Combinatorial, Microparticle-Based Delivery of Immune Modulators Reprograms the Dendritic Cell Phenotype and Promotes Remission of Collagen-Induced Arthritis in Mice
Combinatorial, Microparticle-Based Delivery of Immune Modulators Reprograms the Dendritic Cell Phenotype and Promotes Remission of Collagen-Induced Arthritis in Mice
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DOI：
10.1021/acsabm.9b00092
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发表时间：
2019-06-17
影响因子：
4.7
通讯作者：
Lewis, Jamal S.
中科院分区：
文献类型：
--
作者：
Allen, Riley;Chizari, Shahab;Lewis, Jamal S.
类风湿关节炎（RA）的安全，有效，抗原特异性治疗仍然是一个难以捉摸的临床目标，有一些持久的，可行的选择。现有的治疗干预措施是不加选择的，并且不一致的免疫抑制，通常使患者容易感染。在此，我们研究了使用双尺寸的微粒“调节疫苗”（REGvac），被动靶向树突状细胞的抗原特异性生物材料为基础的免疫治疗类风湿关节炎。该REGvac采用聚（D，L-乳酸-共-乙醇酸）（PLGA）微粒（MP），包裹（i）树突状细胞化学引诱物，（ii）强效免疫抑制分子，（iii）和RA相关自身抗原，以提供治疗的多方面方法胶原诱导的关节炎（CIA），RA的主要小鼠模型。在小鼠出现中度临床症状后，皮下给予REGvac显著减轻了爪中的明显炎症，停止了软骨退化，并在初始治疗后56天内恢复了步态参数。正电子发射断层扫描成像证实REGvac处理的小鼠的爪中的炎症减少。深入的免疫学评估显示，关节相关淋巴结中CD 11 c（+）树突状细胞上的CD 80、CD 86和MHC II表达降低。此外，我们观察到关节近端淋巴结和脾脏中常规调节性CD 25（+）FOXP 3（+）T细胞以及表达程序性细胞死亡蛋白-1（PD-1）的CD 4（+）T细胞显著增加。来自治疗小鼠的关节组织的实时PCR分析显示炎性细胞因子表达（IL-6）显著降低，而IL-10 mRNA水平显著增加。这些观察结果强烈提示通过施用该MP调节性疫苗诱导多种致耐受性机制。关于抗原特异性，离体抗原回忆试验显示REGvac处理小鼠的腘和腹股沟淋巴结的CD 4（+）T细胞对胶原蛋白缺乏应答，与CIA（+）小鼠的CD 4（+）T细胞的增殖应答形成对比。总之，我们的研究结果强烈支持这种MP调节疫苗作为一种有效的，基于生物材料的，抗原特异性治疗RA的应用。
Safe, effective, antigen-specific therapy for rheumatoid arthritis (RA) remains an elusive clinical goal with a few lasting, viable options on the horizon. Existing therapeutic interventions are indiscriminate and inconsistently immunosuppressive, often leaving patients susceptible to infection. Herein, we investigate the use of a dual-sized, microparticle "regulatory vaccine" (REGvac) that passively targets dendritic cells for antigen-specific biomaterial-based immunotherapy of RA. This REGvac employs poly( D,L-lactic-co-glycolic-acid) (PLGA) microparticles (MPs) encapsulating (i) a dendritic cell chemoattractant, (ii) potent immunosuppressive molecules, (iii) and an RA-relevant autoantigen to provide a multifaceted approach for the treatment of collagen-induced arthritis (CIA), the primary mouse model of RA. Subcutaneous administrations of the REGvac after mice had developed moderate clinical symptoms markedly diminished overt inflammation in the paws, halted cartilage degradation, and restored gait parameters within 56 days after initial treatment. Positron emission tomography imaging corroborated reduction of inflammation in the paws of REGvac-treated mice. In-depth immunological assessments showed a decreased expression of CD80, CD86, and MHC II on CD11c(+) dendritic cells in joint-associated lymph nodes. Further, we observed significant increases in conventional regulatory CD25(+)FOXP3(+) T cells, as well as programmed cell death protein-1 (PD-1)-expressing CD4(+) T cells in joint-proximal lymph nodes and the spleen. Real-time PCR analysis of joint tissues from treated mice revealed significant decreases in inflammatory cytokine expression (IL-6), while IL-10 mRNA levels were significantly increased. These observations strongly hint toward the induction of multiple tolerogenic mechanisms by administration of this MP regulatory vaccine. With regards to antigen specificity, ex vivo antigen recall assays revealed a lack of response to collagen by CD4(+) T cells from the popliteal and inguinal lymph nodes of REGvac-treated mice, contrasting with the proliferative response of CD4(+) T cells from CIA(+) mice. Taken altogether, our results strongly support the application of this MP regulatory vaccine as a potent, biomaterial-based, antigen-specific therapy for RA.