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FLT3 signaling augments macrophage production from human pluripotent stem cells. FLT3信号增强了人类多能干细胞产生巨噬细胞的能力。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-02-21 DOI: 10.1093/intimm/dxad047
Kenji Kitajima, Minako Shingai, Hikaru Ando, Takahiko Hara

Recent advances in cell engineering technologies enable immune cells to be utilized for adoptive cell transfer (ACT) immunotherapy against cancers. Macrophages have the potential to directly and indirectly exterminate cancers and are therefore an attractive option for therapies. To develop new ACT therapies using macrophages, a great number of macrophages are required. Human induced pluripotent stem cells (iPSCs) are expected to be a source of macrophages; therefore, a system to efficiently produce macrophages from human iPSCs is needed. Here, we demonstrated that human iPSCs were robustly differentiated into macrophages by enforced FMS-like tyrosine kinase-3 (FLT3) signaling via the introduction of exogenous FLT3 into iPSCs and the addition of its ligand FLT3L to the macrophage induction culture. These iPSC-derived macrophages were identical to those obtained by standard differentiation induction methods. Thus, our novel system enables the preparation of scalable macrophages from human iPSCs. We believe that this system will be useful to develop a novel ACT therapy using macrophages.

细胞工程技术的最新进展使免疫细胞可用于针对癌症的采纳性细胞转移(ACT)免疫疗法。巨噬细胞具有直接或间接消灭癌症的潜力,因此是一种极具吸引力的疗法。要利用巨噬细胞开发新的 ACT 疗法,需要大量的巨噬细胞。人类诱导多能干细胞(iPSCs)有望成为巨噬细胞的来源;因此,需要一种能从人类 iPSCs 高效生产巨噬细胞的系统。在这里,我们证明了通过向iPSCs中引入外源FLT3,并在巨噬细胞诱导培养中加入其配体FLT3L,强化FMS样酪氨酸激酶-3(FLT3)信号,人iPSCs能稳健地分化成巨噬细胞。这些 iPSC 衍生的巨噬细胞与通过标准分化诱导方法获得的巨噬细胞完全相同。因此,我们的新系统可以从人类 iPSCs 制备可扩展的巨噬细胞。我们相信,该系统将有助于利用巨噬细胞开发新型 ACT 疗法。
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引用次数: 0
Near-infrared photoimmunotherapy and anti-cancer immunity. 近红外光免疫疗法和抗癌免疫。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-02-14 DOI: 10.1093/intimm/dxad042
Kohei Nakajima, Mikako Ogawa

The activation of the anti-cancer immune system is an important strategy to control cancer. A new form of cancer phototherapy, near-infrared photoimmunotherapy (NIR-PIT), was approved for clinical use in 2020 and uses IRDye® 700DX (IR700)-conjugated antibodies and NIR light. After irradiation with NIR light, the antibody-IR700 conjugate forms water-insoluble aggregations on the plasma membrane of target cells. This aggregation causes lethal damage to the plasma membrane, and effectively leads to immunogenic cell death (ICD). Subsequently, ICD activates anti-cancer immune cells such as dendritic cells and cytotoxic T cells. Combination therapy with immune-checkpoint blockade has synergistically improved the anti-cancer effects of NIR-PIT. Additionally, NIR-PIT can eliminate immunosuppressive immune cells in light-irradiated tumors by using specific antibodies against regulatory T cells and myeloid-derived suppressor cells. In addition to cancer-cell-targeted NIR-PIT, such immune-cell-targeted NIR-PIT has shown promising results by activating the anti-cancer immune system. Furthermore, NIR-PIT can be used to manipulate the tumor microenvironment by eliminating only targeted cells in the tumor, and thus it also can be used to gain insight into immunity in basic research.

