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Altered donor P2X7 activity in human leukocytes correlates with P2RX7 genotype but does not affect the development of graft-versus-host disease in humanised mice

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Abstract

Graft-versus-host disease (GVHD) is a life-threatening consequence of allogeneic haematopoietic stem cell transplantation, a curative therapy for haematological malignancies. The ATP-gated P2X7 receptor channel is implicated in the development of GVHD. P2X7 activity on human leukocytes can be influenced by gain-of-function (GOF) and loss-of-function (LOF) single nucleotide polymorphisms (SNPs) in the P2RX7 gene. In this study, the P2RX7 gene was sequenced in 25 human donors and the P2X7 activity on subsets of peripheral blood T cells, natural killer (NK) cells and monocytes was measured using an ATP-induced dye uptake assay. GOF and LOF SNPs representing 10 of the 17 known P2RX7 haplotypes were identified, and correlated with P2X7 activity on all leukocyte subsets investigated. Notably, invariant (i) NK T cells displayed the highest P2X7 activity amongst all cell types studied. To determine if donor P2X7 activity influenced the development of GVHD, immunodeficient NOD-SCID-IL2Rγnull (NSG) mice were injected with human peripheral blood mononuclear cells isolated from donors of either GOF (hP2X7GOF mice) or LOF (hP2X7LOF mice) P2RX7 genotype. Both hP2X7GOF and hP2X7LOF mice demonstrated similar human leukocyte engraftment, and showed comparable weight loss, GVHD clinical score and overall survival. Donor P2X7 activity did not affect human leukocyte infiltration or GVHD-mediated tissue damage, or the relative expression of human P2X7 or human interferon-γ (hIFNγ) in tissues. Finally, hP2X7GOF and hP2X7LOF mice demonstrated similar concentrations of serum hIFNγ. This study demonstrates that P2X7 activity correlates with donor P2RX7 genotype on human leukocyte subsets important in GVHD development, but does not affect GVHD development in a humanised mouse model of this disease.

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Acknowledgements

The authors thank all blood donors who contributed to this study, Margaret Phillips (University of Wollongong) for sequencing DNA, Sandra Burrell for assistance with DNA sequencing, the technical staff of the Illawarra Health and Medical Research Institute (Wollongong, Australia) and the animal staff of the University of Wollongong Faculty of Science, Medicine and Health (University of Wollongong) for technical support.

Funding

This project was funded by the Faculty of Science, Medicine and Health, University of Wollongong. SR Adhikary, NJ Geraghty and P Cuthbertson are supported through Australian Government Research Training Program Scholarships. D Watson is supported by AMP’s Tomorrow Fund. D Watson and R Sluyter receive additional support from Molecular Horizons (University of Wollongong).

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  1. R Sluyter and D Watson are co-senior authors.

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  1. School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia

    S. R. Adhikary, N. J. Geraghty, P. Cuthbertson, R. Sluyter & D. Watson

  2. Molecular Horizons, University of Wollongong, Wollongong, NSW, 2522, Australia

    S. R. Adhikary, N. J. Geraghty, P. Cuthbertson, R. Sluyter & D. Watson

  3. Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia

    S. R. Adhikary, N. J. Geraghty, P. Cuthbertson, R. Sluyter & D. Watson

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Sam R Adhikary declares that he has no conflict of interest.

Nicholas J Geraghty declares that he has no conflict of interest.

Peter Cuthbertson declares that he has no conflict of interest.

Ronald Sluyter declares that he has no conflict of interest.

Debbie Watson declares that she has no conflict of interest.

Ethical approval

All animal experiments were approved under protocol AE16/03 by the University of Wollongong Animal Ethics Committee. All human experiments were approved under protocol HE12/290 by the University of Wollongong Human Ethics Committee.

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Adhikary, S.R., Geraghty, N.J., Cuthbertson, P. et al. Altered donor P2X7 activity in human leukocytes correlates with P2RX7 genotype but does not affect the development of graft-versus-host disease in humanised mice. Purinergic Signalling 15, 177–192 (2019). https://doi.org/10.1007/s11302-019-09651-8

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  • DOI: https://doi.org/10.1007/s11302-019-09651-8

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