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Cytokines in Follicular Helper T Cell Biology in Physiologic and Pathologic Conditions. 生理和病理状态下滤泡辅助 T 细胞生物学中的细胞因子
IF 4.3 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-02-14 eCollection Date: 2024-02-01 DOI: 10.4110/in.2024.24.e8
Jinyong Choi, Shane Crotty, Youn Soo Choi

Follicular helper T cells (Tfh) play a crucial role in generating high-affinity antibodies (Abs) and establishing immunological memory. Cytokines, among other functional molecules produced by Tfh, are central to germinal center (GC) reactions. This review focuses on the role of cytokines, including IL-21 and IL-4, in regulating B cell responses within the GC, such as differentiation, affinity maturation, and plasma cell development. Additionally, this review explores the impact of other cytokines like CXCL13, IL-10, IL-9, and IL-2 on GC responses and their potential involvement in autoimmune diseases, allergies, and cancer. This review highlights contributions of Tfh-derived cytokines to both protective immunity and immunopathology across a spectrum of diseases. A deeper understanding of Tfh cytokine biology holds promise for insights into biomedical conditions.

滤泡辅助 T 细胞(Tfh)在产生高亲和力抗体(Abs)和建立免疫记忆方面发挥着至关重要的作用。Tfh产生的细胞因子和其他功能分子是生殖中心(GC)反应的核心。本综述重点探讨细胞因子(包括 IL-21 和 IL-4)在调节生殖中心 B 细胞反应(如分化、亲和力成熟和浆细胞发育)中的作用。此外,本综述还探讨了 CXCL13、IL-10、IL-9 和 IL-2 等其他细胞因子对 GC 反应的影响,以及它们在自身免疫性疾病、过敏症和癌症中的潜在作用。本综述强调了 Tfh 派生细胞因子对各种疾病的保护性免疫和免疫病理的贡献。深入了解 Tfh 细胞因子的生物学特性有望深入了解生物医学状况。
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引用次数: 0
Immune Cells Are Differentially Affected by SARS-CoV-2 Viral Loads in K18-hACE2 Mice. 免疫细胞受 K18-hACE2 小鼠 SARS-CoV-2 病毒载量的不同影响
IF 6 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-02-02 eCollection Date: 2024-04-01 DOI: 10.4110/in.2024.24.e7
Jung Ah Kim, Sung-Hee Kim, Jeong Jin Kim, Hyuna Noh, Su-Bin Lee, Haengdueng Jeong, Jiseon Kim, Donghun Jeon, Jung Seon Seo, Dain On, Suhyeon Yoon, Sang Gyu Lee, Youn Woo Lee, Hui Jeong Jang, In Ho Park, Jooyeon Oh, Sang-Hyuk Seok, Yu Jin Lee, Seung-Min Hong, Se-Hee An, Joon-Yong Bae, Jung-Ah Choi, Seo Yeon Kim, Young Been Kim, Ji-Yeon Hwang, Hyo-Jung Lee, Hong Bin Kim, Dae Gwin Jeong, Daesub Song, Manki Song, Man-Seong Park, Kang-Seuk Choi, Jun Won Park, Jun-Won Yun, Jeon-Soo Shin, Ho-Young Lee, Ho-Keun Kwon, Jun-Young Seo, Ki Taek Nam, Heon Yung Gee, Je Kyung Seong

