PDF(Pubmed)
Abstract：
Chronic antibody mediated rejection (AMR) is the major cause of solid organ graft rejection. Th17 contributes to AMR through the secretion of IL17A, IL21 and IL22. These cytokines promote neutrophilic infiltration, B cell proliferation and donor specific antibodies (DSAs) production. In the current study we investigated the role of Th17 in transplant sensitization. Additionally, we investigated the therapeutic potential of novel inverse agonists of the retinoic acid receptor-related orphan receptor gamma t (RORγt) in the treatment of skin allograft rejection in sensitized mice. Our results show that RORγt inverse agonists reduce cytokine production in human Th17 cells in vitro. In mice, we demonstrate that the RORγt inverse agonist TF-S14 reduces Th17 signature cytokines in vitro and in vivo and leads to blocking neutrophilic infiltration to skin allografts, inhibition of the B-cell differentiation, and the reduction of de novo IgG3 DSAs production. Finally, we show that TF-S14 prolongs the survival of a total mismatch grafts in sensitized mice. In conclusion, RORγt inverse agonists offer a therapeutic intervention through a novel mechanism to treat rejection in highly sensitized patients.
摘要：
慢性抗体介导的排斥反应(AMR)是实体器官移植排斥反应的主要原因。Th17通过分泌IL17A参与AMR,IL21和IL22。这些细胞因子促进嗜中性粒细胞浸润，B细胞增殖和供体特异性抗体(DSA)产生。在当前的研究中，我们研究了Th17在移植致敏中的作用。此外,我们研究了视黄酸受体相关孤儿受体γt(RORγt)的新型反向激动剂在治疗致敏小鼠皮肤移植排斥反应中的治疗潜力.我们的结果显示RORγt反向激动剂在体外减少人Th17细胞中的细胞因子产生。在老鼠身上,我们证明了RORγt反向激动剂TF-S14在体外和体内减少Th17特征细胞因子，并导致阻断中性粒细胞浸润到皮肤同种异体移植物，抑制B细胞分化，以及从头IgG3DSA产量的减少。最后,我们显示TF-S14延长了致敏小鼠中总错配移植物的存活时间。总之,RORγt反向激动剂通过一种新机制提供治疗性干预，以治疗高度致敏患者的排斥反应。
