Abstract Objectives Graft‐versus‐host disease (GVHD) is an inflammatory disorder that arises following allogeneic haematopoietic stem cell transplantation. P2X7 is an extracellular ATP‐gated cation channel present on immune cells. P2X7 blockade with small molecule inhibitors impairs GVHD development in a humanised mouse model. This study investigated whether adeno‐associated viral (AAV) vectors encoding nanobodies (Nbs) that block mouse P2X7 (mP2X7) or both mP2X7 and human P2X7 (m/hP2X7) impair GVHD development in this model. Methods On Day −21, NOD.Cg‐ Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice were injected intramuscularly with 10 × 10 10 viral genomes encoding either green fluorescent protein (GFP), an anti‐mP2X7 Nb or an anti‐m/hP2X7 Nb, or with saline. On Day 0, mice were euthanised or injected intraperitoneally with 10 × 10 6 human peripheral blood mononuclear cells and monitored thrice weekly for signs of GVHD until the experiment or disease endpoint. Results The anti‐m/hP2X7 and anti‐mP2X7 Nbs reduced clinical GVHD and time to disease onset, as well as liver and lung GVHD. Both Nbs reduced liver human T helper (Th)17 cells. Sera collected at Day 0 and disease endpoint from treated mice, but not from control mice, completely blocked P2X7 activity in human RPMI 8226 and/or murine J774 cells, confirming circulating anti‐P2X7 Nbs in mice from Day 0 to disease endpoint. Conclusion This study indicates that P2X7 blockade with an anti‐m/hP2X7 and to a lesser extent an anti‐mP2X7 Nb reduces GVHD progression in humanised mice. This supports the future testing of these P2X7 biologics as a prophylactic therapy for GVHD.
Elhage et al. (Wed,) studied this question.
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