Viral load and the duration of viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important determinants of the transmission of coronavirus disease 2019. In this study, we examined the effects of viral doses on the lung and spleen of K18-hACE2 transgenic mice by temporal histological and transcriptional analyses. Approximately, 1×105 plaque-forming units (PFU) of SARS-CoV-2 induced strong host responses in the lungs from 2 days post inoculation (dpi) which did not recover until the mice died, whereas responses to the virus were obvious at 5 days, recovering to the basal state by 14 dpi at 1×102 PFU. Further, flow cytometry showed that number of CD8+ T cells continuously increased in 1×102 PFU-virus-infected lungs from 2 dpi, but not in 1×105 PFU-virus-infected lungs. In spleens, responses to the virus were prominent from 2 dpi, and number of B cells was significantly decreased at 1×105 PFU; however, 1×102 PFU of virus induced very weak responses from 2 dpi which recovered by 10 dpi. Although the defense responses returned to normal and the mice survived, lung histology showed evidence of fibrosis, suggesting sequelae of SARS-CoV-2 infection. Our findings indicate that specific effectors of the immune response in the lung and spleen were either increased or depleted in response to doses of SARS-CoV-2. This study demonstrated that the response of local and systemic immune effectors to a viral infection varies with viral dose, which either exacerbates the severity of the infection or accelerates its elimination.

严重急性呼吸系统综合征冠状病毒2(SARS-CoV-2)的病毒载量和病毒脱落持续时间是2019年冠状病毒疾病传播的重要决定因素。在本研究中,我们通过时间组织学和转录分析研究了病毒剂量对K18-hACE2转基因小鼠肺和脾脏的影响。大约1×105斑块形成单位(PFU)的SARS-CoV-2从接种后2天(dpi)开始在肺部诱导强烈的宿主反应,这种反应直到小鼠死亡才恢复,而对病毒的反应在5天时明显,在1×102 PFU的情况下,到14 dpi时恢复到基础状态。此外,流式细胞术显示,1×102 PFU 病毒感染的肺中 CD8+ T 细胞数量从 2 dpi 开始持续增加,而 1×105 PFU 病毒感染的肺中 CD8+ T 细胞数量则没有增加。在脾脏中,对病毒的反应从2 dpi开始就很明显,B细胞的数量在1×105 PFU时明显减少;然而,1×102 PFU的病毒从2 dpi开始诱导的反应很弱,到10 dpi才恢复。虽然小鼠的防御反应恢复正常并存活下来,但肺组织学显示有纤维化的迹象,这表明小鼠感染了 SARS-CoV-2 后会留下后遗症。我们的研究结果表明,肺部和脾脏中免疫反应的特异性效应因子会随着 SARS-CoV-2 剂量的增加而增加或减少。这项研究表明,局部和全身免疫效应因子对病毒感染的反应随病毒剂量的变化而变化,这要么加剧了感染的严重程度,要么加速了感染的消除。
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引用次数: 0
Innate Type-2 Cytokines: From Immune Regulation to Therapeutic Targets. 先天性 2 型细胞因子:从免疫调节到治疗目标。
IF 6 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-01-31 eCollection Date: 2024-02-01 DOI: 10.4110/in.2024.24.e6
Hye Young Kim, Dongjin Jeong, Ji Hyung Kim, Doo Hyun Chung

The intricate role of innate type-2 cytokines in immune responses is increasingly acknowledged for its dual nature, encompassing both protective and pathogenic dimensions. Ranging from defense against parasitic infections to contributing to inflammatory diseases like asthma, fibrosis, and obesity, these cytokines intricately engage with various innate immune cells. This review meticulously explores the cellular origins of innate type-2 cytokines and their intricate interactions, shedding light on factors that amplify the innate type-2 response, including TSLP, IL-25, and IL-33. Recent advancements in therapeutic strategies, specifically the utilization of biologics targeting pivotal cytokines (IL-4, IL-5, and IL-13), are discussed, offering insights into both challenges and opportunities. Acknowledging the pivotal role of innate type-2 cytokines in orchestrating immune responses positions them as promising therapeutic targets. The evolving landscape of research and development in this field not only propels immunological knowledge forward but also holds the promise of more effective treatments in the future.

