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Increased splenic human CD4+:CD8+ T cell ratios, serum human interferon-γ and intestinal human interleukin-17 are associated with clinical graft-versus-host disease in humanized mice.
Transplant Immunology ( IF 1.6 ) Pub Date : 2019-02-08 , DOI: 10.1016/j.trim.2019.02.003
Nicholas J Geraghty 1 , Lisa Belfiore 1 , Sam R Adhikary 1 , Stephen I Alexander 2 , Ronald Sluyter 1 , Debbie Watson 1
Affiliation  

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.



中文翻译:

脾脏人类CD4 +:CD8 + T细胞比率增加,血清人类干扰素γ和肠道人类白介素17与人源化小鼠的临床移植物抗宿主病相关。

异体造血干细胞移植(HSCT)后,移植物抗宿主病(GVHD)是一种常见的并发症,目前的治疗方法仅限于一般的免疫抑制。GVHD的人源化小鼠模型正在作为有价值的中介物出现,以允许将同种异体小鼠模型的发现转化为人类,以预防和治疗该疾病,但是此类模型需要进一步表征。在这项研究中,人源化小鼠是通过向人外周血单核细胞(hPBMC)注射免疫缺陷型非肥胖型糖尿病严重合并免疫缺陷白介素(IL)-2受体γ普通链无效(NSG)小鼠而产生的。使用已建立的评分标准(体重减轻,姿势,活动,毛皮质地和皮肤完整性)评估了临床GVHD的发展。然后比较了产生临床或亚临床GVHD的人源化NSG小鼠之间的差异。两组小鼠均显示出相似的人类白细胞植入频率。相反,与具有亚临床GVHD的小鼠相比,具有临床GVHD的小鼠表现出更高的组织学损伤。此外,具有临床GVHD的小鼠脾脏人CD4含量增加+:CD8 + T细胞比率,血清人干扰素(IFN)-γ和肠道人IL-17表达与亚临床GVHD小鼠相比。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。这项研究还提供了对GVHD发育的进一步见解,这可能与人类HSCT受体有关。

更新日期:2019-02-08
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