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Mechanism of NLRP3 inflammasome activation and its role in Alzheimer’s disease NLRP3炎性体激活机制及其在阿尔茨海默病中的作用
Pub Date : 2022-05-07 DOI: 10.37349/ei.2022.00048
Xiaoying Gao, Xiaoxia Zhang, Yaxuan Sun, Xueling Dai
Alzheimer’s disease (AD) is a common neurological disease in the elderly, and the major manifestations are cognitive dysfunction, neuronal loss, and neuropathic lesions in the brain. In the process of AD pathogenesis, the inflammatory response plays an indispensable role. The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome containing NOD, leucine-rich repeat (LRR), and pyran domains is a multi-molecular complex that can detect dangerous signals related to neurological diseases. The assembly of NLRP3 inflammasome promotes the maturation of interleukin-1beta (IL-1β) and IL-18 mediated by caspase-1 in microglia, which leads to neuroinflammation and finally contributes to the occurrence and development of AD. This review aimed to clarify the structure and activating mechanism of NLRP3 inflammasome and its key role in the pathogenesis of AD, summarize the latest findings on the suppression of NLRP3 inflammasome activation for the treatment of AD, as well as indicate that targeting regulation of NLRP3 inflammasome assembly may be a potential strategy for the treatment of AD, providing a theoretical basis for the research of AD.
阿尔茨海默病(AD)是老年人常见的神经系统疾病,主要表现为认知功能障碍、神经元丧失和大脑神经病变。在AD的发病过程中,炎症反应起着不可或缺的作用。核苷酸结合寡聚结构域(NOD)样受体家族pyrin结构域包含3(NLRP3)炎症小体包含NOD、富含亮氨酸重复序列(LRR)和吡喃结构域是一种可以检测与神经疾病相关的危险信号的多分子复合物。NLRP3炎症小体的组装促进了小胶质细胞中由胱天蛋白酶-1介导的白细胞介素-1β(IL-1β)和IL-18的成熟,从而导致神经炎症,最终参与AD的发生和发展,总结了抑制NLRP3炎症小体激活治疗AD的最新发现,并指出靶向调节NLRP3炎性小体组装可能是治疗AD的一种潜在策略,为AD的研究提供了理论依据。
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引用次数: 0
A proposed new paradigm for an anti-AIDS tolerogenic vaccine 一种抗艾滋病耐受原性疫苗的新模式
Pub Date : 2022-04-24 DOI: 10.37349/ei.2022.00046
C. Jacomet
Until now, despite 30 years of intensive work, the RV144 human immunodeficiency virus (HIV) vaccine trial initiated in 2003 remains so far the most protective vaccine prototype of all those tested (32% reduction in the infection rate three years after the vaccination) and the HIV epidemic is still spreading worldwide. In addition, antiretroviral therapy (ART) for people living with HIV is given for life as no other pharmacological intervention has allowed to maintain an undetectable viral load after ART withdrawal. Pr Andrieu and colleagues discovered tolerogenic CD8+T-cells that suppress simian immunodeficiency virus (SIV) specific activation, ensuing SIV reverse transcription suppression and viral replication-defective in Chinese macaques vaccinated by intragastric route with inactivated SIV particles + Lactobacillus rhamnosus. Moreover, in HIV-infected elite controllers with specific genetic features (HLA-1-Bw4-80i and KIR3DL1 genes), Pr Andrieu found out that similar tolerogenic CD8+T-cells suppress in the same manner HIV-specific activation, HIV reverse transcription, and HIV replication. These data justify the development of a tolerogenic vaccine composed of inactivated HIV particles + Lactobacillus rhamnosus that could be used as a preventive or therapeutic vaccine.
