Donor TLR9 gene tagSNPs influence susceptibility to aGVHD and CMV reactivation in the allo-HSCT setting without polymorphisms in the TLR4 and NOD2 genes

Xiao, Huaying; Luo, Yi; Lai, Xiaoyu; Shi, Jimin; Tan, Yamin; He, Jianqin; Xie, Wanzhuo; Zheng, Weiyan; Ye, X J; Yu, Xiaobo; Cai, Zhiyong; Lin, Maofang; Huang, He

doi:10.1038/bmt.2013.160

Cited by 25 publications

(27 citation statements)

References 43 publications

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“…Less consistent results come from human studies: Transplant patients who carry gene variants associated with reduced TLR9 expression showed GVDH occurrence similar to control patients (38). A recent report analyzed two alternative SNPs that have been described to interfere with the TLR signaling pathway (39). While patients receiving stem cells from an unrelated donor with the A1174G variant experienced severe acute GVHD more frequently (49.5 vs. 20.7%), the T1635C variant in donor cells was associated with protective effect against severe acute GVHD (16.7 vs. 49.1%).…”

Section: Toll-like Receptors In Gvhd Pathogenesismentioning

confidence: 99%

The Role of Pattern-Recognition Receptors in Graft-Versus-Host Disease and Graft-Versus-Leukemia after Allogeneic Stem Cell Transplantation

et al. 2014

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with curative potential for certain aggressive hematopoietic malignancies. Its success is limited by acute graft-versus-host disease (GVHD), a life-threatening complication that occurs when allo-reactive donor T cells attack recipient organs. There is growing evidence that microbes and innate pattern-recognition receptors (PRRs) such as toll-like receptors (TLR) and nod-like receptors (NLR) are critically involved in the pathogenesis of acute GVHD. Currently, a widely accepted model postulates that intensive chemotherapy and/or total-body irradiation during pre-transplant conditioning results in tissue damage and a loss of epithelial barrier function. Subsequent translocation of bacterial components as well as release of endogenous danger molecules stimulate PRRs of host antigen-presenting cells to trigger the production of pro-inflammatory cytokines (cytokine storm) that modulate T cell allo-reactivity against host tissues, but eventually also the beneficial graft-versus-leukemia (GVL) effect. Given the limitations of existing immunosuppressive therapies, a better understanding of the molecular mechanisms that govern GVHD versus GVL is urgently needed. This may ultimately allow to design modulators, which protect from GvHD but preserve donor T-cell attack on hematologic malignancies. Here, we will briefly summarize current knowledge about the role of innate immunity in the pathogenesis of GVHD and GVL following allo-HSCT.

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Section: Toll-like Receptors In Gvhd Pathogenesismentioning

confidence: 99%

The Role of Pattern-Recognition Receptors in Graft-Versus-Host Disease and Graft-Versus-Leukemia after Allogeneic Stem Cell Transplantation

et al. 2014

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“…SNPs in these genes in donor and recipient have been associated with the occurrence of CMV reactivation, its duration, the peak levels of CMV DNAaemia and the development of CMV disease. [86][87][88][89] To date study findings have been inconsistent, limited by small numbers and mechanistic data is lacking. Larger confirmatory studies are required before recipient and donor SNPs can be to used for risk stratification or to guide therapeutic interventions.…”

Section: Factors Influencing CMV Immunity Post Transplantmentioning

confidence: 99%

CMV-specific immune reconstitution following allogeneic stem cell transplantation

et al. 2016

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Cytomegalovirus (CMV) remains a major contributor to morbidity and mortality following allogeneic haemopoietic stem cell transplant (HSCT) despite widespread use of viraemia monitoring and preemptive antiviral therapy. Uncontrolled viral replication occurs primarily in the first 100 d post transplant but this high risk period can extend to many months if immune recovery is delayed. The re-establishment of a functional population of cellular effectors is essential for control of virus replication and depends on recipient and donor serostatus, the stem cell source, degree of HLA matching and post-transplant factors such as CMV antigen exposure, presence of GVHD and ongoing use of immune suppression. A number of immune monitoring assays exist but have not yet become widely accessible for routine clinical use. Vaccination, adoptive transfer of CMV specific T cells and a number of graft engineering processes are being evaluated to enhance of CMV specific immune recovery post HSCT.

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“…During recent years, many studies have provided convergent lines of evidence for a link between Single Nucleotide Polymorphisms (SNPs) from specific genes and HSCT outcomes [2] . The nucleotide-binding oligomerization domain containing 2 (NOD2) gene, previously known as the caspase recruitment domain 15 (CARD15) gene, is one such candidate gene.…”

Section: Introductionmentioning

confidence: 99%

Distinct NOD2 polymorphism status is associated with differential outcome in hematopoietic stem cell transplantation: results from a meta-analysis

Zhou¹,

Su²,

Xing³

et al. 2017

IJHT

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Objective: Susceptibility to Graft-Versus-Host Disease (GvHD) following Hematopoietic Stem Cell Transplantation (HSCT) has been linked to the NOD2 gene, but results have been so far conflicting among individual studies. The aim of this meta-analysis was to investigate NOD2 (nucleotide-binding oligomerisation domain containing 2) polymorphisms as possible susceptibility loci for GvHD as well as other life-threatening complications following HSCT. Methods: Available studies addressing a possible contribution of NOD2 polymorphisms to GvHD and complications following HSCT were identified through database searches. We analyzed the HSCT outcomes and any of the NOD2 polymorphisms in either donor or recipient. Pooled relative risks (RRs) and their 95 % CI were calculated to assess the strength of correlation. Results: NOD2 polymorphisms whether in recipient or donor, or recipient and donor-side transplant pairs, were significantly associated with severe GvHD (P = 0.004). However, only trends were observed in terms of the association between polymorphisms and decreasing mild GvHD, 1-year overall survival, disease-free survival, or increasing transplantation-related mortality and relapse (P > 0.05). NOD2 polymorphisms on the donor-side only were associated with higher risk of severe GvHD (P = 0.09), and the association was also observed in pairs where polymorphisms were carried by both the recipient and the donor (P = 0.002). Increased GvHD risk was not associated with polymorphisms in recipient-side only transplant pairs. Furthermore, the association was not attributable to any specific NOD2 genotype. Conclusions: NOD2 polymorphism confers the more negative outcomes following HSCT. Donor and both-side mutation in transplants could increase the risk of severe GvHD. NOD2 genotyping may therefore be of clinical value.

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Donor TLR9 gene tagSNPs influence susceptibility to aGVHD and CMV reactivation in the allo-HSCT setting without polymorphisms in the TLR4 and NOD2 genes

Cited by 25 publications

References 43 publications

The Role of Pattern-Recognition Receptors in Graft-Versus-Host Disease and Graft-Versus-Leukemia after Allogeneic Stem Cell Transplantation

The Role of Pattern-Recognition Receptors in Graft-Versus-Host Disease and Graft-Versus-Leukemia after Allogeneic Stem Cell Transplantation

CMV-specific immune reconstitution following allogeneic stem cell transplantation

Distinct NOD2 polymorphism status is associated with differential outcome in hematopoietic stem cell transplantation: results from a meta-analysis

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