Activation of Innate Immunity in Graft-versus-Host Disease: Implications for Novel Targets?

Zeiser, Robert

doi:10.1159/000381296

Cited by 10 publications

(7 citation statements)

References 67 publications

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“…This allows translocation of GI flora across the mucosal barrier ( 37 , 38 ) resulting in the release of inflammatory cytokines ( 39 ), danger associated molecular patterns (DAMPs), and pathogen associated molecular patterns (PAMPs). These molecules are then recognized by PRRs on APCs, allowing for their activation ( 40 – 42 ).…”

Section: Tlrs In Agvhdmentioning

confidence: 99%

Toll-Like Receptor Stimulation by MicroRNAs in Acute Graft-vs.-Host Disease

2018

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Acute graft-vs.-host disease (aGVHD) is a frequent complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), accounting for substantial morbidity and mortality associated with this treatment modality. The pathogenesis of aGVHD involves a complex cascade of humoral and cellular interactions in which donor T cells target HLA mismatched host tissues, causing tissue injury through secretion of pro-inflammatory cytokines and induction of direct cytotoxicity. Toll-like receptors (TLRs) are key components of the innate immune system that recognize endogenous danger-associated molecular patterns (DAMPs) and exogenous pathogen-associated molecular patterns (PAMPs). Patients receiving conditioning chemotherapy and/or whole-body irradiation prior to all-HSCT are prone to gastrointestinal damage and translocation of microbiota across compromised intestinal epithelium, resulting in release of PAMPs and DAMPs. These “danger signals” play critical roles in disease pathogenesis by both initiating and propagating aGVHD through dendritic cell maturation and alloreactive T cell responses. There are 10–15 TLRs identified in mammalian species, a subset of which recognize single-stranded RNA (ssRNA) and serve as a key component of viral immunity. Recently, ssRNAs other than those of viral origin have been investigated as potential ligands of TLRs. MicroRNAs (miRs) are short (19–24 nt) non-coding RNAs that play critical roles in a variety of diseases. While traditionally miRs post-translationally modulate gene expression, non-canonical functions such as regulating TLR stimulation by acting as TLR ligands have been described. Here, we review the role of TLRs in aGVHD pathogenesis, the function of miRs in TLR stimulation, and the recent literature describing miRs as TLR ligands in aGVHD.

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Section: Tlrs In Agvhdmentioning

confidence: 99%

Toll-Like Receptor Stimulation by MicroRNAs in Acute Graft-vs.-Host Disease

2018

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“…Emerging data showed that donor TLR4 and MyD88 deficiencies are protective against aGVHD [48], while activation of TLR9 with CpG-ODN in recipients markedly accelerates GVHD lethality [38,39]. Hence, novel therapeutic strategies that target TLR-mediated signaling pathways may be able to reduce the occurrence and severity of GVHD [49]. …”

Section: Inhibition Of Tlr Signaling Pathwaysmentioning

confidence: 99%

Role of Toll-Like Receptor Signaling in the Pathogenesis of Graft-versus-Host Diseases

Zhong

Xie

et al. 2016

IJMS

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Graft-versus-host disease (GVHD) and infection are major complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the leading causes of morbidity and mortality in HSCT patients. Recent work has demonstrated that the two complications are interdependent. GVHD occurs when allo-reactive donor T lymphocytes are activated by major histocompatibility antigens or minor histocompatibility antigens on host antigen-presenting cells (APCs), with the eventual attack of recipient tissues or organs. Activation of APCs is important for the priming of GVHD and is mediated by innate immune signaling pathways. Current evidence indicates that intestinal microbes and innate pattern-recognition receptors (PRRs) on host APCs, including both Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs), are involved in the pathogenesis of GVHD. Patients undergoing chemotherapy and/or total body irradiation before allo-HSCT are susceptible to aggravated gastrointestinal epithelial cell damage and the subsequent translocation of bacterial components, followed by the release of endogenous dangerous molecules, termed pathogen-associated molecular patterns (PAMPs), which then activate the PRRs on host APCs to trigger local or systemic inflammatory responses that modulate T cell allo-reactivity against host tissues, which is equivalent to GVHD. In other words, infection can, to some extent, accelerate the progression of GVHD. Therefore, the intestinal flora’s PAMPs can interact with TLRs to activate and mature APCs, subsequently activate donor T cells with the release of pro-inflammatory cytokines, and eventually, induce GVHD. In the present article, we summarize the current perspectives on the understanding of different TLR signaling pathways and their involvement in the occurrence of GVHD.

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“…NETs are identified as a new defensive mechanism of neutrophils against infectious pathogens through delivering a high local concentration of antimicrobial agents, such as myeloperoxidase (MPO) and neutrophil elastase (NE) [3]. Given the role of innate immune cells in the pathogenesis of graft versus host disease (GVHD) [4,5], whether NETs are involved in GVHD remains unclear. In this study, we aimed to evaluate surrogate parameters of NETs formation in patients with acute GVHD (aGVHD).…”

Section: Dear Editormentioning

confidence: 99%