Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive
Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive
复制标题
DOI：
10.1016/j.ymthe.2005.09.015
复制
发表时间：
2006-02-01
影响因子：
12.4
通讯作者：
Robbins, PD
中科院分区：
文献类型：
--
作者：
Kim, SH;Bianco, N;Robbins, PD
我们以前已经证明了原代小鼠骨髓来源的DC（BMDC），通过腺病毒感染表达FasL的基因修饰，抑制建立的胶原诱导的关节炎（CIA）的进展后，全身交付的能力。在这里，我们证明了来源于表达FasL的基因修饰的BM-DC的外泌体能够抑制迟发型超敏反应（DTH）的鼠足垫模型中的炎症。局部施用源自表达FasL的DC（Exo/FasL）的外来体以及亲本DC/FasL导致经处理和未经处理的远端爪中的肿胀显著减少。然而，DC/FasL和Exo/FasL均不能抑制Ipr（Fas缺陷）小鼠的DTH反应。将FasL基因转移至来自gld（FasL缺陷）小鼠的BM-DC导致DC以及DC衍生的外泌体抑制DTH的能力恢复。DC衍生的外泌体和DC抑制DTH应答的能力是抗原特异性的和MHC 11类依赖性的，但不依赖于I类。发现注射的外泌体在注射部位和引流腘淋巴结中内化到CD 11 c（+）细胞中。将外泌体/FasL全身注射到具有已建立的CIA的小鼠中导致显著的疾病改善。这些结果表明，源自表达FasL的DC的外泌体的全身和局部施用都能够通过MHC II类依赖性途径抑制抗原特异性免疫应答，从而有效和持续地治疗已建立的胶原诱导的关节炎并抑制DTH炎症应答。这些结果表明，DC/FasL衍生的外泌体可用于临床治疗炎症和自身免疫性疾病。
We previously have demonstrated the ability of primary murine bone marrow-derived DC (BMDC), genetically modified by adenoviral infection to express FasL, to inhibit progression of established collagen-induced arthritis (CIA) following systemic delivery. Here we demonstrate that exosomes derived from genetically modified BM-DC expressing FasL are able to inhibit inflammation in a murine footpad model of delayed-type hypersensitivity (DTH). Local administration of exosomes derived from DC expressing FasL (Exo/FasL) as well as the parental DC/FasL resulted in a significant reduction in swelling in both the treated and the untreated distal paw. However, both the DC/FasL and the Exo/FasL were unable to suppress the DTH response in Ipr (Fas-deficient) mice. Gene transfer of FasL to BM-DC from gld (FasL-deficient) mice resulted in restoration of the ability of DC as well as DC-derived exosomes to suppress DTH. The ability of DC-derived exosomes and DC to suppress DTH responses was antigen specific and MHC class 11 dependent, but class I independent. The injected exosomes were found to be internalized into CD11c(+) cells at the site of injection and in the draining popliteal lymph node. Systemic injection of exosome/FasL into mice with established CIA resulted in significant disease amelioration. These results demonstrate that both systemic and local administration of exosomes derived from FasL-expressing DC are able to suppress antigen-specific immune responses through an MHC class II-dependent pathway, resulting in effective and sustained treatment of established collagen-induced arthritis and suppression of the DTH inflammatory response. These results suggest that DC/FasL-derived exosomes could be used clinically for the treatment of inflammatory and autoimmune diseases.