到目前为止,尽管经过了30年的密集工作,2003年开始的RV144人类免疫缺陷病毒(HIV)疫苗试验迄今仍是所有试验中最具保护性的疫苗原型(接种疫苗三年后感染率降低32%),艾滋病毒流行病仍在全世界蔓延。此外,对艾滋病毒感染者进行抗逆转录病毒治疗(ART)是终身的,因为没有其他药物干预可以在停药后维持无法检测到的病毒载量。Pr Andrieu及其同事发现,在中国猕猴经经SIV灭活颗粒+鼠李糖乳杆菌经腹腔接种后,耐受性CD8+ t细胞抑制SIV特异性激活,导致SIV逆转录抑制和病毒复制缺陷。此外,在HIV感染的具有特定遗传特征的精英控制者(HLA-1-Bw4-80i和KIR3DL1基因)中,Pr Andrieu发现相似的耐受性CD8+ t细胞以相同的方式抑制HIV特异性激活、HIV逆转录和HIV复制。这些数据证明开发一种由灭活的HIV颗粒+鼠李糖乳杆菌组成的耐受性原疫苗是合理的,这种疫苗可以用作预防性或治疗性疫苗。
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引用次数: 0
Thymosin alpha 1 therapy alleviates organ dysfunction of sepsis patients: a retrospective cohort study 胸腺素- 1治疗可减轻败血症患者的器官功能障碍:一项回顾性队列研究
Pub Date : 2022-04-22 DOI: 10.37349/ei.2022.00045
P. Fei, Yishan Liu, Lingyun Zuo, Bin-fang Gu, Liqun Liang, Luhao Wang, Y. Nie, Minying Chen, X. Guan, Jianfeng Wu
Aim:Thymosin alpha 1 (Tα1) is a promising treatment for the improvement of sepsis patients. Until now, its function in reducing acute organ damage of sepsis patients is still unclear. The aim of this study was to determine whether Tα1 can alleviate organ dysfunction in sepsis patients.Methods:This study retrospectively enrolled sepsis patients from a multicenter randomized controlled trial [efficacy of Tα1 for severe sepsis (ETASS)]. The sequential organ failure assessment (SOFA) score on day 0 (initial), day 3, and day 7 was collected. Absolute SOFAday07 was defined as initial SOFA score minus SOFA score on day 7 (initial SOFA–SOFA day7). Delta SOFA score (ΔSOFAday07) was provided by the formula: (initial SOFA–SOFA day7) × 100/initial SOFA, and it was expressed as a percentage. After propensity score matching (1:1 ratio), baseline characteristics were well-balanced between the Tα1 group and placebo group. The primary outcome was evaluated with a comparison of ΔSOFAday07 decline between patients treated with or without Tα1 therapy.Results:Among 288 enrolled patients, 149 patients received both Tα1 and standard therapy (Tα1 group), and 139 patients received both placebo and standard therapy (placebo group). Compared with the placebo group, the Tα1 group had significantly lower Absolute SOFAday07 [95% confidence interval (CI) 0.8 (0–1.7), P = 0.049]. Among 111 pairs of patients matched by propensity score, the Tα1 group still had lower Absolute SOFAday07 [95% CI 1.0 (0.1–1.9), P = 0.029]. Meanwhile, Tα1 treatment could significantly improve ΔSOFAday07. When the amplitude of ΔSOFAday07 was graded, one third of patients in the Tα1 group had an increase of more than 60%, compared with 22% in the placebo group. Subgroup analysis found that the ΔSOFAday07 improved significantly after Tα1 therapy in sepsis patients with no immunoparalysis at baseline, no complications, and early intervention.Conclusions:For sepsis patients, Tα1 treatment can alleviate organ dysfunction, and ΔSOFAday07 can be used as an indicator of its therapeutic effect (ClinicalTrials.gov identifier: NCT00711620).
