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Janus kinase inhibitors ameliorate clinical symptoms in patients with STAT3 gain-of-function Janus激酶抑制剂可改善STAT3功能增益患者的临床症状
Pub Date : 2023-11-24 DOI: 10.1093/immadv/ltad027
Shuya Kaneko, Fumiaki Sakura, Kay Tanita, A. Shimbo, R. Nambu, Masashi Yoshida, Shuichiro Umetsu, A. Inui, Chizuru Okada, M. Tsumura, Mamiko Yamada, Hisato Suzuki, K. Kosaki, Osamu Ohara, M. Shimizu, Tomohiro Morio, Satoshi Okada, H. Kanegane
Germline gain-of-function (GOF) variants in the signal transducer and activator of transcription 3 (STAT3) gene is an inborn error of immunity presenting with autoimmunity and lymphoproliferation. Symptoms can vary widely, and no effective treatment has been established. This study investigated the efficacy of Janus kinase (JAK) inhibitors (JAKi) in patients with STAT3-GOF. Four patients were enrolled and their clinical symptoms before and after the initiation of treatment with JAKi were described. A cell stimulation assay was performed using Epstein-Barr virus transformed lymphoid cell lines (EBV-LCLs) that were derived from the patients with STAT3-GOF. The patients presented with various symptoms, and these symptoms were mostly improved after the initiation of JAKi treatment. Upon interleukin-6 stimulation, the EBV-LCLs of patients showed enhanced STAT3 phosphorylation compare with those of the EBV-LCLs of healthy controls. In conclusion, four Japanese patients with STAT3-GOF were successfully treated with JAKi. JAKi ameliorated various symptoms and therefore, the use of JAKi could be an effective treatment option for patients with STAT3-GOF.
信号转导和激活因子 3(STAT3)基因的基因功能增益(GOF)变异是一种先天性免疫错误,表现为自身免疫和淋巴细胞增殖。该病的症状千差万别,目前尚无有效的治疗方法。本研究调查了 Janus 激酶(JAK)抑制剂(JAKi)对 STAT3-GOF 患者的疗效。研究共招募了四名患者,并描述了他们在开始接受JAKi治疗前后的临床症状。使用从 STAT3-GOF 患者身上提取的 Epstein-Barr 病毒转化淋巴细胞系(EBV-LCLs)进行了细胞刺激试验。患者表现出各种症状,这些症状在开始接受 JAKi 治疗后大多得到了改善。在白细胞介素-6的刺激下,患者的EBV-LCLs与健康对照组的EBV-LCLs相比,STAT3磷酸化增强。总之,四名患有 STAT3-GOF 的日本患者成功地接受了 JAKi 治疗。JAKi改善了患者的各种症状,因此,对STAT3-GOF患者来说,使用JAKi可能是一种有效的治疗选择。
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引用次数: 0
Efficacy of PD-1 checkpoint inhibitor therapy in melanoma and beyond: are peripheral T cell phenotypes the key? PD-1检查点抑制剂治疗黑色素瘤及其他疾病的疗效:外周T细胞表型是关键吗?
Pub Date : 2023-11-22 eCollection Date: 2023-01-01 DOI: 10.1093/immadv/ltad026
Katie R Flaherty, Stephanie Kucykowicz, Johannes Schroth, Will Traves, Kyle T Mincham, George E Finney
Summary Immunotherapy treatment strategies have proven effective in a limited portion of patients, where identifying responders from non-responders to treatment remains a challenge. While some indications can be drawn from invasive biopsies, we need more accessible methods for predicting response and better correlates of response prior to starting therapy. Recent work has identified differences in immune composition at baseline in peripheral blood from melanoma patients responding to PD-1 blockade treatment. Through flow cytometric analysis of T cell receptors, phenotypical features of CD8+ and CD4+ T cells and Tregs could allow for the stratification of treatment response. Analysing T cells within peripheral blood could potentially allow for the stratification of PD-1 treatment response prior to therapy in different cancer settings.
免疫疗法治疗策略已被证明对有限部分患者有效,在这些患者中,识别对治疗有反应和无反应仍然是一个挑战。虽然可以从侵入性活检中得出一些适应症,但我们需要更容易获得的方法来预测反应,并在开始治疗之前更好地确定反应的相关性。最近的工作已经确定了对PD-1阻断治疗有反应的黑色素瘤患者外周血基线免疫组成的差异。通过T细胞受体的流式细胞术分析,CD8+和CD4+ T细胞和Tregs的表型特征可以对治疗反应进行分层。分析外周血中的T细胞可能允许在不同癌症治疗前对PD-1治疗反应进行分层。
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引用次数: 0
DC-targeting Lentivectors for Cancer Immunotherapy 肿瘤免疫治疗的dc靶向慢载体
Pub Date : 2023-11-01 DOI: 10.1093/immadv/ltad023
Ester Gea-Mallorquí, Sarah Rowland-Jones
Abstract Lentivectors (LVs) induce sustained transgene expression and are attractive vaccine platforms for complex immune scenarios like cancer and persistent infections. This review summarises the literature on lentivectors with potential uses for in vivo immunotherapy, focusing on those targeting the most potent antigen-presenting cells: dendritic cells (DCs). There is a growing interest in myeloid-targeting therapies as, by influencing an early stage in the immune hierarchy, they can orchestrate a more diverse and complex targeted immune response. We dissect the nature of DC-targeting LVs and their induced immune responses to understand the state of the art, identify the knowledge gaps and guide efforts to maximise the generation of potent and effective immune responses. Lentivector-based vaccines provide several advantages over other vaccine platforms, such as directed tropism and limited vector immunogenicity, and have been shown to generate effective and sustained immune responses. Overall, DC-targeting lentivectors stand out as promising tools to be exploited in cancer immunotherapy, and new-generation LVs can further exploit the gained knowledge in the study of naturally-occurring lentiviruses for a more directed and adjuvanted response.
