TY - JOUR AU - Geraghty, Nicholas J AU - Elhage, Amal AU - Cuthbertson, Peter AU - Watson, Debbie AU - Sluyter, Ronald PY - 2022 DA - 2022/09/06 TI - The P2X7 Receptor Antagonist AZ10606120 Does Not Alter Graft-Versus-Host Disease Development and Increases Serum Human Interferon-γ in a Humanized Mouse Model JO - OBM Transplantation SP - 166 VL - 06 IS - 03 AB - Allogeneic hematopoietic stem cell transplantation is a curative therapy for hematological malignancies, but its efficacy is limited by graft-versus-host disease (GVHD). This life-threatening disorder develops when donor (graft) immune cells cause inflammatory damage to recipient (host) tissues. The immune cell receptor channel P2X7 and its ligand adenosine 5’-triphosphate (ATP) have been implicated in GVHD pathogenesis. Therefore, this signaling axis represents a potential therapeutic target. This study aimed to investigate if the specific P2X7 antagonist AZ10606120 (AZ10) could prevent GVHD development in a preclinical, humanized mouse model, in which NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice are injected with human peripheral blood mononuclear cells (hPBMCs). Flow cytometric measurements of ATP-induced cation dye uptake revealed that AZ10 blocked P2X7 activity in human RPMI 8226 multiple myeloma cells (IC50 of 1 ± 1 nM) and murine RAW 264.7 macrophages (IC50 of 3 ± 1 nM), as well as primary donor CD4+ and CD8+ T cells. However, AZ10 (2 mg/kg), injected intraperitonealy (i.p.) daily for the first 10 days post-hPBMC injection, did not reduce clinical or histological GVHD development in mice. AZ10 did not impact engraftment of human leukocytes, predominantly CD4+ and CD8+ T cells. However, AZ10 increased serum human interferon gamma (hIFN-γ) concentrations, with CD8+ T cells being the main hIFN-γ producing T cell subset. In conclusion, this study suggests a role for P2X7 activation in impairing hIFN-γ production during GVHD pathogenesis, with the use of P2X7 blockade as a therapeutic strategy warranting further investigation. SN - 2577-5820 UR - https://doi.org/10.21926/obm.transplant.2203166 DO - 10.21926/obm.transplant.2203166 ID - Geraghty2022 ER -