目的:胸腺素α1 (Tα1)是一种很有希望改善脓毒症患者的治疗方法。迄今为止,其在减轻脓毒症患者急性器官损伤中的作用尚不清楚。本研究旨在探讨Tα1是否能减轻脓毒症患者的器官功能障碍。方法:本研究回顾性纳入了一项多中心随机对照试验[Tα1治疗严重脓毒症(ETASS)的疗效]的脓毒症患者。收集第0天(初始)、第3天和第7天的序贯器官衰竭评估(SOFA)评分。绝对SOFAday07定义为初始SOFA评分减去第7天的SOFA评分(初始SOFA - SOFA第7天)。Delta SOFA评分(ΔSOFAday07)的计算公式为:(initial SOFA - SOFA day7) × 100/initial SOFA,并以百分比表示。倾向评分匹配(1:1)后,Tα1组和安慰剂组的基线特征平衡良好。通过比较接受或不接受t - α1治疗的患者的ΔSOFAday07下降来评估主要结局。结果:288例入组患者中,同时接受Tα1和标准治疗的患者149例(Tα1组),同时接受安慰剂和标准治疗的患者139例(安慰剂组)。与安慰剂组相比,Tα1组的绝对SOFAday07明显降低[95%置信区间(CI) 0.8 (0-1.7), P = 0.049]。在倾向评分匹配的111对患者中,Tα1组的绝对SOFAday07仍较低[95% CI 1.0 (0.1 ~ 1.9), P = 0.029]。同时t - α1处理可显著改善ΔSOFAday07。当ΔSOFAday07的振幅被分级时,Tα1组中三分之一的患者增加超过60%,而安慰剂组为22%。亚组分析发现,基线时无免疫瘫痪、无并发症、早期干预的败血症患者经Tα1治疗后ΔSOFAday07明显改善。结论:对于脓毒症患者,Tα1治疗可减轻器官功能障碍,ΔSOFAday07可作为其治疗效果的指标(ClinicalTrials.gov标识符:NCT00711620)。
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引用次数: 2
Single-cell differentiation trajectories define early stages of a human cutaneous T-cell lymphoma 单细胞分化轨迹定义人类皮肤T细胞淋巴瘤的早期阶段
Pub Date : 2022-04-15 DOI: 10.37349/ei.2022.00044
J. Cerapio, M. Perrier, F. Pont, C. Laurent, Stéphane Bertani, J. Fournié
Aim: The aim of this article is to characterize in detail the γδ T lymphocytes from an adult patient with primary cutaneous T-cell lymphoma of γδ subtype (γδ CTCL).Methods: Here this article reports trajectory mapping on high-resolution differentiation trajectories of γδ T lymphocytes digitally extracted from a scRNAseq dataset.Results: In the patch-to-plaque progression of CTCL, the TCRVγnon9 subset of γδ T cells differentiated from naive T cells (Tn) and central memory T cells (Tcm) to abundant effector memory T cells (Tem) while other cutaneous γδ T and CD8 T cells remained unchanged.Conclusions: This transcriptomic switch underlies the emergence of a CTCL-like progression of the TCRVγnon9 γδ T subtype and suggests new routes for treating these diseases.
目的:本文的目的是详细描述一名患有γδ亚型原发性皮肤T细胞淋巴瘤(γδCTCL)的成年患者的γδT淋巴细胞。结果:在CTCL斑块-斑块进展过程中,γδT细胞的TCRVγnon9亚群从幼稚T细胞(Tn)和中央记忆T细胞(Tcm)分化为丰富的效应记忆T细胞,而其他皮肤γδT和CD8 T细胞保持不变。结论:这种转录组转换是TCRVγnon9γδT亚型CTCL样进展的基础,并为治疗这些疾病提供了新的途径。
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引用次数: 0
Paradigms in HIV vaccine research HIV疫苗研究的范式
Pub Date : 2022-03-17 DOI: 10.37349/ei.2022.00043
M. V. van Regenmortel
Although a large number of preventative human immunodeficiency virus (HIV) vaccine trials have been carried out during the last 30 years, it is remarkable that an effective HIV vaccine has not yet been developed. Research paradigms correspond to theoretical assumptions and particular strategies that scientists use when they try to solve a particular problem. Many paradigms used successfully in vaccinology were ineffective with HIV. For instance: 1) The structure-based reverse vaccinology approach failed because investigators tried to generate a vaccine starting with the antigenic structure of HIV-envelope (Env) epitopes bound to neutralizing monoclonal antibodies (mAbs) derived from HIV-infected individuals. They assumed that this antigenic structure would also possess the immunogenic capacity of inducing in vaccinees a polyclonal antibody (Ab) response with the same neutralizing capacity as the mAb. 2) The structures observed in epitope-paratope crystallographic complexes result from mutually induced fit between the two partners and do not correspond to the structures present in the free molecules before they had interacted. 3) The affinity-matured neutralizing mAbs obtained from chronically infected individuals did not recognize the germline predecessors of these Abs present in vaccinees. 4) The HIV p17 matrix protein that lines the inner surface of the viral membrane is one of the most disordered proteins identified on our planet and this prevents the induced Abs from binding to the glycosylated HIV gp120 protein. 5) Vaccinologists need to solve so-called inverse problems, for instance, guessing what are the multiple causes that produced an earlier wanted beneficial effect such as the absence of deleterious HIV infection in elite controllers. Since the immune system consists of numerous subsystems that have not yet been elucidated, it is impossible to solve the inverse problems posed by each subsystem. 6) Vaccinology is an empirical science that only sometimes succeeds because we do not understand the complex mechanisms that lead to protective immune responses.