慢载体(LVs)诱导持续的转基因表达,是复杂免疫场景(如癌症和持续感染)有吸引力的疫苗平台。本文综述了在体内免疫治疗中具有潜在用途的慢载体的文献,重点介绍了针对最有效的抗原呈递细胞:树突状细胞(dc)的慢载体。人们对骨髓靶向治疗越来越感兴趣,因为通过影响免疫层次的早期阶段,它们可以协调更多样化和复杂的靶向免疫反应。我们剖析了dc靶向lv的性质及其诱导的免疫反应,以了解最新的技术状况,确定知识差距,并指导努力最大限度地产生有效的免疫反应。与其他疫苗平台相比,基于慢载体的疫苗具有若干优势,如定向性和有限载体免疫原性,并已证明可产生有效和持续的免疫反应。总的来说,靶向dc的慢病毒载体是癌症免疫治疗中很有前途的工具,新一代lv可以进一步利用在自然存在的慢病毒研究中获得的知识,以获得更直接和辅助的应答。
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引用次数: 0
Time to treat the climate and nature crisis as one indivisible global health emergency. 是时候将气候和自然危机视为一个不可分割的全球卫生紧急事件了。
Pub Date : 2023-10-25 eCollection Date: 2023-01-01 DOI: 10.1093/immadv/ltad021
Kamran Abbasi, Parveen Ali, Virginia Barbour, Thomas Benfield, Kirsten Bibbins-Domingo, Stephen Hancocks, Richard Horton, Laurie Laybourn-Langton, Robert Mash, Peush Sahni, Wadeia Mohammad Sharief, Paul Yonga, Chris Zielinski
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引用次数: 0
NLRP3 inflammasome activation in sensory neurons promotes chronic inflammatory and osteoarthritis pain 感觉神经元中NLRP3炎性小体的激活促进慢性炎症和骨关节炎疼痛
Pub Date : 2023-10-24 DOI: 10.1093/immadv/ltad022
Patrícia Silva Santos Ribeiro, Hanneke L D M Willemen, Sabine Versteeg, Christian Martin Gil, Niels Eijkelkamp
Abstract Pain is one of the most debilitating symptoms in rheumatic diseases. Pain often persists after total knee replacement in osteoarthritis, or when inflammation is minimal/absent in rheumatoid arthritis. This suggests that pain transitions to a chronic state independent of the original damage/inflammation. Mitochondrial dysfunction in the nervous system promotes chronic pain and is linked to NLRP3 inflammasome activation. Therefore, we investigated the role of mitochondrial dysfunction and NLRP3 inflammasome activation in the transition from acute to persistent inflammation-induced nociplastic pain and in persistent monoiodoacetate-induced osteoarthritis pain. Intraplantar injection of carrageenan in mice induced transient inflammatory pain that resolved within 7 days. A subsequent intraplantar PGE2 injection induced persistent mechanical hypersensitivity, while in naive mice it resolved within one day. Thus, this initial transient inflammation induced maladaptive nociceptor neuroplasticity, so-called hyperalgesic priming. At day 7, when mice were primed, expression of NLRP3 inflammasome pathway components were increased, and dorsal root ganglia neurons displayed signs of activated NLRP3 inflammasome. Inhibition of NLRP3 inflammasome with MCC950 prevented the transition from acute to chronic pain in this hyperalgesic priming model. In mice with persistent monoiodoacetate-induced osteoarthritis pain, neurons displayed signs of mitochondrial oxidative stress and NLRP3 inflammasome activation. Blocking NLRP3 inflammasome activity attenuated established osteoarthritis pain. In males, NLPR3 inhibition had longer lasting effects than in females. Overall, these data suggest that NLRP3 inflammasome activation in sensory neurons, potentially caused by neuronal oxidative stress, promotes development of persistent inflammatory and osteoarthritis pain. Therefore, targeting NLRP3 inflammasome pathway may be a promising approach to treat chronic pain.
疼痛是风湿病中最使人衰弱的症状之一。骨关节炎患者在全膝关节置换术后,或类风湿关节炎患者炎症轻微或无炎症时,疼痛常持续存在。这表明疼痛转变为一种独立于原始损伤/炎症的慢性状态。神经系统线粒体功能障碍促进慢性疼痛,并与NLRP3炎性体激活有关。因此,我们研究了线粒体功能障碍和NLRP3炎性小体激活在从急性到持续炎症诱导的伤害性疼痛和持续单碘乙酸诱导的骨关节炎疼痛的转变中的作用。小鼠足底注射角叉菜胶可引起短暂性炎性疼痛,7天内消退。随后足底注射PGE2诱导了持续的机械过敏,而在幼稚小鼠中,它在一天内消退。因此,这种初始的短暂炎症引起了伤害感受器神经可塑性不良,即所谓的痛觉过敏启动。在第7天,当小鼠被启动时,NLRP3炎症小体通路组分的表达增加,背根神经节神经元显示NLRP3炎症小体被激活的迹象。MCC950对NLRP3炎性体的抑制阻止了痛觉过敏启动模型中由急性疼痛向慢性疼痛的转变。在持续单碘酸盐诱导的骨关节炎疼痛小鼠中,神经元表现出线粒体氧化应激和NLRP3炎性体激活的迹象。阻断NLRP3炎性体活性可减轻已建立的骨关节炎疼痛。在男性中,NLPR3抑制作用比女性持久。总的来说,这些数据表明,感觉神经元中NLRP3炎性小体的激活,可能是由神经元氧化应激引起的,促进了持续性炎症和骨关节炎疼痛的发展。因此,靶向NLRP3炎性体通路可能是治疗慢性疼痛的一种有希望的方法。
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引用次数: 0
Correction to: Blockade of innate inflammatory cytokines TNFα, IL-1β, or IL-6 overcomes virotherapy-induced cancer equilibrium to promote tumor regression. 更正:先天性炎性细胞因子TNFα、IL-1β或IL-6的阻断克服了病毒治疗诱导的癌症平衡,促进肿瘤消退。
Pub Date : 2023-10-12 eCollection Date: 2023-01-01 DOI: 10.1093/immadv/ltad019

