International Education and Research Center for Food and Agricultural Immunology, Tohoku University Graduate School of Agricultural Science, Miyagi, Japan; International Research and Development Center for Mucosal Vaccine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Division of Animal Science, Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, Tsukuba, Japan.
Cell Mol Gastroenterol Hepatol. 2020;10(1):83-100. doi: 10.1016/j.jcmgh.2020.01.011. Epub 2020 Feb 1.
BACKGROUND & AIMS: Organ-level research using an animal model lacking Il2rg, the gene responsible for X-linked severe combined immunodeficiency (X-SCID), is clinically unavailable and would be a powerful tool to gain deeper insights into the symptoms of patients with X-SCID.
We used an X-SCID animal model, which was first established in our group by the deletion of Il2rg gene in pigs, to understand the clinical signs from multiple perspectives based on pathology, immunology, microbiology, and nutrition. We also treated the X-SCID pigs with bone marrow transplantation (BMT) for mimicking a current therapeutic treatment for patients with X-SCID and investigated the effect at the organ-level. Moreover, the results were confirmed using serum and fecal samples collected from patients with X-SCID.
We demonstrated that X-SCID pigs completely lacked Peyer's patches (PPs) and IgA production in the small intestine, but possessed some dysfunctional intestinal T and B cells. Another novel discovery was that X-SCID pigs developed a heterogeneous intestinal microflora and possessed abnormal plasma metabolites, indicating that X-SCID could be an immune disorder that affects various in vivo functions. Importantly, the organogenesis of PPs in X-SCID pigs was not promoted by BMT. Although a few isolated lymphoid follicles developed in the small intestine of BMT-treated X-SCID pigs, there was no evidence that they contributed to IgA production and microflora formation. Consistently, most patients with X-SCID who received BMT possessed abnormal intestinal immune and microbial environments regardless of the presence of sufficient serum IgG.
These results indicate that the current BMT therapies for patients with X-SCID may be insufficient to induce the organogenesis of intestinal lymphoid tissues that are associated with numerous functions in vivo.
使用缺乏 Il2rg 基因（负责 X 连锁严重联合免疫缺陷症（X-SCID）的基因）的动物模型进行器官水平的研究在临床上不可用，但这将是深入了解 X-SCID 患者症状的有力工具。
我们使用了一种 X-SCID 动物模型，该模型最初由我们小组通过在猪中删除 Il2rg 基因建立，从多个角度基于病理学、免疫学、微生物学和营养学来了解临床症状。我们还对 X-SCID 猪进行了骨髓移植（BMT）治疗，以模拟目前对 X-SCID 患者的治疗方法，并研究器官水平的效果。此外，还使用从 X-SCID 患者收集的血清和粪便样本对结果进行了确认。
我们证明 X-SCID 猪完全缺乏派尔集合淋巴结（PPs）和小肠中的 IgA 产生，但具有一些功能失调的肠道 T 和 B 细胞。另一个新发现是，X-SCID 猪发展出了异质的肠道微生物群，并具有异常的血浆代谢物，表明 X-SCID 可能是一种影响各种体内功能的免疫紊乱。重要的是，BMT 不能促进 X-SCID 猪 PPs 的器官发生。尽管在 BMT 治疗的 X-SCID 猪的小肠中发育了一些孤立的淋巴滤泡，但没有证据表明它们有助于 IgA 产生和微生物群的形成。一致地，尽管大多数接受 BMT 的 X-SCID 患者具有异常的肠道免疫和微生物环境，但无论是否存在足够的血清 IgG，都存在这种情况。
这些结果表明，目前用于 X-SCID 患者的 BMT 疗法可能不足以诱导与体内众多功能相关的肠道淋巴组织的器官发生。
