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Increased P2X7 expression in the gastrointestinal tract and skin in a humanised mouse model of graft-versus-host disease.
Clin Sci (Lond). 2020 01 31; 134(2):207-223.CS

Abstract

BACKGROUND

Allogeneic haematopoietic stem cell transplantation (HSCT) is a curative therapy for blood cancers; but results in the development of graft-versus-host disease (GVHD) in up to 70% of recipients. During GVHD, tissue damage results in ATP release into the extracellular compartment activating P2X7 on antigen-presenting cells, leading to the release of pro-inflammatory cytokines and subsequent activation of donor T cells. Therefore, the aim of the present study was to examine murine (m) P2rx7 and human (h) P2RX7 gene expression in GVHD target organs of humanised mice, and further characterise disease impact in these organs.

METHODS

NOD-scid IL2Rγnull (NSG) mice were injected with human peripheral blood mononuclear cells (hu-PBMC-NSG mice) or phosphate-buffered saline (PBS, control). Leucocytes were assessed by flow cytometry; gene expression was measured by quantitative polymerase chain reaction (qPCR), and tissue sections examined by histology.

RESULTS

Compared with control mice, hu-PBMC-NSG mice had increased mP2rx7 and mP2rx4 expression in the duodenum, ileum and skin. hP2RX7 was expressed in all tissues examined. hu-PBMC-NSG mice also displayed increased mReg3g expression in the duodenum and ileum, despite limited histological gut GVHD. hu-PBMC-NSG mice showed histological evidence of GVHD in the skin, liver and lung. Compared with control mice, hu-PBMC-NSG mice displayed increased ear swelling.

CONCLUSION

Combined data revealed that P2rx7 is up-regulated in gut and skin GVHD and that P2RX7 is present in target tissues of GVHD, corresponding to human leucocyte infiltration. Data also reveal increased mReg3g expression and ear swelling in hu-PBMC-NSG mice, offering new measurements of early-stage gut GVHD and skin GVHD, respectively.

Authors+Show Affiliations

Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia. Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia. Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia. Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia.Department of Pathology, Nepean Hospital, Penrith, NSW 2747, Australia.Sydney Medical School Nepean, University of Sydney, Nepean Hospital, Penrith, NSW 2747, Australia.Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia. Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia. Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia. Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.

Pub Type(s)

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

Language

eng

PubMed ID

31934722

Citation

Cuthbertson, Peter, et al. "Increased P2X7 Expression in the Gastrointestinal Tract and Skin in a Humanised Mouse Model of Graft-versus-host Disease." Clinical Science (London, England : 1979), vol. 134, no. 2, 2020, pp. 207-223.
Cuthbertson P, Adhikary SR, Geraghty NJ, et al. Increased P2X7 expression in the gastrointestinal tract and skin in a humanised mouse model of graft-versus-host disease. Clin Sci. 2020;134(2):207-223.
Cuthbertson, P., Adhikary, S. R., Geraghty, N. J., Guy, T. V., Hadjiashrafi, A., Fuller, S. J., Ly, D., Watson, D., & Sluyter, R. (2020). Increased P2X7 expression in the gastrointestinal tract and skin in a humanised mouse model of graft-versus-host disease. Clinical Science (London, England : 1979), 134(2), 207-223. https://doi.org/10.1042/CS20191086
Cuthbertson P, et al. Increased P2X7 Expression in the Gastrointestinal Tract and Skin in a Humanised Mouse Model of Graft-versus-host Disease. Clin Sci. 2020 01 31;134(2):207-223. PubMed PMID: 31934722.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Increased P2X7 expression in the gastrointestinal tract and skin in a humanised mouse model of graft-versus-host disease. AU - Cuthbertson,Peter, AU - Adhikary,Sam R, AU - Geraghty,Nicholas J, AU - Guy,Thomas V, AU - Hadjiashrafi,Amirazin, AU - Fuller,Stephen J, AU - Ly,Diane, AU - Watson,Debbie, AU - Sluyter,Ronald, PY - 2019/10/23/received PY - 2019/12/20/revised PY - 2020/01/14/accepted PY - 2020/1/15/pubmed PY - 2020/7/17/medline PY - 2020/1/15/entrez KW - P2X4 receptor KW - bone marrow transplantation KW - cutaneous lymphocyte antigen KW - integrin beta-7 KW - purinergic signalling KW - regenerating islet-derived 3 SP - 207 EP - 223 JF - Clinical science (London, England : 1979) JO - Clin. Sci. VL - 134 IS - 2 N2 - BACKGROUND: Allogeneic haematopoietic stem cell transplantation (HSCT) is a curative therapy for blood cancers; but results in the development of graft-versus-host disease (GVHD) in up to 70% of recipients. During GVHD, tissue damage results in ATP release into the extracellular compartment activating P2X7 on antigen-presenting cells, leading to the release of pro-inflammatory cytokines and subsequent activation of donor T cells. Therefore, the aim of the present study was to examine murine (m) P2rx7 and human (h) P2RX7 gene expression in GVHD target organs of humanised mice, and further characterise disease impact in these organs. METHODS: NOD-scid IL2Rγnull (NSG) mice were injected with human peripheral blood mononuclear cells (hu-PBMC-NSG mice) or phosphate-buffered saline (PBS, control). Leucocytes were assessed by flow cytometry; gene expression was measured by quantitative polymerase chain reaction (qPCR), and tissue sections examined by histology. RESULTS: Compared with control mice, hu-PBMC-NSG mice had increased mP2rx7 and mP2rx4 expression in the duodenum, ileum and skin. hP2RX7 was expressed in all tissues examined. hu-PBMC-NSG mice also displayed increased mReg3g expression in the duodenum and ileum, despite limited histological gut GVHD. hu-PBMC-NSG mice showed histological evidence of GVHD in the skin, liver and lung. Compared with control mice, hu-PBMC-NSG mice displayed increased ear swelling. CONCLUSION: Combined data revealed that P2rx7 is up-regulated in gut and skin GVHD and that P2RX7 is present in target tissues of GVHD, corresponding to human leucocyte infiltration. Data also reveal increased mReg3g expression and ear swelling in hu-PBMC-NSG mice, offering new measurements of early-stage gut GVHD and skin GVHD, respectively. SN - 1470-8736 UR - https://www.unboundmedicine.com/medline/citation/31934722/Increased_P2X7_expression_in_the_gastrointestinal_tract_and_skin_in_a_humanised_mouse_model_of_graft_versus_host_disease_ L2 - https://portlandpress.com/clinsci/article-lookup/doi/10.1042/CS20191086 DB - PRIME DP - Unbound Medicine ER -