[This corrects the article DOI: 10.1093/immadv/ltad011.].

[这更正了文章DOI:10.1093/imadv/ltad011.]。
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引用次数: 0
Correction to: TIM-3: a tumor-associated antigen beyond checkpoint inhibition? 更正:TIM-3:一种超越检查点抑制的肿瘤相关抗原?
Pub Date : 2023-10-12 eCollection Date: 2023-01-01 DOI: 10.1093/immadv/ltad018

[This corrects the article DOI: 10.1093/immadv/ltac021.].

[这更正了文章DOI:10.1093/imadv/ltac021.]。
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引用次数: 0
Correction to: Immunology of allergen immunotherapy. 更正:过敏原免疫疗法的免疫学。
Pub Date : 2023-10-12 eCollection Date: 2023-01-01 DOI: 10.1093/immadv/ltad017

[This corrects the article DOI: 10.1093/immadv/ltac022.].

[这更正了文章DOI:10.1093/imadv/ltac022.]。
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引用次数: 0
Efficacy of smallpox vaccines against Mpox infections in humans. 天花疫苗对人类猴痘感染的有效性。
Pub Date : 2023-10-07 eCollection Date: 2023-01-01 DOI: 10.1093/immadv/ltad020
Melissa M Christodoulidou, Neil A Mabbott

