The Coming of Age of the P2X7 Receptor in Diagnostic Medicine

Virgilio, Francesco Di; Vultaggio-Poma, Valentina; Falzoni, Simonetta

doi:10.3390/ijms24119465

Cited by 9 publications

(5 citation statements)

References 78 publications

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“…Combined, these studies support the future use of anti-hP2X7 biologics as potential therapeutics in people in which a role of P2X7 activation is indicated. The use of such biologics may help overcome some of the limitations observed with small molecule P2X7 antagonists in clinical trials, which to date have yielded unsatisfying results [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

A Species-Specific Anti-Human P2X7 Monoclonal Antibody Reduces Graft-versus-Host Disease in Humanised Mice

Elhage,

Cuthbertson,

Sligar

et al. 2023

Pharmaceutics

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Graft-versus-host disease (GVHD) is a T cell-mediated inflammatory disorder that arises from allogeneic haematopoietic stem cell transplantation and is often fatal. The P2X7 receptor is an extracellular adenosine 5′-triphosphate-gated cation channel expressed on immune cells. Blockade of this receptor with small molecule inhibitors impairs GVHD in a humanised mouse model. A species-specific blocking monoclonal antibody (mAb) (clone L4) for human P2X7 is available, affording the opportunity to determine whether donor (human) P2X7 contributes to the development of GVHD in humanised mice. Using flow cytometric assays of human RPMI 8266 and murine J774 cells, this study confirmed that this mAb bound and impaired human P2X7. Furthermore, this mAb prevented the loss of human regulatory T cells (hTregs) and natural killer (hNK) T cells in vitro. NOD-scid IL2Rγnull mice were injected with 10 × 106 human peripheral blood mononuclear cells (Day 0) and an anti-hP2X7 or control mAb (100 μg i.p. per mouse, Days 0, 2, 4, 6, and 8). The anti-hP2X7 mAb increased hTregs and hNK cells at Day 21. Moreover, anti-hP2X7 mAb-treatment reduced clinical and histological GVHD in the liver and lung compared to the control treatment at disease endpoint. hTregs, hNK, and hNK T cell proportions were increased, and human T helper 17 cell proportions were decreased at endpoint. These studies indicate that blockade of human (donor) P2X7 reduces GVHD development in humanised mice, providing the first direct evidence of a role for donor P2X7 in GVHD.

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Section: Discussionmentioning

confidence: 99%

A Species-Specific Anti-Human P2X7 Monoclonal Antibody Reduces Graft-versus-Host Disease in Humanised Mice

Elhage,

Cuthbertson,

Sligar

et al. 2023

Pharmaceutics

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“…Meanwhile, many P2X7R radioligands have been developed to be used as tracers for imaging and inflammatory responses in CNS disorders, including cancer [140]. This gives rise to hope that P2X7Rs could soon be used as tumor markers for possible early diagnosis of human diseases, until new data allows the use of the ligands of these receptors as new therapeutic agents [141].…”

Section: Discussionmentioning

confidence: 99%

Changes Induced by P2X7 Receptor Stimulation of Human Glioblastoma Stem Cells in the Proteome of Extracellular Vesicles Isolated from Their Secretome

Di Giuseppe,

Ricci-Vitiani,

Pallini

et al. 2024

Cells

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Extracellular vesicles (EVs) are secreted from many tumors, including glioblastoma multiforme (GBM), the most common and lethal brain tumor in adults, which shows high resistance to current therapies and poor patient prognosis. Given the high relevance of the information provided by cancer cell secretome, we performed a proteomic analysis of microvesicles (MVs) and exosomes (EXOs) released from GBM-derived stem cells (GSCs). The latter, obtained from the brain of GBM patients, expressed P2X7 receptors (P2X7Rs), which positively correlate with GBM growth and invasiveness. P2X7R stimulation of GSCs caused significant changes in the EV content, mostly ex novo inducing or upregulating the expression of proteins related to cytoskeleton reorganization, cell motility/spreading, energy supply, protection against oxidative stress, chromatin remodeling, and transcriptional regulation. Most of the induced/upregulated proteins have already been identified as GBM diagnostic/prognostic factors, while others have only been reported in peripheral tumors. Our findings indicate that P2X7R stimulation enhances the transport and, therefore, possible intercellular exchange of GBM aggressiveness-increasing proteins by GSC-derived EVs. Thus, P2X7Rs could be considered a new druggable target of human GBM, although these data need to be confirmed in larger experimental sets.

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“…Pore formation after prolonged activation of the P2X7 receptor leads to apoptosis. P2X7 receptor activation is reported to be involved in multiple pathologies, from immune disorders to degenerative diseases [ 51 , 52 , 53 , 54 , 55 , 56 ]. There is evidence to suggest that the P2X7 receptor may play a role in the pathophysiology of various placental disorders, including preeclampsia and intrauterine growth restriction (IUGR) [ 57 ].…”

Section: Need For New Methodsmentioning

confidence: 99%

Advancing Endocrine Disruptors via In Vitro Evaluation: Recognizing the Significance of the Organization for Economic Co-Operation and Development and United States Environmental Protection Agency Guidelines, Embracing New Assessment Methods, and the Urgent Need for a Comprehensive Battery of Tests

Fouyet,

Ferger,

Leproux

et al. 2024

Toxics

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Efforts are being made globally to improve the evaluation and understanding of endocrine-disrupting chemicals. Recognition of their impact on human health and the environment has stimulated attention and research in this field. Various stakeholders, including scientists, regulatory agencies, policymakers, and industry representatives, are collaborating to develop robust methodologies and guidelines for assessing these disruptors. A key aspect of these efforts is the development of standardized testing protocols and guidelines that aim to provide consistent and reliable methods for identifying and characterizing endocrine disruptors. When evaluating the potential endocrine-disrupting activity of chemicals, no single test is capable of detecting all relevant endocrine-disrupting agents. The test battery approach is designed to reduce the risk of false negative results for compounds with toxic potential. A weight-of-evidence approach is therefore necessary for endocrine disruptor evaluation. This approach considers various types of data from multiple sources, assessing the overall strength, consistency, and reliability of the evidence. OECD guidelines are highly regarded for their scientific rigor, transparency, and consensus-based development process. It is crucial to explore and develop new methodologies that can effectively evaluate the risks associated with potential endocrine disruptors. Integrating these methods into a comprehensive weight-of-evidence framework will enhance risk assessments and facilitate informed decisions regarding the regulation and management of these substances, ensuring the protection of human health and the environment from their adverse effects.

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The Coming of Age of the P2X7 Receptor in Diagnostic Medicine

Cited by 9 publications

References 78 publications

A Species-Specific Anti-Human P2X7 Monoclonal Antibody Reduces Graft-versus-Host Disease in Humanised Mice

A Species-Specific Anti-Human P2X7 Monoclonal Antibody Reduces Graft-versus-Host Disease in Humanised Mice

Changes Induced by P2X7 Receptor Stimulation of Human Glioblastoma Stem Cells in the Proteome of Extracellular Vesicles Isolated from Their Secretome

Advancing Endocrine Disruptors via In Vitro Evaluation: Recognizing the Significance of the Organization for Economic Co-Operation and Development and United States Environmental Protection Agency Guidelines, Embracing New Assessment Methods, and the Urgent Need for a Comprehensive Battery of Tests

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