Purinergic Signalling in Allogeneic Haematopoietic Stem Cell Transplantation and Graft-versus-Host Disease

Cuthbertson, Peter; Geraghty, Nicholas J.; Adhikary, Sam; Bird, Katrina M.; Fuller, Stephen J.; Watson, Debbie; Sluyter, Ronald

doi:10.3390/ijms22158343

Cited by 11 publications

(11 citation statements)

References 138 publications

(210 reference statements)

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“…The P2X7 receptor is an extracellular adenosine 5'-triphosphate (ATP)-gated receptor channel present on the cell surface of immune cells including antigen presenting cells (APCs) and T cells [4], cell types central in the development of GVHD [5]. To date various studies have established a role for the ATP-P2X7 signaling axis in the development of GVHD [6]. Intraperitoneal (i.p.)…”

Section: Introductionmentioning

confidence: 99%

The P2X7 Receptor Antagonist AZ10606120 Does Not Alter Graft-Versus-Host Disease Development and Increases Serum Human Interferon-γ in a Humanized Mouse Model

Geraghty¹,

Elhage²,

Cuthbertson³

et al. 2022

OBM Transplant

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Allogeneic hematopoietic stem cell transplantation is a curative therapy for hematological malignancies, but its efficacy is limited by graft-versus-host disease (GVHD). This life-threatening disorder develops when donor (graft) immune cells cause inflammatory damage to recipient (host) tissues. The immune cell receptor channel P2X7 and its ligand adenosine 5’-triphosphate (ATP) have been implicated in GVHD pathogenesis. Therefore, this signaling axis represents a potential therapeutic target. This study aimed to investigate if the specific P2X7 antagonist AZ10606120 (AZ10) could prevent GVHD development in a preclinical, humanized mouse model, in which NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice are injected with human peripheral blood mononuclear cells (hPBMCs). Flow cytometric measurements of ATP-induced cation dye uptake revealed that AZ10 blocked P2X7 activity in human RPMI 8226 multiple myeloma cells (IC50 of 1 ± 1 nM) and murine RAW 264.7 macrophages (IC50 of 3 ± 1 nM), as well as primary donor CD4+ and CD8+ T cells. However, AZ10 (2 mg/kg), injected intraperitonealy (i.p.) daily for the first 10 days post-hPBMC injection, did not reduce clinical or histological GVHD development in mice. AZ10 did not impact engraftment of human leukocytes, predominantly CD4+ and CD8+ T cells. However, AZ10 increased serum human interferon gamma (hIFN-γ) concentrations, with CD8+ T cells being the main hIFN-γ producing T cell subset. In conclusion, this study suggests a role for P2X7 activation in impairing hIFN-γ production during GVHD pathogenesis, with the use of P2X7 blockade as a therapeutic strategy warranting further investigation.

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Section: Introductionmentioning

confidence: 99%

The P2X7 Receptor Antagonist AZ10606120 Does Not Alter Graft-Versus-Host Disease Development and Increases Serum Human Interferon-γ in a Humanized Mouse Model

Geraghty¹,

Elhage²,

Cuthbertson³

et al. 2022

OBM Transplant

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“…Conversely, hydrolysis of extracellular ATP by CD39 and CD73 can lead to the generation of adenosine, which can bind A 2A receptors on immune cells to dampen GVHD (139).…”

Section: Damage-associated Molecular Patterns and Their Receptorsmentioning

confidence: 99%

“…Conversely, hydrolysis of extracellular ATP by CD39 and CD73 can lead to the generation of adenosine, which can bind A 2A receptors on immune cells to dampen GVHD [ 139 ]. Consistent with this, activation of the A 2A receptor in humanised mice resulted in a decrease in liver GVHD and human TNF-α [ 140 ].…”