先天性 2 型细胞因子在免疫反应中的作用错综复杂,越来越多的人认识到其双重性,既有保护作用,也有致病作用。从抵御寄生虫感染到导致哮喘、纤维化和肥胖等炎症性疾病,这些细胞因子与各种先天性免疫细胞错综复杂地相互作用。这篇综述细致地探讨了先天性 2 型细胞因子的细胞起源及其错综复杂的相互作用,揭示了 TSLP、IL-25 和 IL-33 等扩大先天性 2 型反应的因子。本文还讨论了治疗策略的最新进展,特别是针对关键细胞因子(IL-4、IL-5 和 IL-13)的生物制剂的使用,为我们提供了有关挑战和机遇的见解。认识到先天性 2 型细胞因子在协调免疫反应中的关键作用,将它们定位为有前景的治疗靶点。该领域不断发展的研究和开发成果不仅推动了免疫学知识的进步,也为未来更有效的治疗方法带来了希望。
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引用次数: 0
Optimising IL-2 for Cancer Immunotherapy. 优化用于癌症免疫疗法的 IL-2。
IF 4.3 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-01-26 eCollection Date: 2024-02-01 DOI: 10.4110/in.2024.24.e5
Jonathan Sprent, Onur Boyman

The key role of T cells in cancer immunotherapy is well established and is highlighted by the remarkable capacity of Ab-mediated checkpoint blockade to overcome T-cell exhaustion and amplify anti-tumor responses. However, total or partial tumor remission following checkpoint blockade is still limited to only a few types of tumors. Hence, concerted attempts are being made to devise new methods for improving tumor immunity. Currently, much attention is being focused on therapy with IL-2. This cytokine is a powerful growth factor for T cells and optimises their effector functions. When used at therapeutic doses for cancer treatment, however, IL-2 is highly toxic. Nevertheless, recent work has shown that modifying the structure or presentation of IL-2 can reduce toxicity and lead to effective anti-tumor responses in synergy with checkpoint blockade. Here, we review the complex interaction of IL-2 with T cells: first during normal homeostasis, then during responses to pathogens, and finally in anti-tumor responses.

T 细胞在癌症免疫疗法中的关键作用已得到充分证实,Ab 介导的检查点阻断疗法在克服 T 细胞衰竭和增强抗肿瘤反应方面的显著能力也凸显了这一点。然而,检查点阻断后肿瘤的完全或部分缓解仍仅限于少数类型的肿瘤。因此,人们正齐心协力,试图设计出改善肿瘤免疫的新方法。目前,IL-2疗法备受关注。这种细胞因子是一种强大的 T 细胞生长因子,能优化 T 细胞的效应功能。然而,当以治疗剂量用于癌症治疗时,IL-2 具有很强的毒性。然而,最近的研究表明,改变 IL-2 的结构或表达方式可以降低毒性,并与检查点阻断协同作用,产生有效的抗肿瘤反应。在此,我们回顾了 IL-2 与 T 细胞的复杂相互作用:首先是在正常稳态过程中,然后是在对病原体的反应过程中,最后是在抗肿瘤反应过程中。
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引用次数: 0
TNF in Human Tuberculosis: A Double-Edged Sword. 人类结核病中的 TNF:一把双刃剑
IF 6 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-01-26 eCollection Date: 2024-02-01 DOI: 10.4110/in.2024.24.e4
Jae-Min Yuk, Jin Kyung Kim, In Soo Kim, Eun-Kyeong Jo

TNF, a pleiotropic proinflammatory cytokine, is important for protective immunity and immunopathology during Mycobacterium tuberculosis (Mtb) infection, which causes tuberculosis (TB) in humans. TNF is produced primarily by phagocytes in the lungs during the early stages of Mtb infection and performs diverse physiological and pathological functions by binding to its receptors in a context-dependent manner. TNF is essential for granuloma formation, chronic infection prevention, and macrophage recruitment to and activation at the site of infection. In animal models, TNF, in cooperation with chemokines, contributes to the initiation, maintenance, and clearance of mycobacteria in granulomas. Although anti-TNF therapy is effective against immune diseases such as rheumatoid arthritis, it carries the risk of reactivating TB. Furthermore, TNF-associated inflammation contributes to cachexia in patients with TB. This review focuses on the multifaceted role of TNF in the pathogenesis and prevention of TB and underscores the importance of investigating the functions of TNF and its receptors in the establishment of protective immunity against and in the pathology of TB. Such investigations will facilitate the development of therapeutic strategies that target TNF signaling, which makes beneficial and detrimental contributions to the pathogenesis of TB.

