Modulation of CD4+ T lymphocyte lineage outcomes with targeted, nanoparticle-mediated cytokine delivery.
Modulation of CD4+ T lymphocyte lineage outcomes with targeted, nanoparticle-mediated cytokine delivery.
复制标题
DOI：
10.1021/mp100203a
复制
发表时间：
2011-02-07
影响因子：
4.9
通讯作者：
Fahmy TM
中科院分区：
文献类型：
--
作者：
Park J;Gao W;Whiston R;Strom TB;Metcalfe S;Fahmy TM
在免疫系统内，有一种由抗原特异性T淋巴细胞协调的区分“自我”和“非我”的精妙能力。基因组的可塑性使幼稚的CD4+T淋巴细胞能够分化为表达转录因子Foxp3并积极防止自身免疫自毁的调节细胞(Treg)，或者攻击并摧毁其同源靶点的效应细胞(Tef)。这种可塑性的一个例子是我们最近发现白血病抑制因子(LIF)支持Treg成熟，而IL-6驱动致病Th17效应表型的发展。这揭示了T细胞发育中的LIF/IL6轴，可利用靶向细胞因子传递进行调节。在这里，我们展示了针对CD4+T细胞的LIF纳米颗粒(NPs)：(I)对抗IL6驱动的Th17的发育；(Ii)延长小鼠血管心脏移植物的存活；(Iii)在体外非人类灵长类动物模型中扩大FOXP3+CD4+T细胞的数量。相反，携带IL-6的纳米颗粒直接作用于CD4+T细胞可促进Th17的发育。值得注意的是，纳米颗粒介导的传递被证明是关键的：未加载的纳米颗粒和可溶的LIF或IL-6对照未能概括负载细胞因子的纳米颗粒在诱导和/或扩增Foxp3+细胞或Th17细胞方面的功效。因此，这种有针对性的纳米颗粒方法能够利用内源性免疫调节途径，为在免疫介导的疾病适应症中调节T细胞发育可塑性提供了一种强有力的新方法。
Within the immune system there is an exquisite ability to discriminate between “self “ and “non-self” that is orchestrated by antigen-specific T lymphocytes. Genomic plasticity enables differentiation of naïve CD4+ T lymphocytes into either regulatory cells (Treg) that express the transcription factor Foxp3 and actively prevent auto-immune self destruction, or effector cells (Teff) that attack and destroy their cognate target. An example of such plasticity is our recent discovery that leukemia inhibitory factor (LIF) supports Treg maturation in contrast to IL-6 which drives development of the pathogenic Th17 effector phenotype. This has revealed a LIF/IL6 axis in T cell development which can be exploited for modulation using targeted cytokine delivery. Here we demonstrate that LIF-loaded nanoparticles (NPs) directed to CD4+ T cells (i) oppose IL6-driven Th17 development; (ii) prolong survival of vascularized heart grafts in mice; and (iii) expand FOXP3+ CD4+ T cell numbers in a non-human primate model in vitro. In contrast, IL-6 loaded nanoparticles directed to CD4+ T cells increase Th17 development. Notably, nanoparticle-mediated delivery was demonstrated to be critical: unloaded nanoparticles and soluble LIF or IL-6 controls failed to recapitulate the efficacy of cytokine-loaded nanoparticles in induction and/or expansion of Foxp3+ cells or Th17 cells. Thus, this targeted nanoparticle approach is able to harness endogenous immune-regulatory pathways, providing a powerful new method to modulating T cell developmental plasticity in immune-mediated disease indications.
登录
查看更多内容
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
12.4
作者：
Steenblock, Erin R.;Fahmy, Tarek M.
通讯作者：
Fahmy, Tarek M.
DOI：
10.4161/cc.8.9.8348
发表时间：
2009-05-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Gao W;Thompson L;Zhou Q;Putheti P;Fahmy TM;Strom TB;Metcalfe SM
通讯作者：
Metcalfe SM
影响因子：
5.5
作者：
Demento SL;Eisenbarth SC;Foellmer HG;Platt C;Caplan MJ;Mark Saltzman W;Mellman I;Ledizet M;Fikrig E;Flavell RA;Fahmy TM
通讯作者：
Fahmy TM
影响因子：
4.4
作者：
Cobbold, SP;Castejon, R;Waldmann, H
通讯作者：
Waldmann, H