Section: Cell Signalling Mechanisms In Gvhdmentioning

confidence: 99%

Insights into mechanisms of graft-versus-host disease through humanised mouse models

et al. 2022

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Graft-versus-host disease (GVHD) is a major complication that occurs following allogeneic haematopoietic stem cell transplantation (HSCT) for the treatment of haematological cancers and other blood-related disorders. GVHD is an inflammatory disorder, where the transplanted donor immune cells can mediate an immune response against the recipient and attack host tissues. Despite over 60 years of research, broad-range immune suppression is still used to prevent or treat GVHD, leading to an increased risk of cancer relapse and infection. Therefore, further insights into the disease mechanisms and development of predictive and prognostic biomarkers are key to improving outcomes and reducing GVHD development following allogeneic HSCT. An important preclinical tool to examine the pathophysiology of GVHD, and to understand the key mechanisms that lead to GVHD development, are preclinical humanised mouse models. Such models of GVHD are now well-established and can provide valuable insights into disease development. This review will focus on models where human peripheral blood mononuclear cells are injected into immune-deficient non-obese diabetic (NOD)-scid-interleukin-2(IL-2)Rγ mutant (NOD-scid-IL2Rγnull) mice. Humanised mouse models of GVHD can mimic the clinical setting for GVHD development, with disease progression and tissues impacted like that observed in humans. This review will highlight key findings from preclinical humanised mouse models regarding the role of donor human immune cells, the function of cytokines and cell signalling molecules and their impact on specific target tissues and GVHD development. Further, specific therapeutic strategies tested in these preclinical models reveal key molecular pathways important in reducing the burden of GVHD following allogeneic HSCT.

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“…Graft-Versus-Host Disease: Pathogenesis and Treatment DOI: http://dx.doi.org/10.5772/intechopen.104450 literature precedent suggests that the activation of the P2Y2 receptor can promote the migration of Tregs to sites of inflammation and thereby mitigate aGVHD [63]. Due to the dual functions of the P2Y2 receptor, targeting the P2Y2 receptor for the treatment has been challenging and there have been no reports about systemic injection of P2Y2 inhibitors/activators for the treatment of aGVHD [64].…”

Section: Link Between Gvhd and The Therapeutically Targetable Puriner...mentioning

confidence: 99%

Graft-Versus-Host Disease: Pathogenesis and Treatment

Mukai¹

2022

Purinergic System

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Graft-versus-host disease (GVHD) is a disabling complication after allogeneic hematopoietic stem cell transplantation (HSCT) and negatively impacts patients’ quality of life. GVHD is classified into 2 forms according to clinical manifestations. Acute GVHD (aGVHD) typically affects the skin, gastrointestinal tract, and liver, whereas chronic GVHD occurs systemically and shows diverse manifestations similar to autoimmune diseases such as eosinophilic fasciitis, scleroderma-like skin disease. GVHD is induced by complicated pathological crosstalk between immune cells of the host and donor and involves various signaling pathways such as purinergic signaling. Although the past several decades have seen significant progress in the understanding of mechanisms of GVHD and several drugs have been approved by FDA for the prevention and treatment of GVHD, there is still vast scope for improvement in the therapy for GVHD. Thus, new drugs for GVHD will need to be developed. Towards this goal, this chapter succinctly summarises the pathogenic process of GVHD and emerging GVHD treatments in order to provide some insights into the mechanisms of GVHD and facilitate the development of novel drugs.

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Purinergic Signalling in Allogeneic Haematopoietic Stem Cell Transplantation and Graft-versus-Host Disease

Cited by 11 publications

References 138 publications

The P2X7 Receptor Antagonist AZ10606120 Does Not Alter Graft-Versus-Host Disease Development and Increases Serum Human Interferon-γ in a Humanized Mouse Model

The P2X7 Receptor Antagonist AZ10606120 Does Not Alter Graft-Versus-Host Disease Development and Increases Serum Human Interferon-γ in a Humanized Mouse Model

Insights into mechanisms of graft-versus-host disease through humanised mouse models

Graft-Versus-Host Disease: Pathogenesis and Treatment

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