TNF 是一种多向性促炎细胞因子,在结核分枝杆菌(Mtb)感染期间对保护性免疫和免疫病理起着重要作用。TNF 主要由肺部吞噬细胞在 Mtb 感染的早期阶段产生,并通过与受体结合的方式发挥多种生理和病理功能。TNF 对于肉芽肿的形成、慢性感染的预防以及巨噬细胞在感染部位的招募和活化至关重要。在动物模型中,TNF 与趋化因子合作,有助于肉芽肿中分枝杆菌的形成、维持和清除。虽然抗 TNF 治疗对类风湿性关节炎等免疫性疾病有效,但它也有可能使结核病重新活化。此外,与 TNF 相关的炎症也会导致结核病患者出现恶病质。本综述侧重于 TNF 在结核病发病机制和预防中的多方面作用,并强调了研究 TNF 及其受体在建立针对结核病的保护性免疫以及在结核病病理学中的功能的重要性。这些研究将有助于开发针对 TNF 信号转导的治疗策略,TNF 信号转导对结核病的发病机制既有利也有弊。
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引用次数: 0
IL-17 and IL-21: Their Immunobiology and Therapeutic Potentials. IL-17 和 IL-21:它们的免疫生物学和治疗潜力。
IF 6 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-01-19 eCollection Date: 2024-02-01 DOI: 10.4110/in.2024.24.e2
Choong-Hyun Koh, Byung-Seok Kim, Chang-Yuil Kang, Yeonseok Chung, Hyungseok Seo

Studies over the last 2 decades have identified IL-17 and IL-21 as key cytokines in the modulation of a wide range of immune responses. IL-17 serves as a critical defender against bacterial and fungal pathogens, while maintaining symbiotic relationships with commensal microbiota. However, alterations in its levels can lead to chronic inflammation and autoimmunity. IL-21, on the other hand, bridges the adaptive and innate immune responses, and its imbalance is implicated in autoimmune diseases and cancer, highlighting its important role in both health and disease. Delving into the intricacies of these cytokines not only opens new avenues for understanding the immune system, but also promises innovative advances in the development of therapeutic strategies for numerous diseases. In this review, we will discuss an updated view of the immunobiology and therapeutic potential of IL-17 and IL-21.

过去 20 年的研究发现,IL-17 和 IL-21 是调节各种免疫反应的关键细胞因子。IL-17 是抵御细菌和真菌病原体的关键防御因子,同时还能维持与共生微生物群的共生关系。然而,其水平的改变会导致慢性炎症和自身免疫。另一方面,IL-21 是适应性免疫反应和先天性免疫反应的桥梁,它的失衡与自身免疫性疾病和癌症有关,突出了它在健康和疾病中的重要作用。深入研究这些错综复杂的细胞因子不仅为了解免疫系统开辟了新的途径,而且有望在众多疾病的治疗策略开发方面取得创新性进展。在这篇综述中,我们将讨论有关 IL-17 和 IL-21 免疫生物学和治疗潜力的最新观点。
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引用次数: 0
Cigarette Smoke Extract-Treated Mouse Airway Epithelial Cells-Derived Exosomal LncRNA MEG3 Promotes M1 Macrophage Polarization and Pyroptosis in Chronic Obstructive Pulmonary Disease by Upregulating TREM-1 via m6A Methylation. 香烟烟雾提取物处理过的小鼠气道上皮细胞衍生的外泌体 LncRNA MEG3 通过 m6A 甲基化上调 TREM-1 促进慢性阻塞性肺病中 M1 型巨噬细胞的极化和嗜热性。
IF 6 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-01-19 eCollection Date: 2024-04-01 DOI: 10.4110/in.2024.24.e3
Lijing Wang, Qiao Yu, Jian Xiao, Qiong Chen, Min Fang, Hongjun Zhao

