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-IL2Rγ^null (NSG) mice were injected with human peripheral blood mononuclear cells isolated from donors of either GOF (hP2X7^GOF mice) or LOF (hP2X7^LOF mice) P2RX7 genotype. Both hP2X7^GOF and hP2X7^LOF 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, hP2X7^GOF and hP2X7^LOF 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.

中文翻译：

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人白细胞中供体P2X7活性的改变与P2RX7基因型相关，但不影响人源化小鼠中移植物抗宿主病的发展。

移植物抗宿主病（GVHD）是同种异体造血干细胞移植的致命威胁，这是血液系统恶性肿瘤的治疗方法。ATP门控的P2X7受体通道与GVHD的发生有关。P2RX7基因中的功能获得（GOF）和功能丧失（LOF）单核苷酸多态性（SNP）可影响人白细胞上的P2X7活性。在这项研究中，在25位人类供体中对P2RX7基因进行了测序，并使用ATP诱导的染料吸收测定法测量了P2X7在外周血T细胞，自然杀伤（NK）细胞和单核细胞上的活性。GOF和LOF SNP代表17种已知P2RX7中的10种鉴定了单倍型，并与所研究的所有白细胞亚群上的P2X7活性相关。值得注意的是，在所有研究的细胞类型中，不变（i）NK T细胞显示出最高的P2X7活性。要确定是否供体P2X7活动影响GVHD的发展，免疫缺陷NOD-SCID-IL2Rγ^空（NSG）小鼠用从任GOF（hP2X7的供体分离的人外周血单核细胞注射的^GOF小鼠）或LOF（hP2X7 ^LOF只小鼠）P2RX7基因型。hP2X7 ^GOF和hP2X7 ^LOF小鼠表现出相似的人类白细胞植入，并显示出相当的体重减轻，GVHD临床评分和总生存期。供体P2X7活性不影响人白细胞浸润或GVHD介导的组织损伤，也不影响组织中人P2X7或人干扰素-γ（hIFNγ）的相对表达。最后，hP2X7 ^GOF和hP2X7 ^LOF小鼠表现出相似的血清hIFNγ浓度。这项研究表明，P2X7活性与在GVHD发育中重要的人白细胞亚群上的供体P2RX7基因型相关，但在该疾病的人源化小鼠模型中不影响GVHD的发育。