Combined administration of a mutant TGF-beta1/Fc and rapamycin promotes induction of regulatory T cells and islet allograft tolerance.
Combined administration of a mutant TGF-beta1/Fc and rapamycin promotes induction of regulatory T cells and islet allograft tolerance.
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DOI：
10.4049/jimmunol.1000769
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发表时间：
2010-10-15
期刊：
影响因子：
--
通讯作者：
Zheng XX
中科院分区：
文献类型：
--
作者：
Zhang W;Zhang D;Shen M;Liu Y;Tian Y;Thomson AW;Lee WP;Zheng XX
TGF-β在促进耐受性的CD 4 + Foxp 3+调节性T细胞（Treg）和促炎性Th 17效应细胞的相互分化中的关键作用影响同种免疫反应性和移植结果。我们推断，利用TGF-β和阻断促炎细胞因子的策略将抑制Th 17细胞的分化，并加强Treg干部，以促进耐受诱导和长期同种异体移植物存活。在本文中，我们报告了一种新型的、持久的自激活的人突变型TGF-β1/Fc融合蛋白的开发，该融合蛋白与雷帕霉素联合作用以抑制T细胞增殖并诱导外周中Foxp 3 + Treg的从头产生，同时抑制IL-6介导的Th 17细胞分化。在小鼠模型中，TGF-β1/Fc和雷帕霉素的短期联合治疗实现了胰岛移植物的长期存活和供体特异性耐受。这种作用伴随着Foxp 3 + Treg的扩增、同种异体抗原特异性Treg功能的增强以及Foxp 3、IL-6和IL-17的转录水平的调节。我们联合TGF-β1/Fc和雷帕霉素靶向IL-6相关的Treg和Th 17信号通路的策略为诱导移植耐受及其临床应用提供了一种有希望的方法。
The critical roles of TGF-β in the reciprocal differentiation of tolerance-promoting CD4+Foxp3+ regulatory T cells (Treg) and pro-inflammatory Th17 effector cells impact alloimmune reactivity and transplant outcome. We reasoned that a strategy that harnessed TGF-β and blocked pro-inflammatory cytokines would inhibit the differentiation of Th17 cells and strengthen the cadre of Treg to promote tolerance induction and long-term allograft survival. Herein we report the development of a novel, long-lasting auto-active human mutant TGF-β1/Fc fusion protein that acts in conjunction with rapamycin to inhibit T cell proliferation and induce the de novo generation of Foxp3+ Treg in the periphery, while at the same time inhibiting IL-6-mediated Th17 cell differentiation. Short-term combined treatment with TGF-β1/Fc and rapamycin achieved long-term pancreatic islet allograft survival and donor-specific tolerance in a mouse model. This effect was accompanied by expansion of Foxp3+ Treg, enhanced alloantigen-specific Treg function, and modulation of transcript levels of Foxp3, IL-6 and IL-17. Our strategy of combined TGF-β1/Fc and rapamycin to target the IL-6-related Treg and Th17 signaling pathways provides a promising approach for inducing transplant tolerance and its clinical application.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
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作者：
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作者：
COFFEY, RJ;KOST, LJ;LARUSSO, NF
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