Immunomodulatory Dual-Sized Microparticle System Conditions Human Antigen Presenting Cells Into a Tolerogenic Phenotype In Vitro and Inhibits Type 1 Diabetes-Specific Autoreactive T Cell Responses.
Immunomodulatory Dual-Sized Microparticle System Conditions Human Antigen Presenting Cells Into a Tolerogenic Phenotype In Vitro and Inhibits Type 1 Diabetes-Specific Autoreactive T Cell Responses.
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DOI：
10.3389/fimmu.2020.574447
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发表时间：
2020
影响因子：
7.3
通讯作者：
Keselowsky BG
中科院分区：
文献类型：
--
作者：
Brusko MA;Stewart JM;Posgai AL;Wasserfall CH;Atkinson MA;Brusko TM;Keselowsky BG
目前的单克隆抗体药物不能恢复自身免疫个体对自身抗原的耐受性，而没有全身性免疫抑制。我们假设由聚乳酸-共-乙醇酸（PLGA）双尺寸微粒（dMP）系统递送的组合药物制剂将促进可调节的药物递送以引起免疫耐受。具体而言，我们利用30 μm MP提供粒细胞-巨噬细胞集落刺激因子（GM-CSF）和转化生长因子β1（TGF-β1）的局部持续释放，同时沿着1 μm MP促进吞噬细胞摄取包封的抗原和1α，25（OH）2维生素D3（VD 3），随后进行致耐受性抗原呈递。我们以前证明了dMP系统改善1型糖尿病（T1 D）和实验性自身免疫性脑脊髓炎（EAE）的小鼠模型。在这里，我们研究了该系统在体外影响人类细胞活性以推进临床转化的能力。dMP处理直接减少T细胞增殖和炎性细胞因子产生。dMP递送至单核细胞和单核细胞衍生的树突状细胞（DC）增加了它们的表面和细胞内抗炎介质的表达。在共培养中，dMP处理的DC（dMP-DC）减少同种异体T细胞受体（TCR）信号传导和增殖，同时增加PD-1表达、IL-10产生和调节性T细胞（Treg）频率。为了模拟抗原特异性活化和下游功能，我们将TCR工程化的自身反应性T细胞“化身”与dMP-DC或对照DC共培养，随后是β细胞系（β lox 5）靶细胞。对于G6 PC 2特异性CD 8+化身（克隆32），dMP-DC暴露降低了颗粒酶B并抑制了细胞毒性。GAD 65反应性CD 4+化身（克隆4.13）在dMP-DC存在下表现出无反应性/衰竭表型。总的来说，这些数据表明这种dMP制剂使人抗原呈递细胞朝向致耐受性表型调节，诱导调节性和抑制性T细胞应答。
Current monotherapeutic agents fail to restore tolerance to self-antigens in autoimmune individuals without systemic immunosuppression. We hypothesized that a combinatorial drug formulation delivered by a poly-lactic-co-glycolic acid (PLGA) dual-sized microparticle (dMP) system would facilitate tunable drug delivery to elicit immune tolerance. Specifically, we utilized 30 µm MPs to provide local sustained release of granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor β1 (TGF-β1) along with 1 µm MPs to facilitate phagocytic uptake of encapsulated antigen and 1α,25(OH)2 Vitamin D3 (VD3) followed by tolerogenic antigen presentation. We previously demonstrated the dMP system ameliorated type 1 diabetes (T1D) and experimental autoimmune encephalomyelitis (EAE) in murine models. Here, we investigated the system’s capacity to impact human cell activity in vitro to advance clinical translation. dMP treatment directly reduced T cell proliferation and inflammatory cytokine production. dMP delivery to monocytes and monocyte-derived dendritic cells (DCs) increased their expression of surface and intracellular anti-inflammatory mediators. In co-culture, dMP-treated DCs (dMP-DCs) reduced allogeneic T cell receptor (TCR) signaling and proliferation, while increasing PD-1 expression, IL-10 production, and regulatory T cell (Treg) frequency. To model antigen-specific activation and downstream function, we co-cultured TCR-engineered autoreactive T cell “avatars,” with dMP-DCs or control DCs followed by β-cell line (ßlox5) target cells. For G6PC2-specific CD8+ avatars (clone 32), dMP-DC exposure reduced Granzyme B and dampened cytotoxicity. GAD65-reactive CD4+ avatars (clone 4.13) exhibited an anergic/exhausted phenotype with dMP-DC presence. Collectively, these data suggest this dMP formulation conditions human antigen presenting cells toward a tolerogenic phenotype, inducing regulatory and suppressive T cell responses.
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影响因子：
7.7
作者：
Hagopian, William;Ferry, Robert J., Jr.;Ludvigsson, Johnny
通讯作者：
Ludvigsson, Johnny
影响因子：
120.7
作者：
Bonifacio, Ezio;Ziegler, Anette-G.;Achenbach, Peter
通讯作者：
Achenbach, Peter
影响因子：
5.4
作者：
Gebe, JA;Masewicz, SA;Nepom, GT
通讯作者：
Nepom, GT
DOI：
10.1001/jama.2017.17070
发表时间：
2017-11-21
期刊：
JAMA
影响因子：
--
作者：
Writing Committee for the Type 1 Diabetes TrialNet Oral Insulin Study Group;Krischer JP;Schatz DA;Bundy B;Skyler JS;Greenbaum CJ
通讯作者：
Greenbaum CJ
影响因子：
14
作者：
Cho JJ;Stewart JM;Drashansky TT;Brusko MA;Zuniga AN;Lorentsen KJ;Keselowsky BG;Avram D
通讯作者：
Avram D