The Mpox virus (MPXV) is endemic in certain countries in Central and West Africa, where several mammalian species, especially rodents, are natural reservoirs. However, the MPXV can infect nonhuman primates and cause zoonotic infections in humans after close contact with an infected animal. Human-to-human transmission of MPXV can also occur through direct close contact with an infected individual or infected materials. In May 2022 an initial cluster of human Mpox cases was identified in the UK, with the first case confirmed in a patient who had recently travelled to Nigeria. The infection subsequently spread via human-to-human transmission within the UK and Mpox cases began to appear in many other countries around the world where the MPXV is not endemic. No specific treatments for MPXV infection in humans are available. However, data from studies undertaken in Zaire in the 1980s revealed that those with a history of smallpox vaccination during the global smallpox eradication campaign also had good cross-protection against MPXV infection. However, the vaccines used during the global eradication campaign are no longer available. During the 2022 global Mpox outbreak over a million doses of the Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) smallpox vaccine were offered either as pre or postexposure prophylaxis to those at high risk of MPXV infection. Here, we review what has been learned about the efficacy of smallpox vaccines in reducing the incidence of MPXV infections in high-risk close contacts.

猴痘病毒(MPXV)在中非和西非的某些国家流行,那里的几种哺乳动物,尤其是啮齿类动物,是天然的宿主。然而,MPXV可以感染非人类灵长类动物,并在与受感染动物密切接触后导致人类人畜共患感染。MPXV的人传人也可通过与受感染个体或受感染材料的直接密切接触发生。2022年5月,英国发现了首批人类猴痘病例,第一例确诊病例是最近前往尼日利亚的患者。感染随后在英国通过人与人之间的传播传播,猴痘病例开始出现在世界上MPXV不是地方病的许多其他国家。目前还没有针对人类MPXV感染的特效治疗方法。然而,1980年代在扎伊尔进行的研究数据显示,在全球根除天花运动期间有天花疫苗接种史的人也对MPXV感染有良好的交叉保护作用。然而,在全球根除运动中使用的疫苗已不复存在。在2022年全球猴痘疫情期间,超过100万剂改良的Ankara-Bavarian Nordic(MVA-BN)天花疫苗被提供给MPXV感染高危人群,作为暴露前或暴露后的预防。在这里,我们回顾了天花疫苗在降低高危密切接触者MPXV感染率方面的疗效。
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引用次数: 0
Prevention vs treatment of rheumatoid arthritis. 类风湿性关节炎的预防与治疗。
IF 4.1 Q2 IMMUNOLOGY Pub Date : 2023-08-29 eCollection Date: 2023-01-01 DOI: 10.1093/immadv/ltad016
Lars Klareskog, Lars Alfredsson

Whether a yet chronic and not curable disease like rheumatoid arthritis (RA) can be subject to prevention or whether available resources should be focused on treatment is a classical dilemma. Similar to the case in most other chronic diseases, the focus in research as well as in clinical practice has been on the treatment of established diseases, resulting in drugs that are efficient in eliminating most joint damage but not able to cure the disease or stop needs for continuous treatment of the disease. Less effort has been spent on identifying and implementing ways to prevent the disease. We argue in this review that knowledge concerning the longitudinal evolvement of the major, 'seropositive' subset of RA has now come to a stage where prevention should be a large part of the research agenda and that we should prepare for prevention as part of clinical practice in RA. We describe briefly the knowledge basis for broad public health-based prevention as well as for a 'precision prevention' strategy. In the latter, individuals at high risk for RA will be identified, monitored, and ultimately provided with advice on how to change lifestyle/environment or be given treatment with drugs able to delay and ultimately stop the development of RA. Whether this potential of precision prevention for RA will change the broader clinical practice will depend on whether specific and long-lasting interference with disease-inducing immunity, ultimately 'tolerance therapy', will become a reality.

对于类风湿性关节炎(RA)这种无法治愈的慢性疾病,究竟是应该预防,还是应该将现有资源集中用于治疗,这是一个传统的难题。与大多数其他慢性疾病的情况类似,研究和临床实践的重点一直放在治疗已确诊的疾病上,结果是药物能有效消除大部分关节损伤,但无法治愈疾病或停止对疾病的持续治疗。在确定和实施疾病预防方法方面所做的努力较少。我们在这篇综述中认为,有关主要的 "血清阳性 "RA亚群纵向发展的知识现在已经到了这样一个阶段,即预防应该成为研究议程的一个重要部分,我们应该准备将预防作为RA临床实践的一部分。我们简要介绍了以公共卫生为基础的广泛预防以及 "精准预防 "策略的知识基础。在后者中,我们将对RA高危人群进行识别、监测,并最终提供如何改变生活方式/环境的建议,或给予能够延缓并最终阻止RA发展的药物治疗。这种精准预防RA的潜力是否会改变更广泛的临床实践,将取决于对疾病诱导免疫的特异性和持久性干扰,即最终的 "耐受疗法",是否会成为现实。
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引用次数: 0
期刊
Immunotherapy advances
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