虽然在过去30年中进行了大量预防性人体免疫缺陷病毒(艾滋病毒)疫苗试验,但值得注意的是,迄今尚未研制出有效的艾滋病毒疫苗。研究范式对应于科学家在试图解决特定问题时使用的理论假设和特定策略。疫苗学中成功使用的许多范例对艾滋病毒无效。例如:1)基于结构的反向疫苗学方法失败了,因为研究人员试图从hiv包膜(Env)表位的抗原结构开始产生疫苗,这些抗原结构与来自hiv感染者的中和单克隆抗体(mab)结合。他们假设这种抗原结构也具有免疫原性,在疫苗中诱导多克隆抗体(Ab)反应,具有与单抗相同的中和能力。2)表位-旁位晶体学复合物中观察到的结构是由两个伙伴之间相互诱导的配合引起的,与它们相互作用之前自由分子中存在的结构不一致。3)从慢性感染个体获得的亲和成熟的中和单克隆抗体不能识别这些抗体存在于接种者体内的种系前体。4)排列在病毒膜内表面的HIV p17基质蛋白是我们这个星球上发现的最混乱的蛋白之一,这阻止了诱导的抗体与糖基化的HIV gp120蛋白结合。5)疫苗学家需要解决所谓的逆问题,例如,猜测是什么多重原因产生了早期想要的有益效果,例如精英控制者中没有有害的艾滋病毒感染。由于免疫系统由许多尚未被阐明的子系统组成,因此不可能解决每个子系统所带来的逆问题。6)疫苗学是一门经验科学,因为我们不了解导致保护性免疫反应的复杂机制,所以它有时会成功。
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引用次数: 0
The role of γδ T cells in the context of allogeneic stem cell transplantation γδT细胞在异基因干细胞移植中的作用
Pub Date : 2022-03-16 DOI: 10.37349/ei.2022.00041
R. Handgretinger, P. Lang, M. Queudeville
Allogeneic stem cell transplantation is currently the only curative approach for a variety of malignant and non-malignant diseases. In the early transplant era, the intent of this treatment was to apply an intensive myeloablative regimen to eliminate residual malignant cells followed by the hematopoietic rescue of the patients with donor hematopoietic stem cells. However, the focus has shifted over time and allogeneic transplantation is nowadays seen as a cellular therapy in which the donor-derived immune system mounts an anti-infectious and especially an anti-tumor effect in the posttransplant phase. In order to further augment the anti-tumor effect, various approaches have been developed, including the manipulation of the donor-derived immune system in vivo or the adoptive transfer of ex vivo-expanded donor-derived effector cells. Based on their lack of alloreactivity, γδ+ T cells are shifting into the spotlight of research in the context of allogeneic transplantation. Their exploitation with regard to their anti-infectious and anti-tumor properties and their in vivo and ex vivo manipulation will lead to new therapeutic approaches to improve the outcome of patients after allogeneic stem cell transplantation. In this review, the important role of γδ+ T cells in allogeneic matched and mismatched transplantation is summarized and an outlook is discussed on how to best make use of this unique cell population.
