P2X7 receptor activation impairs antitumour activity of natural killer cells

Baroja‐Mazo, Alberto; Peñín‐Franch, Alejandro; Lucas‐Ruiz, Fernando; Torre‐Minguela, Carlos de; Alarcón‐Vila, Cristina; Hernández‐Caselles, Trinidad; Pelegrı́n, Pablo

doi:10.1111/bph.15951

Cited by 7 publications

(2 citation statements)

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“…Consistent with this and as discussed above, this mAb also altered the proportions of hTregs, hNK T cells, and hTh17 cells, and so collectively, a greater number of lymphocyte subsets are impacted by the anti-hP2X7 mAb than by any of the small molecule P2X7 antagonists used previously in this model [ 20 , 21 , 22 , 37 ]. Of note, it has been observed that P2X7 activation impairs the antitumour activity of NK cells to human chronic myeloid leukaemia K562 cells [ 54 ]. Thus, combined with the notion that NK cells may help to both prevent GVHD and contribute to graft-versus-leukaemia immunity [ 55 ], use of an anti-hP2X7 mAb in such recipients may help improve outcomes in people with leukaemia following allogeneic HSCT.…”

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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“…This 7.5-Mb region shows an extended reduction in nucleotide diversity relative to other clades (Additional file 2: Fig. S5), and includes genes associated with canine body size and height [4] as well as glioma risk [123] and other cancer phenotypes [124][125][126].…”

Section: Discussionmentioning

confidence: 99%

Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture

Meadows,

Kidd,

Wang

et al. 2023

Genome Biol

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Background The international Dog10K project aims to sequence and analyze several thousand canine genomes. Incorporating 20 × data from 1987 individuals, including 1611 dogs (321 breeds), 309 village dogs, 63 wolves, and four coyotes, we identify genomic variation across the canid family, setting the stage for detailed studies of domestication, behavior, morphology, disease susceptibility, and genome architecture and function. Results We report the analysis of > 48 M single-nucleotide, indel, and structural variants spanning the autosomes, X chromosome, and mitochondria. We discover more than 75% of variation for 239 sampled breeds. Allele sharing analysis indicates that 94.9% of breeds form monophyletic clusters and 25 major clades. German Shepherd Dogs and related breeds show the highest allele sharing with independent breeds from multiple clades. On average, each breed dog differs from the UU_Cfam_GSD_1.0 reference at 26,960 deletions and 14,034 insertions greater than 50 bp, with wolves having 14% more variants. Discovered variants include retrogene insertions from 926 parent genes. To aid functional prioritization, single-nucleotide variants were annotated with SnpEff and Zoonomia phyloP constraint scores. Constrained positions were negatively correlated with allele frequency. Finally, the utility of the Dog10K data as an imputation reference panel is assessed, generating high-confidence calls across varied genotyping platform densities including for breeds not included in the Dog10K collection. Conclusions We have developed a dense dataset of 1987 sequenced canids that reveals patterns of allele sharing, identifies likely functional variants, informs breed structure, and enables accurate imputation. Dog10K data are publicly available.

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