Suppression of Murine Lupus by CD4+ and CD8+ Treg Cells Induced by T Cell-Targeted Nanoparticles Loaded With Interleukin-2 and Transforming Growth Factor β.
Suppression of Murine Lupus by CD4+ and CD8+ Treg Cells Induced by T Cell-Targeted Nanoparticles Loaded With Interleukin-2 and Transforming Growth Factor β.
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DOI：
10.1002/art.40773
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发表时间：
2019-04
期刊：
影响因子：
--
通讯作者：
La Cava A
中科院分区：
文献类型：
--
作者：
Horwitz DA;Bickerton S;Koss M;Fahmy TM;La Cava A
开发一种纳米颗粒平台，可以在体内扩增CD4+和CD8+ T调节细胞（Tregs），以抑制系统性红斑狼疮（SLE）的自身免疫反应。将包封IL-2和TGF-β的聚乳酸-羟基乙酸（PLGA）纳米颗粒（NPs）包被抗cd2 /CD4抗体，并给予DBA/2 T细胞转染（C57BL/6 × DBA/2）F1 （BDF1）小鼠引起的狼疮样疾病小鼠。体外流式细胞术检测Tregs外周血频率。ELISA检测血清抗dsdna抗体，评估疾病进展。肾脏疾病评估为蛋白尿和肾脏组织病理学。抗cd2 /4抗体包被的NPs包被IL-2和TGF-β，体外诱导CD4+和CD8+ Foxp3+ Tregs。非狼疮小鼠的体内研究确定了NPs扩大CD4+和CD8+ treg的最佳给药方案，然后在BDF1狼疮小鼠中进行了测试。给药包封IL-2和TGF-β的抗cd2 /4抗体包被的NPs导致CD4+和CD8+ Tregs的扩增，显著抑制抗dna抗体的产生，并减少肾脏疾病。本研究首次发现，包埋IL-2和TGF-β的T细胞靶向PLGA NPs能够在体内扩增CD4+和CD8+ Tregs，并抑制小鼠狼疮。这种方法能够在体内扩展Tregs并抑制SLE的致病性免疫反应，可能代表了一种潜在的新治疗方式，其特征是Tregs功能受损与IL-2缺乏相关。
To develop a nanoparticle platform that can expand both CD4+ and CD8+ T regulatory cells (Tregs) in vivo for the suppression of autoimmune responses in systemic lupus erythematosus (SLE). Poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) encapsulating IL-2 and TGF-β were coated with anti-CD2/CD4 antibodies and administered to mice with lupus-like disease induced by the transfer of DBA/2 T cells into (C57BL/6 x DBA/2)F1 (BDF1) mice. Peripheral frequency of Tregs was monitored ex vivo by flow cytometry. Disease progression was assessed by measuring serum anti-dsDNA antibodies by ELISA. Kidney disease was evaluated as proteinuria and by renal histopathology. Anti-CD2/4 antibody-coated, but not non-coated NPs encapsulating IL-2 and TGF-β, induced CD4+ and CD8+ Foxp3+ Tregs in vitro. In vivo studies in non-lupus mice determined the optimal dosing regimen of NPs for expansion of CD4+ and CD8+ Tregs that was then tested in BDF1 lupus mice. The administration of anti-CD2/4 antibody-coated NPs encapsulating IL-2 and TGF-β resulted in the expansion of CD4+ and CD8+ Tregs, a marked suppression of anti-DNA antibody production, and reduced renal disease. This study shows for the first time that T cell-targeted PLGA NPs encapsulating IL-2 and TGF-β can expand both CD4+ and CD8+ Tregs in vivo and suppress murine lupus. This approach that enables the expansion of Tregs in vivo and inhibits pathogenic immune responses in SLE could represent a potential new therapeutic modality in autoimmune conditions characterized by impaired Tregs function associated with IL-2 deficiency.
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影响因子：
17.1
作者：
Hunter Z;McCarthy DP;Yap WT;Harp CT;Getts DR;Shea LD;Miller SD
通讯作者：
Miller SD
影响因子：
4.9
作者：
Park J;Gao W;Whiston R;Strom TB;Metcalfe S;Fahmy TM
通讯作者：
Fahmy TM
DOI：
10.1016/j.nano.2014.12.019
发表时间：
2015-05-01
影响因子：
5.4
作者：
Labowsky, Michael;Lowenthal, Justin;Fahmy, Tarek M.
通讯作者：
Fahmy, Tarek M.
DOI：
10.1073/pnas.1408686111
发表时间：
2015-01-13
影响因子：
11.1
作者：
Maldonado, Roberto A.;LaMothe, Robert A.;Kishimoto, Takashi Kei
通讯作者：
Kishimoto, Takashi Kei
影响因子：
4.4
作者：
Otomo, Kotaro;Koga, Tomohiro;Tsokos, George C.
通讯作者：
Tsokos, George C.