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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.
Purinergic Signal. 2019 06; 15(2):177-192.PS

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.

Authors+Show Affiliations

School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia. Molecular Horizons, University of Wollongong, Wollongong, NSW, 2522, Australia. Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia.School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia. Molecular Horizons, University of Wollongong, Wollongong, NSW, 2522, Australia. Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia.School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia. Molecular Horizons, University of Wollongong, Wollongong, NSW, 2522, Australia. Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia.School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia. rsluyter@uow.edu.au. Molecular Horizons, University of Wollongong, Wollongong, NSW, 2522, Australia. rsluyter@uow.edu.au. Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia. rsluyter@uow.edu.au.School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia. dwatson@uow.edu.au. Molecular Horizons, University of Wollongong, Wollongong, NSW, 2522, Australia. dwatson@uow.edu.au. Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia. dwatson@uow.edu.au.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31001750

Citation

Adhikary, S R., 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, vol. 15, no. 2, 2019, pp. 177-192.
Adhikary SR, Geraghty NJ, 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 Signal. 2019;15(2):177-192.
Adhikary, S. R., Geraghty, N. J., Cuthbertson, P., Sluyter, R., & Watson, D. (2019). 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(2), 177-192. https://doi.org/10.1007/s11302-019-09651-8
Adhikary SR, 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 Signal. 2019;15(2):177-192. PubMed PMID: 31001750.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Adhikary,S R, AU - Geraghty,N J, AU - Cuthbertson,P, AU - Sluyter,R, AU - Watson,D, Y1 - 2019/04/18/ PY - 2018/10/11/received PY - 2019/03/04/accepted PY - 2019/4/20/pubmed PY - 2020/2/23/medline PY - 2019/4/20/entrez KW - Bone marrow transplantation KW - Humanised mice KW - Leukocyte KW - P2RX7 gene single nucleotide polymorphism KW - P2X7 receptor KW - Purinergic receptor KW - Xenogeneic graft-versus-host disease SP - 177 EP - 192 JF - Purinergic signalling JO - Purinergic Signal. VL - 15 IS - 2 N2 - 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. SN - 1573-9546 UR - https://www.unboundmedicine.com/medline/citation/31001750/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_ L2 - https://dx.doi.org/10.1007/s11302-019-09651-8 DB - PRIME DP - Unbound Medicine ER -