School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2252, Australia; Molecular Horizons, University of Wollongong, Wollongong, NSW 2252, Australia; Illawarra Health and Medical Research Institute, Wollongong, NSW 2252, Australia.
Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, NSW, Australia.
Transpl Immunol. 2019 Jun;54:38-46. doi: 10.1016/j.trim.2019.02.003. Epub 2019 Feb 8.
Graft-versus-host disease (GVHD) is a frequent complication following allogeneic hematopoietic stem cell transplantation (HSCT) with current therapies limited to general immunosuppression. Humanized mouse models of GVHD are emerging as valuable intermediaries to allow translation of findings from allogeneic mouse models to humans to prevent and treat this disease, but such models require further characterization. In this study, humanized mice were generated by injecting immunodeficient non-obese diabetic severe combined immunodeficiency interleukin (IL)-2 receptor γ common chain null (NSG) mice with human peripheral blood mononuclear cells (hPBMCs). Clinical GVHD development was assessed using established scoring criteria (weight loss, posture, activity, fur texture and skin integrity). Differences between humanized NSG mice that developed clinical or subclinical GVHD were then compared. Both groups of mice demonstrated similar frequencies of human leukocyte engraftment. In contrast, mice that developed clinical GVHD demonstrated increased histological damage compared to mice with subclinical GVHD. Furthermore, mice with clinical GVHD exhibited increases in the splenic human CD4:CD8 T cell ratio, serum human interferon (IFN)-γ and intestinal human IL-17 expression compared to mice with subclinical GVHD. These cellular and molecular changes could be used as potential markers of disease progression in this preclinical model. This study also provides further insights into GVHD development which may be relevant to human HSCT recipients.
移植物抗宿主病（GVHD）是异基因造血干细胞移植（HSCT）后的常见并发症，目前的治疗方法仅限于一般免疫抑制。GVHD 的人源化小鼠模型作为有价值的中介正在出现，以允许将异体小鼠模型的研究结果转化为人类，从而预防和治疗这种疾病，但此类模型需要进一步表征。在这项研究中，通过向免疫缺陷非肥胖糖尿病严重联合免疫缺陷白细胞介素（IL）-2 受体 γ 共同链缺失（NSG）小鼠注射人外周血单核细胞（hPBMCs）来生成人源化小鼠。使用既定的评分标准（体重减轻、姿势、活动、毛发质地和皮肤完整性）评估临床 GVHD 的发展。然后比较发生临床或亚临床 GVHD 的人源化 NSG 小鼠之间的差异。两组小鼠均表现出相似的人白细胞植入频率。相比之下，与发生亚临床 GVHD 的小鼠相比，发生临床 GVHD 的小鼠表现出更高的组织学损伤。此外，与发生亚临床 GVHD 的小鼠相比，发生临床 GVHD 的小鼠的脾人 CD4：CD8 T 细胞比、血清人干扰素（IFN）-γ 和肠道人白细胞介素（IL）-17 表达增加。这些细胞和分子变化可用作该临床前模型中疾病进展的潜在标志物。本研究还进一步深入了解 GVHD 的发展，这可能与人类 HSCT 受者相关。
