Kim Seon Hee, Bianco Nicole R, Shufesky William J, Morelli Adrian E, Robbins Paul D
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
J Immunol. 2007 Aug 15;179(4):2242-9. doi: 10.4049/jimmunol.179.4.2242.
In this study, we demonstrate that genetically modified bone marrow-derived dendritic cells (DC) and exosomes derived from the DC, expressing either secreted IL-4 or membrane-bound IL-4, can reduce the severity and the incidence of established collagen-induced arthritis and inhibit inflammation of delayed-type hypersensitivity (DTH) in mice. The ability of the DC and DC-derived exosomes to suppress the DTH response was MHC class II and, in part, Fas ligand/Fas dependent. The DC-derived exosomes were internalized by CD11c(+) DC in the dermis at the site of injection and in the draining lymph node as well as by CD11c(+) DC and F4/80(+) macrophages in the spleen. Moreover, adoptive transfer of CD11c(+) or CD3(+) splenic cells from mice treated with exosomes showed significant reduction of footpad swelling in the DTH model. These results demonstrate that administration of DC/IL-4 or exosomes derived from DC/IL-4 are able to modulate the activity of APC and T cells in vivo through a MHC class II and partly Fas ligand/Fas-dependent mechanism, resulting in effective treatment of established collagen-induced arthritis and suppression of the DTH inflammatory response. Thus, APC-derived exosomes could be used therapeutically for the treatment of autoimmune disease and inflammatory disorders.
在本研究中，我们证明，表达分泌型IL-4或膜结合型IL-4的基因工程化骨髓来源的树突状细胞（DC）以及源自DC的外泌体，可减轻已建立的胶原诱导性关节炎的严重程度和发病率，并抑制小鼠迟发型超敏反应（DTH）的炎症。DC和DC来源的外泌体抑制DTH反应的能力是MHC II类依赖性的，且部分依赖Fas配体/Fas。DC来源的外泌体可被注射部位真皮以及引流淋巴结中的CD11c(+) DC内化，也可被脾脏中的CD11c(+) DC和F4/80(+)巨噬细胞内化。此外，用外泌体处理过的小鼠的CD11c(+)或CD3(+)脾细胞的过继转移显示，在DTH模型中足垫肿胀明显减轻。这些结果表明，给予DC/IL-4或源自DC/IL-4的外泌体能够通过MHC II类和部分Fas配体/Fas依赖性机制在体内调节APC和T细胞的活性，从而有效治疗已建立的胶原诱导性关节炎并抑制DTH炎症反应。因此，APC来源的外泌体可用于自身免疫性疾病和炎症性疾病的治疗。