异基因干细胞移植是目前治疗各种恶性和非恶性疾病的唯一方法。在早期移植时代,这种治疗的目的是应用强化清髓方案来清除残留的恶性细胞,然后用供体造血干细胞对患者进行造血挽救。然而,随着时间的推移,焦点已经转移,异基因移植如今被视为一种细胞疗法,其中供体来源的免疫系统在移植后阶段产生抗感染,尤其是抗肿瘤作用。为了进一步增强抗肿瘤效果,已经开发了各种方法,包括在体内操纵供体衍生的免疫系统或过继转移体外扩增的供体衍生的效应细胞。由于缺乏同种异体反应性,γδ+T细胞正成为异基因移植研究的焦点。它们的抗感染和抗肿瘤特性以及体内和离体操作将为改善异基因干细胞移植后患者的预后带来新的治疗方法。本文综述了γδ+T细胞在异基因匹配和不匹配移植中的重要作用,并对如何最好地利用这种独特的细胞群体进行了展望。
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引用次数: 0
High avidity of vaccine-induced immunoglobulin G against SARS-CoV-2: potential relevance for protective humoral immunity 疫苗诱导的免疫球蛋白G对严重急性呼吸系统综合征冠状病毒2型的高亲和力:与保护性体液免疫的潜在相关性
Pub Date : 2022-03-16 DOI: 10.37349/ei.2022.00040
G. Bauer
Avidity of immunoglobulin G (IgG) is defined as its binding strength to its target antigen. As a consequence of affinity maturation of the IgG response, avidity is maturing as well. Therefore, acute infections are characterized by low-avidity IgG, whereas past infections are usually associated with high-avidity IgG. Avidity maturation is also observed as a consequence of optimal vaccination. Avidity has been shown to play a significant role in protective humoral immunity in many microbial systems. After severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the situation is different compared to other viral infections, as the moderate degree of avidity reached in most cases of infection is similar to that reached after only one vaccination step. In contrast, two vaccination steps lead to a much higher avidity of IgG directed towards viral spike protein S1 (S1) in the majority of vaccinated individuals. Therefore, it seems that two vaccination steps allow for a more extended affinity/avidity maturation than natural infection. The degree of avidity maturation after two vaccination steps is heterogeneous. It can be further enhanced by a third vaccination step. Complete avidity maturation seems to depend on sustained availability of antigen during the maturation process. Variants of concern seem to increase the affinity of their receptor-binding domain (RBD) to angiotensin-converting enzyme-2 (ACE2) and/or to decrease the susceptibility for neutralizing antibodies. Classical neutralization tests do not necessarily reflect the avidity of neutralizing IgG, as they operationally dissect the binding reaction between S1 and IgG from the binding of the S1 to ACE2. This approach fades out critical competition reactions between IgG and ACE for RBD of the S1. Quantitative avidity determination might be an essential tool to define individuals that only possess suboptimal protective immunity after vaccination and therefore might benefit from an additional booster immunization.
免疫球蛋白G (IgG)的亲和力是指其与靶抗原的结合强度。由于IgG反应的亲和成熟,贪婪也在成熟。因此,急性感染的特点是低贪婪的IgG,而过去的感染通常与高贪婪的IgG相关。贪婪成熟也被观察到作为最佳疫苗接种的结果。贪婪已被证明在许多微生物系统的保护性体液免疫中起重要作用。严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)感染后,情况与其他病毒感染不同,因为大多数感染病例所达到的中等程度的贪婪程度与仅接种一次疫苗所达到的程度相似。相比之下,在大多数接种疫苗的个体中,两个接种步骤导致针对病毒刺突蛋白S1 (S1)的IgG的亲和力高得多。因此,两个接种步骤似乎比自然感染允许更广泛的亲和力/亲和性成熟。两个接种步骤后的贪婪成熟程度是不均匀的。它可以通过第三步接种进一步加强。完全的贪婪成熟似乎依赖于成熟过程中抗原的持续可用性。值得关注的变异似乎增加了它们的受体结合域(RBD)对血管紧张素转换酶-2 (ACE2)的亲和力和/或降低了对中和抗体的敏感性。经典的中和试验并不一定反映中和IgG的快速性,因为它们从S1与ACE2的结合中解析S1与IgG之间的结合反应。这种方法减弱了IgG和ACE对S1 RBD的关键竞争反应。定量贪婪度测定可能是确定接种疫苗后仅具有次优保护性免疫的个体的必要工具,因此可能从额外的加强免疫中受益。
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引用次数: 9
γδ T cell costimulatory ligands in antitumor immunity γδT细胞共刺激配体在抗肿瘤免疫中的作用
Pub Date : 2022-02-24 DOI: 10.37349/ei.2022.00038
J. M. McGraw, D. Witherden
Antitumor immunity relies on the ability of T cells to recognize and kill tumor targets. γδ T cells are a specialized subset of T cells that predominantly localizes to non-lymphoid tissue such as the skin, gut, and lung where they are actively involved in tumor immunosurveillance. γδ T cells respond to self-stress ligands that are increased on many tumor cells, and these interactions provide costimulatory signals that promote their activation and cytotoxicity. This review will cover costimulatory molecules that are known to be critical for the function of γδ T cells with a specific focus on mouse dendritic epidermal T cells (DETC). DETC are a prototypic tissue-resident γδ T cell population with known roles in antitumor immunity and are therefore useful for identifying mechanisms that may control activation of other γδ T cell subsets within non-lymphoid tissues. This review concludes with a brief discussion on how γδ T cell costimulatory molecules can be targeted for improved cancer immunotherapy.
