Taurodeoxycholic acid and valine reverse obesity-associated augmented alloimmune responses and prolong allograft survival.
Taurodeoxycholic acid and valine reverse obesity-associated augmented alloimmune responses and prolong allograft survival.
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DOI：
10.1111/ajt.16856
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发表时间：
2022-02
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肥胖会引发与围手术期并发症相关的慢性炎症网络，并增加器官移植中的急性排斥率。减肥手术是治疗肥胖最有效的方法，并被推荐用于病态肥胖的移植受者。在这里，我们描述了肥胖和减肥手术对饮食诱导肥胖（DIO）小鼠的同种免疫和移植结果的影响。肥胖小鼠的同种异体移植物存活率显着缩短。当在移植前进行袖状胃切除术 (SGx) 时，我们发现 T 细胞衍生的同种免疫反应显着减弱，同种异体移植物的存活时间与瘦小鼠相当。此外，给予牛磺脱氧胆酸 (TDCA) 和缬氨酸（DIO 小鼠中代谢物耗尽并通过 SGx 恢复），我们观察到肥胖小鼠的移植物存活时间与 SGx 后观察到的相当。 TDCA/缬氨酸减少了局部区域和脾脏 CD4+IFNγ+ 和 CD8+IFNγ+ T 细胞，同时 Treg 频率和 CD4+ T 细胞衍生的 IL-10 产量增加。 TDCA/缬氨酸还改善了 MLR 中的 CD4+IFNγ+ 和 CD4+IL17A+ 频率，并通过损害 cAMP 信号传导的 TGR5 抑制炎症性 M1-巨噬细胞极化。一致地，给 DIO 小鼠施用 TGR5 激动剂可延长同种异体移植物的存活时间。总的来说，我们对肥胖引起的炎症及其对影响移植结果的同种免疫的影响提供了新的见解。此外，我们引入 TDCA/缬氨酸作为肥胖移植患者的非侵入性替代治疗。
Obesity initiates a chronic inflammatory network linked to perioperative complications and increased acute rejection rates in organ transplantation. Bariatric surgery is the most effective treatment of obesity and has been recommended for morbidly obese transplant recipients. Here, we delineated the effects of obesity and bariatric surgery on alloimmunity and transplant outcomes in diet-induced obese (DIO) mice. Allograft survival was significantly shorter in obese mice. When performing sleeve gastrectomies (SGx) prior to transplantation, we found significantly attenuated T cell-derived alloimmune responses and prolonged allograft survival comparable to that in lean mice. Moreover, administering taurodeoxycholic acid (TDCA) and valine, metabolites depleted in DIO mice and restored through SGx, we observed comparable prolongation of graft survival in obese mice as observed after SGx. TDCA/valine reduced loco-regional and splenic CD4+IFNγ+ and CD8+IFNγ+ T-cells while Treg frequencies and CD4+ T cell-derived IL-10 production was augmented. TDCA/valine also ameliorated CD4+IFNγ+ and CD4+IL17A+ frequencies in MLR and restrained inflammatory M1-macrophage polarization through TGR5 that compromised cAMP signaling. Consistently, administering a TGR5 agonist to DIO mice prolonged allograft survival. Overall, we provide novel insights into obesity-induced inflammation and its impact on alloimmunity affecting transplant outcomes. Furthermore, we introduce TDCA/valine as a non-invasive alternative treatment for obese transplant patients.
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影响因子：
29
作者：
Deng T;Lyon CJ;Minze LJ;Lin J;Zou J;Liu JZ;Ren Y;Yin Z;Hamilton DJ;Reardon PR;Sherman V;Wang HY;Phillips KJ;Webb P;Wong ST;Wang RF;Hsueh WA
通讯作者：
Hsueh WA
影响因子：
6.2
作者：
Heinbokel, Timm;Floerchinger, Bernhard;Tullius, Stefan G.
通讯作者：
Tullius, Stefan G.
影响因子：
6.1
作者：
Flabouris, Katerina;Chadban, Steven;Clayton, Philip
通讯作者：
Clayton, Philip
DOI：
10.1007/978-1-60327-409-8_9
发表时间：
2011-01-01
期刊：
DNA DAMAGE DETECTION IN SITU, EX VIVO, AND IN VIVO: METHODS AND PROTOCOLS
影响因子：
--
作者：
Darzynkiewicz, Zbigniew;Pozarowski, Piotr;Johnson, Gary L.
通讯作者：
Johnson, Gary L.
影响因子：
82.9
作者：
通讯作者：
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