Genetic in situ engineering of myeloid regulatory cells controls inflammation in autoimmunity.
Genetic in situ engineering of myeloid regulatory cells controls inflammation in autoimmunity.
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DOI：
10.1016/j.jconrel.2021.08.040
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发表时间：
2021-11-10
期刊：
影响因子：
--
通讯作者：
Stephan MT
中科院分区：
文献类型：
--
作者：
Parayath NN;Hao S;Stephan SB;Koehne AL;Watson CE;Stephan MT
髓系调节细胞(MRCs)控制免疫反应和促进耐受的能力引起了人们对将其用于治疗炎症、自身免疫或改善移植结果的极大兴趣。虽然免疫调节性小分子化合物和抗体对一些患者起到了缓解作用，但剂量会导致系统性药物暴露，从而增加非靶标不良反应的风险。最近，基于MRC的细胞治疗产品已经进入耐受诱导的临床测试。然而，目前在体外制造工程MRCs所需的复杂而昂贵的方案使这种方法超出了许多可能受益的患者的能力范围。一种解决方案可能是直接在体内对MRCs进行编程。在这里，我们描述了一种靶向的纳米载体，它在体外转录的mRNA编码关键的抗炎介质。在系统性红斑狼疮的模型中，我们证明了输入含有编码糖皮质激素诱导的亮氨酸拉链(GILZ)的mRNA的纳米颗粒有效地控制了疾病。我们进一步证实，这些纳米试剂重复给药是安全的。在临床上实施这种新的疗法，可以使医生能够治疗自身免疫性疾病，同时避免破坏免疫动态平衡的全身治疗。
The ability of myeloid regulatory cells (MRCs) to control immune responses and to promote tolerance has prompted enormous interest in exploiting them therapeutically to treat inflammation, autoimmunity, or to improve outcomes in transplantation. While immunomodulatory small-molecule compounds and antibodies have provided relief for some patients, the dosing entails high systemic drug exposures and thus increased risk of off-target adverse effects. More recently, MRC-based cell-therapy products have entered clinical testing for tolerance induction. However, the elaborate and expensive protocols currently required to manufacture engineered MRCs ex vivo put this approach beyond the reach of many patients who might benefit. A solution could be to directly program MRCs in vivo. Here we describe a targeted nanocarrier that delivers in vitro-transcribed mRNA encoding a key anti-inflammatory mediator. We demonstrate in models of systemic lupus erythematosus that infusions of nanoparticles formulated with mRNA encoding glucocorticoid-induced leucine zipper (GILZ) effectively control the disease. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this new therapy could enable physicians to treat autoimmune disease while avoiding systemic treatments that disrupt immune homeostasis.
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影响因子：
12.4
作者：
Kariko, Katalin;Muramatsu, Hiromi;Welsh, Frank A.;Ludwig, Janos;Kato, Hiroki;Akira, Shizuo;Weissman, Drew
通讯作者：
Weissman, Drew
影响因子：
4.6
作者：
Lee JH;Park CS;Jang S;Kim JW;Kim SH;Song S;Kim K;Lee CK
通讯作者：
Lee CK
DOI：
10.15386/cjmed-574
发表时间：
2016
期刊：
Clujul medical (1957)
影响因子：
--
作者：
Mocan T;Matea CT;Iancu C;Agoston-Coldea L;Mocan L;Orasan R
通讯作者：
Orasan R
影响因子：
9.1
作者：
Freire Carvalho, Jozelio;Blank, Miri;Shoenfeld, Yehuda
通讯作者：
Shoenfeld, Yehuda
影响因子：
32.4
作者：
D'Adamio, F;Zollo, O;Riccardi, C
通讯作者：
Riccardi, C