPCs) to restore the bone marrow (BM) function after intensive cancer-eradicating treatments or to replace defective bone marrow with normal bone marrow in non-malignant hematologic disorders (Gratwohl et al, 2010; Passweg et al, 2016). Several groups, including our own, have reported that genetic variants outside of the HLA region, especially in genes encoding components of the immune system, are predictive of the outcome following HSCT (Espinoza et al, 2009; Takami, 2013; Bogunia-Kubik and Łacina, 2017) Many of these gene-association studies were conducted in small series, and some included heterogeneous diseases with patients treated across multiple years with variable transplant regimens; the data were often not adjusted to a standardized format (Karaesmen et al, 2017). Rs1049174 is implicated in HSCT outcomes via the regulation of the NKG2D expression by immune cells
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