Acute cellular rejection (ACR) remains as one of the main causes of graft loss and death in intestinal transplant (ITx) patients. ACR promotes intestinal injury, disruption of the mucosal barrier, bacterial translocation, and organ dysfunction. As epithelial regeneration is critical in reversing these consequences, the functional axis between the innate lymphoid cell subpopulation 3 (ILC3) and interleukin 22 plays an essential role in that process. Natural-cytotoxic-receptor–positive (NCR⁺) ILC3 cells have been demonstrated to induce intestinal-stem-cell proliferation along with an IL-22–dependent expansion of that population in several intestinal pathologies, though thus far not after ITx. Therefore, we intended to determine the impact of chronic immunosuppression and ACR on ILC3 cells and interleukin-22 (IL-22) production in the lamina propria after that intervention.

Materials and methods

We compared biopsies from healthy volunteers with biopsies from ITx recipients without or with mild-to-moderate ACR, using flow cytometry and the quantitative-PCR.

Results

NCR⁺ ILC3 cells were found to be unaffected by immunosuppression at different time points posttransplant when patients did not experience ACR, but were diminished upon the occurrence of ACR independently of the post-ITx time. Moreover, IL-22–expression levels were notably reduced in ACR.

Conclusion

The NCR⁺-ILC3/IL-22 axis is impaired during ACR contributing to a delay in or lack of a complete and efficient epithelial regeneration. Thus, our findings reveal that IL-22 analogues could potentially be used as a new complementary therapeutic approach, in conjunction with immunosuppressant drugs, in order to promote mucosal regeneration upon ACR.

中文翻译：

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小肠移植中的急性细胞排斥反应损害NCR +先天性淋巴样细胞亚群3 /白介素22轴。

急性细胞排斥反应（ACR）仍然是肠移植（ITx）患者移植物丢失和死亡的主要原因之一。ACR促进肠道损伤，粘膜屏障破坏，细菌移位和器官功能障碍。由于上皮再生对于逆转这些后果至关重要，因此先天淋巴样细胞亚群3（ILC3）和白介素22之间的功能轴在该过程中起着至关重要的作用。天然细胞毒性受体阳性（NCR ⁺）已证明，ILC3细胞可在几种肠道病理学中诱导肠干细胞增殖以及该人群的IL-22依赖性扩增，尽管到目前为止还没有在ITx之后。因此，我们打算确定在干预后，慢性免疫抑制和ACR对固有层中ILC3细胞和白细胞介素22（IL-22）产生的影响。

材料和方法

我们使用流式细胞术和定量PCR，将健康志愿者的活检与未接受或接受轻至中度ACR的ITx接受者的活检进行了比较。

结果

NCR ⁺ ILC3细胞在患者未经历ACR的情况下在移植后的不同时间点不受免疫抑制的影响，但在发生ACR时会减少，而与ITx后的时间无关。而且，ACR中IL-22的表达水平明显降低。

结论

NCR ⁺ -ILC3 / IL-22轴在ACR期间受损，导致延迟或缺乏完整而有效的上皮再生。因此，我们的发现表明，IL-22类似物可能与免疫抑制剂药物一起用作新的辅助治疗方法，以促进ACR时的粘膜再生。