Cigarette smoke extract (CSE)-treated mouse airway epithelial cells (MAECs)-derived exosomes accelerate the progression of chronic obstructive pulmonary disease (COPD) by upregulating triggering receptor expressed on myeloid cells 1 (TREM-1); however, the specific mechanism remains unclear. We aimed to explore the potential mechanisms of CSE-treated MAECs-derived exosomes on M1 macrophage polarization and pyroptosis in COPD. In vitro, exosomes were extracted from CSE-treated MAECs, followed by co-culture with macrophages. In vivo, mice exposed to cigarette smoke (CS) to induce COPD, followed by injection or/and intranasal instillation with oe-TREM-1 lentivirus. Lung function and pathological changes were evaluated. CD68+ cell number and the levels of iNOS, TNF-α, IL-1β (M1 macrophage marker), and pyroptosis-related proteins (NOD-like receptor family pyrin domain containing 3, apoptosis-associated speck-like protein containing a caspase-1 recruitment domain, caspase-1, cleaved-caspase-1, gasdermin D [GSDMD], and GSDMD-N) were examined. The expression of maternally expressed gene 3 (MEG3), spleen focus forming virus proviral integration oncogene (SPI1), methyltransferase 3 (METTL3), and TREM-1 was detected and the binding relationships among them were verified. MEG3 increased N6-methyladenosine methylation of TREM-1 by recruiting SPI1 to activate METTL3. Overexpression of TREM-1 or METTL3 negated the alleviative effects of MEG3 inhibition on M1 polarization and pyroptosis. In mice exposed to CS, EXO-CSE further aggravated lung injury, M1 polarization, and pyroptosis, which were reversed by MEG3 inhibition. TREM-1 overexpression negated the palliative effects of MEG3 inhibition on COPD mouse lung injury. Collectively, CSE-treated MAECs-derived exosomal long non-coding RNA MEG3 may expedite M1 macrophage polarization and pyroptosis in COPD via the SPI1/METTL3/TREM-1 axis.

香烟烟雾提取物(CSE)处理过的小鼠气道上皮细胞(MAECs)衍生的外泌体通过上调髓系细胞上表达的触发受体1(TREM-1)加速了慢性阻塞性肺病(COPD)的进展;然而,其具体机制仍不清楚。我们旨在探索经 CSE 处理的 MAECs 衍生外泌体对慢性阻塞性肺病中 M1 巨噬细胞极化和嗜热的潜在机制。在体外,从 CSE 处理过的 MAECs 中提取外泌体,然后与巨噬细胞共同培养。在体内,小鼠暴露于香烟烟雾(CS)以诱导慢性阻塞性肺病,然后注射或/和鼻内灌注oe-TREM-1慢病毒。对肺功能和病理变化进行了评估。研究人员检测了CD68+细胞的数量、iNOS、TNF-α、IL-1β(M1巨噬细胞标记物)和热凋亡相关蛋白(NOD样受体家族含吡咯啉结构域的3、含caspase-1募集结构域的凋亡相关斑点样蛋白、caspase-1、裂解的caspase-1、gasdermin D [GSDMD]和GSDMD-N)的水平。检测了母体表达基因3(MEG3)、脾脏病灶形成病毒前病毒整合癌基因(SPI1)、甲基转移酶3(METTL3)和TREM-1的表达,并验证了它们之间的结合关系。MEG3通过招募SPI1激活METTL3来增加TREM-1的N6-甲基腺苷甲基化。TREM-1或METTL3的过表达抵消了MEG3抑制对M1极化和脓毒症的缓解作用。在暴露于 CS 的小鼠中,EXO-CSE 进一步加重了肺损伤、M1 极化和脓毒症,而抑制 MEG3 则可逆转这些情况。TREM-1 的过表达否定了 MEG3 抑制对 COPD 小鼠肺损伤的缓解作用。总之,CSE处理的MAECs衍生的外泌体长非编码RNA MEG3可通过SPI1/METTL3/TREM-1轴加速COPD中M1巨噬细胞的极化和脓毒症。
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引用次数: 0
Interleukin-18 Binding Protein (IL-18BP): A Long Journey From Discovery to Clinical Application. 白细胞介素-18 结合蛋白 (IL-18BP):从发现到临床应用的漫长历程。
IF 6 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-01-15 eCollection Date: 2024-02-01 DOI: 10.4110/in.2024.24.e1
Soohyun Kim, Hyeon Yu, Tania Azam, Charles A Dinarello