抗肿瘤免疫依赖于T细胞识别和杀死肿瘤靶点的能力。γδ T细胞是T细胞的一个特殊亚群,主要定位于非淋巴组织,如皮肤、肠道和肺,在那里它们积极参与肿瘤免疫监视。γδ T细胞对许多肿瘤细胞上增加的自应激配体作出反应,这些相互作用提供共刺激信号,促进其激活和细胞毒性。这篇综述将涵盖已知的对γδ T细胞功能至关重要的共刺激分子,并特别关注小鼠树突状表皮T细胞(DETC)。DETC是一种典型的组织内γδ T细胞群,已知在抗肿瘤免疫中起作用,因此可用于鉴定非淋巴组织中其他γδ T细胞亚群激活的控制机制。本文最后简要讨论了γδ T细胞共刺激分子如何靶向改善肿瘤免疫治疗。
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引用次数: 2
Novel insights based on the plasticity of γδ T cells in the tumor microenvironment 基于肿瘤微环境中γδ T细胞可塑性的新见解
Pub Date : 2022-02-24 DOI: 10.37349/ei.2022.00039
Yue-Zhong Wang, Yi Xu, Hui Chen, Jianmin Zhang, Wei He
γδ T cells express unique T cell receptor (TCR) γ and TCR δ chains, with structural and functional heterogeneity. Taking advantage of the diverse γδ TCR repertoire or other ligand-receptor interactions, γδ T cells can recognize a broad spectrum of tumor-associated antigens (TAAs) in a major histocompatibility complex (MHC)-independent manner, thereby activating downstream pleiotropic effects. γδ T cells recruited into the tumor microenvironment can act as effector cells to mediate cancer immune surveillance. Their advantage lies in the ability to perceive tumors with a low mutation load, thus establishing the first line of defense against pathogens. Activated γδ T cells exhibit strong cytotoxic activity and cytokine secretion functions and are effective antitumor lymphocytes with simple and direct recognition modes and rapid responses. However, the clinical application of tumor-infiltrating γδ T cells has certain limitations. First, γδ T cells exposed to complicated cytokine networks are potentially affected by multiple inhibitory mechanisms. Additionally, these cells show highly flexible and dynamic plasticity and are extremely easily polarized into regulatory phenotypes. This review further emphasizes the diversified cross-talk between γδ T cells and other immune cells. Effective immunity of the body is often manifested by counterbalance under mutual restriction. Therefore, an in-depth understanding of γδ T cells that play conflicting roles in the tumor microenvironment is necessary. These cells may be a key factor ultimately mediating the deviation of the antagonistic response between tumor inhibition and tumor promotion. Finally, it retrospectively analyze the activation strategies and clinical relevance of existing γδ T cell adoptive immunotherapies. According to current challenges, there is a need to explore innovative immunotherapies, maximize the tumor-killing efficacy of γδ T cells, and attenuate or eliminate tumor immunosuppression. It is hoped that the host immune status can be accurately predicted and gradually advance γδ T cell precise individualized medicine.
