Enhanced Immunosuppression of T Cells by Sustained Presentation of Bioactive Interferon-γ Within Three-Dimensional Mesenchymal Stem Cell Constructs.
Enhanced Immunosuppression of T Cells by Sustained Presentation of Bioactive Interferon-γ Within Three-Dimensional Mesenchymal Stem Cell Constructs.
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DOI：
10.5966/sctm.2016-0044
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发表时间：
2017-01
影响因子：
6
通讯作者：
McDevitt TC
中科院分区：
文献类型：
--
作者：
Zimmermann JA;Hettiaratchi MH;McDevitt TC
间充质干/基质细胞（MSC）抑制先天性和适应性免疫应答的免疫调节活性为调节炎症和促进组织再生提供了有效的细胞疗法。然而，炎性细胞因子环境在刺激MSC免疫调节活性中起关键作用。特别地，干扰素-γ（IFN-γ）诱导的吲哚胺2，3-双加氧酶（IDO）的表达主要负责MSC抑制T细胞增殖和活化。虽然IFN-γ预处理通常用于在移植前使MSC具有免疫调节活性，但预处理的瞬时效应可能限制MSC有效调节免疫应答的潜力。因此，本研究的目的是研究三维球形MSC聚集体中微粒介导的生物活性IFN-γ的呈递是否可以精确调节和诱导持续的免疫调节活性。通过MSC聚集体内的肝素微粒递送IFN-γ在1周培养期间诱导持续的IDO表达，而IFN-γ预处理的MSC球状体的IDO表达在2天期间迅速降低。此外，由IFN-γ负载的微粒诱导的持续IDO表达导致MSC与CD 3/CD 28活化的外周血单核细胞共培养物中T细胞活化和增殖的增加和持续抑制。含有IFN-γ负载微粒的MSC球体对T细胞的抑制增加依赖于IDO的诱导，并通过影响单核细胞从促炎细胞因子到抗炎细胞因子的分泌来支持。总之，MSC球状体内IFN-γ的微粒递送提供了增强和维持免疫调节活性的有效手段，以控制移植后的MSC免疫调节，从而提高旨在治疗炎症和免疫疾病的基于MSC的疗法的功效。干细胞转化医学2017;6：223-237
The immunomodulatory activity of mesenchymal stem/stromal cells (MSCs) to suppress innate and adaptive immune responses offers a potent cell therapy for modulating inflammation and promoting tissue regeneration. However, the inflammatory cytokine milieu plays a critical role in stimulating MSC immunomodulatory activity. In particular, interferon‐γ (IFN‐γ)‐induced expression of indoleamine 2,3‐dioxygenase (IDO) is primarily responsible for MSC suppression of T‐cell proliferation and activation. Although pretreatment with IFN‐γ is commonly used to prime MSCs for immunomodulatory activity prior to transplantation, the transient effects of pretreatment may limit the potential of MSCs to potently modulate immune responses. Therefore, the objective of this study was to investigate whether microparticle‐mediated presentation of bioactive IFN‐γ within three‐dimensional spheroidal MSC aggregates could precisely regulate and induce sustained immunomodulatory activity. Delivery of IFN‐γ via heparin‐microparticles within MSC aggregates induced sustained IDO expression during 1 week of culture, whereas IDO expression by IFN‐γ‐pretreated MSC spheroids rapidly decreased during 2 days. Furthermore, sustained IDO expression induced by IFN‐γ‐loaded microparticles resulted in an increased and sustained suppression of T‐cell activation and proliferation in MSC cocultures with CD3/CD28‐activated peripheral blood mononuclear cells. The increased suppression of T cells by MSC spheroids containing IFN‐γ‐loaded microparticles was dependent on induction of IDO and supported by affecting monocyte secretion from pro‐ to anti‐inflammatory cytokines. Altogether, microparticle delivery of IFN‐γ within MSC spheroids provides a potent means of enhancing and sustaining immunomodulatory activity to control MSC immunomodulation after transplantation and thereby improve the efficacy of MSC‐based therapies aimed at treating inflammatory and immune diseases. Stem Cells Translational Medicine 2017;6:223–237