IL-18 binding protein (IL-18BP) was originally discovered in 1999 while attempting to identify an IL-18 receptor ligand binding chain (also known as IL-18Rα) by subjecting concentrated human urine to an IL-18 ligand affinity column. The IL-18 ligand chromatography purified molecule was analyzed by protein microsequencing. The result revealed a novel 40 amino acid polypeptide. To isolate the complete open reading frame (ORF), various human and mouse cDNA libraries were screened using cDNA probe derived from the novel IL-18 affinity column bound molecule. The identified entire ORF gene was thought to be an IL-18Rα gene. However, IL-18BP has been proven to be a unique soluble antagonist that shares homology with a variety of viral proteins that are distinct from the IL-18Rα and IL-18Rβ chains. The IL-18BP cDNA was used to generate recombinant IL-18BP (rIL-18BP), which was indispensable for characterizing the role of IL-18BP in vitro and in vivo. Mammalian cell lines were used to produce rIL-18BP due to its glycosylation-dependent activity of IL-18BP (approximately 20 kDa). Various forms of rIL-18BP, intact, C-terminal his-tag, and Fc fusion proteins were produced for in vitro and in vivo experiments. Data showed potent neutralization of IL-18 activity, which seems promising for clinical application in immune diseases involving IL-18. However, it was a long journey from discovery to clinical use although there have been various clinical trials since IL-18BP was discovered in 1999. This review primarily covers the discovery of IL-18BP along with how basic research influences the clinical development of IL-18BP.

IL-18 结合蛋白(IL-18BP)最初发现于 1999 年,当时人们试图通过将浓缩的人体尿液置于 IL-18 配体亲和柱中来鉴定 IL-18 受体配体结合链(也称为 IL-18Rα)。通过蛋白质微序列分析了经 IL-18 配体色谱纯化的分子。结果发现了一个新的 40 个氨基酸的多肽。为了分离出完整的开放阅读框(ORF),使用来自新型 IL-18 亲和柱结合分子的 cDNA 探针筛选了各种人类和小鼠 cDNA 文库。鉴定出的整个 ORF 基因被认为是 IL-18Rα 基因。但事实证明,IL-18BP 是一种独特的可溶性拮抗剂,它与多种病毒蛋白具有同源性,与 IL-18Rα 和 IL-18Rβ 链不同。IL-18BP cDNA 被用于生成重组 IL-18BP (rIL-18BP),这对于鉴定 IL-18BP 在体外和体内的作用不可或缺。由于 IL-18BP(约 20 kDa)具有糖基化依赖性活性,因此使用哺乳动物细胞系来生产 rIL-18BP。在体外和体内实验中生产了各种形式的 rIL-18BP,包括完整的、C-端 his-tag 和 Fc 融合蛋白。数据显示,该蛋白能有效中和 IL-18 的活性,有望用于涉及 IL-18 的免疫疾病的临床治疗。然而,尽管自 1999 年发现 IL-18BP 以来已进行了各种临床试验,但从发现到临床应用仍是一个漫长的过程。本综述主要涉及 IL-18BP 的发现以及基础研究如何影响 IL-18BP 的临床开发。
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引用次数: 0
Recombinant Human Bone Morphogenetic Protein-2 Priming of Mesenchymal Stem Cells Ameliorate Acute Lung Injury by Inducing Regulatory T Cells. 重组人骨形态发生蛋白-2 诱导间充质干细胞通过诱导调节性 T 细胞改善急性肺损伤
IF 6 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-12-18 eCollection Date: 2023-12-01 DOI: 10.4110/in.2023.23.e48
Jooyeon Lee, Jimin Jang, Sang-Ryul Cha, Se Bi Lee, Seok-Ho Hong, Han-Sol Bae, Young Jin Lee, Se-Ran Yang

