An antigen-specific semi-therapeutic treatment with local delivery of tolerogenic factors through a dual-sized microparticle system blocks experimental autoimmune encephalomyelitis.
An antigen-specific semi-therapeutic treatment with local delivery of tolerogenic factors through a dual-sized microparticle system blocks experimental autoimmune encephalomyelitis.
复制标题
DOI：
10.1016/j.biomaterials.2017.07.029
复制
发表时间：
2017-10
期刊：
影响因子：
14
通讯作者：
Avram D
中科院分区：
文献类型：
--
作者：
Cho JJ;Stewart JM;Drashansky TT;Brusko MA;Zuniga AN;Lorentsen KJ;Keselowsky BG;Avram D
与诱导全身性免疫抑制的治疗相比，抗原特异性治疗对于自身免疫性疾病是高度期望的。已经开发了一种新的抗原特异性疗法，当以半治疗方式施用时，其在治疗多发性硬化症的小鼠模型，即实验性自身免疫性脑脊髓炎（EAE）中是高度有效的。该治疗使用双重尺寸的聚合物微粒（dMP），其装载有用于细胞内和细胞外递送的特异性抗原和耐受性因子，其设计用于募集和调节树突状细胞朝向致耐受性表型而不全身释放。这种方法表现出强大的功效，并提供了完全的疾病保护。治疗功效需要将因子封装在控释微粒中，并且是抗原特异性的。疾病阻断与浸润性CD4+ T细胞、产生炎性嘌呤的致病性CD4+ T细胞以及中枢神经系统中活化的巨噬细胞和小胶质细胞的减少相关。此外，从DMP处理的小鼠中分离的CD4+ T细胞对疾病特异性抗原负载的脾细胞无反应性。此外，用Ag特异性dMP处理的EAE小鼠的引流淋巴结中的CD86hiMHCIIhi树突状细胞的频率降低。我们的研究结果突出了基于微粒的药物递送介导抗原特异性耐受的功效，并表明这种多因素组合方法可以起到阻断自身免疫的作用。
Antigen-specific treatments are highly desirable for autoimmune diseases in contrast to treatments which induce systemic immunosuppression. A novel antigen-specific therapy has been developed which, when administered semi-therapeutically, is highly efficacious in the treatment of the mouse model for multiple sclerosis, namely experimental autoimmune encephalomyelitis (EAE). The treatment uses dual-sized, polymeric microparticles (dMPs) loaded with specific antigen and tolerizing factors for intra- and extra-cellular delivery, designed to recruit and modulate dendritic cells toward a tolerogenic phenotype without systemic release. This approach demonstrated robust efficacy and provided complete protection against disease. Therapeutic efficacy required encapsulation of the factors in controlled-release microparticles and was antigen-specific. Disease blocking was associated with a reduction of infiltrating CD4+ T cells, inflammatory cytokine-producing pathogenic CD4+ T cells, and activated macrophages and microglia in the central nervous system. Furthermore, CD4+ T cells isolated from dMP-treated mice were anergic in response to disease-specific, antigen-loaded splenocytes. Additionally, the frequency of CD86hiMHCIIhi dendritic cells in draining lymph nodes of EAE mice treated with Ag-specific dMPs was reduced. Our findings highlight the efficacy of microparticle-based drug delivery to mediate antigen-specific tolerance, and suggest that such a multi-factor combinatorial approach can act to block autoimmunity.
登录
查看更多内容
T-BET的丧失，但不是STAT1阻止了实验性自身免疫性脑脊髓炎的发展。
影响因子：
15.3
作者：
Bettelli, E;Sullivan, B;Szabo, SJ;Sobel, RA;Glimcher, H;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
4.9
作者：
Alexis F;Pridgen E;Molnar LK;Farokhzad OC
通讯作者：
Farokhzad OC
影响因子：
32.4
作者：
Califano D;Cho JJ;Uddin MN;Lorentsen KJ;Yang Q;Bhandoola A;Li H;Avram D
通讯作者：
Avram D
影响因子：
4.4
作者：
Bielekova, B;Sung, MH;Martin, R
通讯作者：
Martin, R
雷帕霉素对胰腺 β 细胞毒性的证据以及潜在分子机制的回顾。
影响因子：
7.7
作者：
Barlow AD;Nicholson ML;Herbert TP
通讯作者：
Herbert TP