γδT细胞表达独特的T细胞受体(TCR)γ和TCRδ链,具有结构和功能的异质性。利用不同的γδTCR库或其他配体-受体相互作用,γδT细胞可以以不依赖于主要组织相容性复合体(MHC)的方式识别广泛的肿瘤相关抗原(TAAs),从而激活下游多效性效应。被招募到肿瘤微环境中的γδT细胞可以作为效应细胞介导癌症免疫监测。它们的优势在于能够以低突变量感知肿瘤,从而建立抵御病原体的第一道防线。活化的γδT细胞具有较强的细胞毒性和细胞因子分泌功能,是一种有效的抗肿瘤淋巴细胞,具有简单直接的识别模式和快速反应。然而,肿瘤浸润性γδT细胞的临床应用有一定的局限性。首先,暴露于复杂细胞因子网络的γδT细胞可能受到多种抑制机制的影响。此外,这些细胞表现出高度灵活和动态可塑性,极易分化为调节表型。这篇综述进一步强调了γδT细胞和其他免疫细胞之间的多样化串扰。身体的有效免疫往往表现为在相互制约下的平衡。因此,有必要深入了解在肿瘤微环境中发挥冲突作用的γδT细胞。这些细胞可能是最终介导肿瘤抑制和肿瘤促进之间拮抗反应偏差的关键因素。最后,回顾性分析了现有γδT细胞过继免疫疗法的激活策略和临床相关性。根据当前的挑战,需要探索创新的免疫疗法,最大限度地发挥γδT细胞的肿瘤杀伤功效,并减弱或消除肿瘤免疫抑制。希望能准确预测宿主免疫状态,逐步推进γδT细胞精准个体化用药。
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引用次数: 1
Tumor-associated protein ligands recognized by human γδ T cell receptor and their implications in cancer therapy 人γδT细胞受体识别的肿瘤相关蛋白配体及其在癌症治疗中的意义
Pub Date : 2022-02-22 DOI: 10.37349/ei.2022.00037
Chang Liu, Yi Xu, Jianmin Zhang, Wei He
In recent years, immunologists have been working to utilize the functional mechanism of the immune system to research new tumor treatment methods and achieved a major breakthrough in 2013, which was listed as one of the top 10 scientific breakthroughs of 2013 by Science magazine (see “Cancer immunotherapy”. Science. 2013;342:1417. doi: 10.1126/science.1249481). Currently, two main methods are used in clinical tumor immunotherapy: immune checkpoint inhibitors and chimeric antigen receptor (CAR) T cells. Clinical responses to checkpoint inhibitors rely on blockade of the target neoantigens expressed on the surfaces of tumor cells, which can inhibit T cell activity and prevent the T cell immune response; therefore, the therapeutic effect is limited by the tumor antigen expression level. While CAR-T cell therapy can partly enhance neoantigen recognition of T cells, problems remain in the current treatment for solid tumors, such as restricted transport of adoptively transferred cells to the tumor site and off-targets. Immunologists have therefore turned their attention to γδ T cells, which are not restricted by the major histocompatibility complex (MHC) for neoantigen recognition and are able to initiate a rapid immune response at an early stage. However, due to the lack of an understanding of the antigens that γδ T cells recognize, the role of γδ T cells in tumorigenesis and tumor development is not clearly understood. In the past few years, extensive data identifying antigen ligands recognized by γδ T cells have been obtained, mainly focusing on bisphosphonates and small-molecule polypeptides, but few studies have focused on protein ligands recognized by γδ T cells. In this paper, it is reviewed and analyzed that the tumor-associated protein ligands of γδ T cells that have been discovered thus far, hoping to provide new ideas for the comprehensive application of γδ T cells in tumor immunotherapy.
近年来,免疫学家一直致力于利用免疫系统的功能机制来研究新的肿瘤治疗方法,并于2013年取得了重大突破,被《科学》杂志列为2013年十大科学突破之一(见“癌症免疫治疗”)。科学。2013;342:1417。doi: 10.1126 / science.1249481)。目前,临床肿瘤免疫治疗主要采用两种方法:免疫检查点抑制剂和CAR - T细胞。检查点抑制剂的临床应答依赖于阻断肿瘤细胞表面表达的靶新抗原,从而抑制T细胞活性,阻止T细胞免疫应答;因此,治疗效果受到肿瘤抗原表达水平的限制。虽然CAR-T细胞疗法可以在一定程度上增强T细胞对新抗原的识别,但目前对实体瘤的治疗仍然存在一些问题,例如过继转移细胞到肿瘤部位的运输受限和脱靶。因此,免疫学家将注意力转向了γδ T细胞,它不受主要组织相容性复合体(MHC)对新抗原识别的限制,能够在早期阶段启动快速的免疫反应。然而,由于缺乏对γδ T细胞识别的抗原的了解,γδ T细胞在肿瘤发生和肿瘤发展中的作用尚不清楚。近年来,关于γδ T细胞识别抗原配体的研究数据较多,主要集中在双膦酸盐类和小分子多肽类,而关于γδ T细胞识别蛋白质配体的研究较少。本文对目前已发现的γδ T细胞肿瘤相关蛋白配体进行综述和分析,希望为γδ T细胞在肿瘤免疫治疗中的综合应用提供新的思路。
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Exploration of immunology
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