Mesenchymal stromal/stem cells (MSCs) possess immunoregulatory properties and their regulatory functions represent a potential therapy for acute lung injury (ALI). However, uncertainties remain with respect to defining MSCs-derived immunomodulatory pathways. Therefore, this study aimed to investigate the mechanism underlying the enhanced effect of human recombinant bone morphogenic protein-2 (rhBMP-2) primed ES-MSCs (MSCBMP2) in promoting Tregs in ALI mice. MSC were preconditioned with 100 ng/ml rhBMP-2 for 24 h, and then administrated to mice by intravenous injection after intratracheal injection of 1 mg/kg LPS. Treating MSCs with rhBMP-2 significantly increased cellular proliferation and migration, and cytokines array reveled that cytokines release by MSCBMP2 were associated with migration and growth. MSCBMP2 ameliorated LPS induced lung injury and reduced myeloperoxidase activity and permeability in mice exposed to LPS. Levels of inducible nitric oxide synthase were decreased while levels of total glutathione and superoxide dismutase activity were further increased via inhibition of phosphorylated STAT1 in ALI mice treated with MSCBMP2. MSCBMP2 treatment increased the protein level of IDO1, indicating an increase in Treg cells, and Foxp3+CD25+ Treg of CD4+ cells were further increased in ALI mice treated with MSCBMP2. In co-culture assays with MSCs and RAW264.7 cells, the protein level of IDO1 was further induced in MSCBMP2. Additionally, cytokine release of IL-10 was enhanced while both IL-6 and TNF-α were further inhibited. In conclusion, these findings suggest that MSCBMP2 has therapeutic potential to reduce massive inflammation of respiratory diseases by promoting Treg cells.

间充质基质/干细胞(MSCs)具有免疫调节特性,其调节功能是治疗急性肺损伤(ALI)的潜在疗法。然而,间充质干细胞衍生免疫调节途径的定义仍存在不确定性。因此,本研究旨在探讨人重组骨形态发生蛋白-2(rhBMP-2)诱导的ES-间充质干细胞(MSCBMP2)促进ALI小鼠Tregs的增强效应的机制。用 100 ng/ml rhBMP-2 预处理间充质干细胞 24 小时,然后在气管内注射 1 mg/kg LPS 后静脉注射给小鼠。细胞因子阵列显示,MSCBMP2释放的细胞因子与迁移和生长有关。MSCBMP2 可改善 LPS 诱导的肺损伤,降低暴露于 LPS 的小鼠的髓过氧化物酶活性和通透性。在接受 MSCBMP2 治疗的 ALI 小鼠中,诱导型一氧化氮合酶水平降低,而总谷胱甘肽水平和超氧化物歧化酶活性则通过抑制磷酸化 STAT1 而进一步提高。用 MSCBMP2 处理 ALI 小鼠后,IDO1 蛋白水平升高,表明 Treg 细胞增加,CD4+ 细胞中的 Foxp3+CD25+ Treg 进一步增加。在间充质干细胞和 RAW264.7 细胞的共培养试验中,MSCBMP2 进一步诱导了 IDO1 的蛋白水平。此外,IL-10 的细胞因子释放增强,而 IL-6 和 TNF-α 则进一步受到抑制。总之,这些研究结果表明,MSCBMP2 具有治疗潜力,可通过促进 Treg 细胞减少呼吸系统疾病的大规模炎症。
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引用次数: 0
Intranasal Immunization With Nanoparticles Containing an Orientia tsutsugamushi Protein Vaccine Candidate and a Polysorbitol Transporter Adjuvant Enhances Both Humoral and Cellular Immune Responses. 用含有恙虫病候选蛋白疫苗和聚山梨醇转运体佐剂的纳米颗粒进行鼻内免疫可增强体液和细胞免疫反应。
IF 6 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-12-15 eCollection Date: 2023-12-01 DOI: 10.4110/in.2023.23.e47
Cheol Gyun Kim, Won Kyong Kim, Narae Kim, Young Jin Pyung, Da-Jeong Park, Jeong-Cheol Lee, Chong-Su Cho, Hyuk Chu, Cheol-Heui Yun

