Recombinant IL-33 prolongs leflunomide-mediated graft survival by reducing IFN-γ and expanding CD4+Foxp3+ T cells in concordant heart transplantation
Recombinant IL-33 prolongs leflunomide-mediated graft survival by reducing IFN-γ and expanding CD4+Foxp3+ T cells in concordant heart transplantation
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DOI：
10.1038/labinvest.2016.54
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发表时间：
2016-08-01
影响因子：
5
通讯作者：
Qi, Zhong-Quan
中科院分区：
文献类型：
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作者：
Dai, Chen;Lu, Fang-Na;Qi, Zhong-Quan
白细胞介素（IL）-33是一种新的IL-1家族成员，其给药与体内辅助性T细胞2型（Th 2）活性和细胞因子，特别是IL-4和IL-5的促进有关。最近，在小鼠同种异体心脏移植中，IL-33被证明可以增加CD 4（+）Foxp 3（+）调节性T细胞（TCLs）并抑制Th 1型细胞因子IFN-γ的水平。因此，我们假设，IL-33和来氟米特（Lef）可以延长移植物的存活在一致的小鼠到大鼠心脏移植模型。在该模型中，异种移植物通常在第3天经历急性体液异种移植物排斥（AHXR），或者如果AHXR被Lef处理抑制，则大约在第7天经历细胞介导的排斥。接受者用Lef（n = 6）、IL-33（n = 6）、IL-33与Lef的组合（n = 6）处理，或不处理（n = 6）用于存活研究。心脏移植物被监测，直到他们停止跳动。进行小鼠异位移植，并在第2天和第7天处死受体进行组织学和流式细胞术分析。与未处理的对照组相比，IL-33和Lef的组合显著延长了移植物从17.3 +/- 2.3天至2.8 +/- 0.4天。与仅Lef治疗相比，IL-33与Lef联合给药在促进Th 2相关细胞因子（IL-4在第2天但不是第7天）的同时，也降低了第2天和第7天的IFN-γ。此外，IL-33与Lef给药引起大鼠中抑制性CD 4（+）Foxp 3（+）T细胞的扩增。IL-33和Lef联合治疗导致移植物存活显著延长，与Th 1细胞显著减少和IL-10水平增加相关。此外，与单药治疗相比，联合治疗显著降低了第2天和第7天CD-45（+）B细胞的百分比。这些发现揭示了IL-33的新的免疫调节特性。具体而言，它促进调节细胞，特别是功能性CD 4（+）Foxp 3（+）T细胞，其是IL-33介导的心脏异种移植物存活的基础。此外，它可以减少异种移植受体中的Th 1细胞和Th 1 T细胞的细胞因子表达，例如IFN-γ。
Interleukin (IL)-33 is a novel IL-1 family member, and its administration has been associated with promotion of T helper type-2 (Th2) cell activity and cytokines, particularly IL-4 and IL-5 in vivo. Recently, IL-33 was shown to increase CD4(+)Foxp3(+) regulatory T cells (Tregs) and to suppress levels of the Th1-type cytokine IFN-gamma in allogeneic heart transplantation in mice. Therefore, we hypothesized that IL-33 and leflunomide (Lef) could prolong graft survival in the concordant mouse-to-rat heart transplantation model. In this model, xenografts undergo acute humoral xenograft rejection (AHXR) typically on day 3 or cell-mediated rejection approximately on day 7 if AHXR is inhibited by Lef treatment. Recipients were treated with Lef (n = 6), IL-33 (n = 6), IL-33 combined with Lef (n = 6), or left untreated (n = 6) for survival studies. Heart grafts were monitored until they stopped beating. Mouse heterotopic grafts were performed, and recipients were sacrificed on days 2 and 7 for histological and flow cytometric analyses. The combination of IL-33 and Lef significantly prolonged the grafts from 17.3 +/- 2.3 to 2.8 +/- 0.4 days, compared to untreated controls. IL-33 administration with Lef, while facilitating Th2-associated cytokines (IL-4 on day 2 but not day 7), also decreased IFN-gamma on day 2 and day 7, compared with Lef treatment only. Furthermore, IL-33 with Lef administration caused an expansion of suppressive CD4(+)Foxp3(+) Tregs in rats. The IL-33 and Lef combination therapy resulted in significantly prolonged graft survival, associated with markedly decreased Th1 cells and increased IL-10 levels. In addition, the combination therapy significantly decreased the percentage of CD-45(+) B cells on days 2 and 7, compared with monotherapy. These findings reveal a new immunoregulatory property of IL-33. Specifically, it facilitates regulatory cells, particularly functional CD4(+)Foxp3(+) Tregs that underlie IL-33-mediated cardiac xenograft survival. Moreover, it can decrease Th1 cells and cytokine expression of Th1 T cells in xenograft recipients, for example IFN-gamma.