Scrub typhus, a mite-borne infectious disease, is caused by Orientia tsutsugamushi. Despite many attempts to develop a protective strategy, an effective preventive vaccine has not been developed. The identification of appropriate Ags that cover diverse antigenic strains and provide long-lasting immunity is a fundamental challenge in the development of a scrub typhus vaccine. We investigated whether this limitation could be overcome by harnessing the nanoparticle-forming polysorbitol transporter (PST) for an O. tsutsugamushi vaccine strategy. Two target proteins, 56-kDa type-specific Ag (TSA56) and surface cell Ag A (ScaA) were used as vaccine candidates. PST formed stable nano-size complexes with TSA56 (TSA56-PST) and ScaA (ScaA-PST); neither exhibited cytotoxicity. The formation of Ag-specific IgG2a, IgG2b, and IgA in mice was enhanced by intranasal vaccination with TSA56-PST or ScaA-PST. The vaccines containing PST induced Ag-specific proliferation of CD8+ and CD4+ T cells. Furthermore, the vaccines containing PST improved the mouse survival against O. tsutsugamushi infection. Collectively, the present study indicated that PST could enhance both Ag-specific humoral immunity and T cell response, which are essential to effectively confer protective immunity against O. tsutsugamushi infection. These findings suggest that PST has potential for use in an intranasal vaccination strategy.

恙虫病是一种螨媒传染病,由恙虫病原虫(Orientia tsutsugamushi)引起。尽管人们多次尝试开发保护性策略,但仍未研制出有效的预防性疫苗。在开发恙虫病疫苗的过程中,一个基本的挑战是如何确定适当的抗原,以覆盖不同的抗原菌株并提供持久的免疫力。我们研究了利用纳米颗粒形成的多聚山梨醇转运体(PST)来开发恙虫疫苗是否能克服这一限制。两种目标蛋白,56-kDa 型特异性 Ag(TSA56)和表面细胞 Ag A(ScaA)被用作候选疫苗。PST 与 TSA56(TSA56-PST)和 ScaA(ScaA-PST)形成稳定的纳米级复合物;两者均不表现细胞毒性。通过鼻内接种 TSA56-PST 或 ScaA-PST 可增强小鼠体内 Ag 特异性 IgG2a、IgG2b 和 IgA 的形成。含有 PST 的疫苗可诱导 Ag 特异性 CD8+ 和 CD4+ T 细胞增殖。此外,含有 PST 的疫苗提高了小鼠在恙虫感染中的存活率。总之,本研究表明,PST 可增强恙虫特异性体液免疫和 T 细胞应答,而这两种免疫对于有效抵抗恙虫感染至关重要。这些研究结果表明,PST 有潜力用于鼻内疫苗接种策略。
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Immune Network
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