激活抗癌免疫系统是控制癌症的重要策略。一种新型癌症光疗法,近红外光免疫疗法(NIR-PIT)于2020年获准临床使用,使用IRDye®700DX(IR700)-结合抗体和近红外光。在用近红外光照射后,抗体-IR700缀合物在靶细胞的质膜上形成不溶于水的聚集体。这种聚集会对质膜造成致命损伤,并有效地导致免疫原性细胞死亡(ICD)。随后,ICD激活抗癌免疫细胞,例如树突细胞和细胞毒性T细胞。免疫检查点阻断联合治疗协同提高了NIR-PIT的抗癌效果。此外,NIR-PIT可以通过使用针对调节性T细胞和骨髓来源的抑制细胞的特异性抗体来消除光照射肿瘤中的免疫抑制免疫细胞。除了癌细胞靶向NIR-PIT外,这种免疫细胞靶向的NIR-PIT通过激活抗癌免疫系统显示出有希望的结果。此外,NIR-PIT可以通过仅消除肿瘤中的靶向细胞来操纵肿瘤微环境,因此它也可以用于深入了解基础研究中的免疫。
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引用次数: 0
Trends in cell medicine: from autologous cells to allogeneic universal-use cells for adoptive T-cell therapies. 细胞医学的发展趋势:从自体细胞到用于收养性 T 细胞疗法的异体通用细胞。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-02-14 DOI: 10.1093/intimm/dxad051
Hiroshi Kawamoto, Kyoko Masuda

In currently ongoing adoptive T-cell therapies, T cells collected from patients are given back to them after ex vivo activation and expansion. In some cases, T cells are transduced with chimeric antigen receptor (CAR) or T-cell receptor (TCR) genes during the ex vivo culture period in order to endow T cells with the desired antigen specificity. Although such strategies are effective in some types of cancer, there remain issues to be solved: (i) the limited number of cells, (ii) it is time-consuming, (iii) it is costly, and (iv) the quality can be unstable. Points (ii) and (iv) can be solved by preparing allogeneic T cells and cryopreserving them in advance and methods are being developed using healthy donor-derived T cells or pluripotent stem cells as materials. Whereas it is difficult to solve (i) and (iii) in the former case, all the issues can be cleared in the latter case. However, in either case, a new problem arises: rejection by the patient's immune system. Deletion of human leukocyte antigen (HLA) avoids rejection by recipient T cells, but causes rejection by NK cells, which can recognize loss of HLA class I. Various countermeasures have been developed, but no definitive solution is yet available. Therefore, further research and development are necessary.

在目前正在进行的收养 T 细胞疗法中,从患者身上采集的 T 细胞经过体外激活和扩增后再还给患者。在某些情况下,T 细胞会在体外培养期间转导嵌合抗原受体(CAR)或 T 细胞受体(TCR)基因,以赋予 T 细胞所需的抗原特异性。虽然这种策略已被证明对某些类型的癌症有效,但仍有一些问题有待解决:(i) 细胞数量有限;(ii) 耗时;(iii) 成本高;(iv) 质量不稳定。第(ii)和(iv)点可以通过事先制备异体 T 细胞并将其冷冻保存来解决,使用健康供体来源的 T 细胞或多能干细胞作为材料的方法正在开发中。前者很难解决(i)和(iii),而后者则可以解决所有问题。然而,无论哪种情况,都会出现一个新问题:患者免疫系统的排斥反应。删除 HLA 可避免受体 T 细胞的排斥反应,但会引起 NK 细胞的排斥反应,因为 NK 细胞能识别 HLA I 类的缺失。
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引用次数: 0
Cytokine signaling in chimeric antigen receptor T-cell therapy. 嵌合抗原受体 T 细胞疗法中的细胞因子信号转导。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-02-14 DOI: 10.1093/intimm/dxad033
Yuki Kagoya

Adoptive immunotherapy using chimeric antigen-receptor (CAR)-engineered T cells can induce robust antitumor responses against hematologic malignancies. However, its efficacy is not durable in the majority of the patients, warranting further improvement of T-cell functions. Cytokine signaling is one of the key cascades regulating T-cell survival and effector functions. In addition to cytokines that use the common γ chain as a receptor subunit, multiple cytokines regulate T-cell functions directly or indirectly. Modulating cytokine signaling in CAR-T cells by genetic engineering is one promising strategy to augment their therapeutic efficacy. These strategies include ectopic expression of cytokines, cytokine receptors, and synthetic molecules that mimic endogenous cytokine signaling. Alternatively, autocrine IL-2 signaling can be augmented through reprogramming of CAR-T cell properties through transcriptional and epigenetic modification. On the other hand, cytokine production by CAR-T cells triggers systemic inflammatory responses, which mainly manifest as adverse events such as cytokine-release syndrome (CRS) and neurotoxicity. In addition to inhibiting direct inflammatory mediators such as IL-6 and IL-1 released from activated macrophages, suppression of T-cell-derived cytokines associated with the priming of macrophages can be accomplished through genetic modification of CAR-T cells. In this review, I will outline recently developed synthetic biology approaches to exploit cytokine signaling to enhance CAR-T cell functions. I will also discuss therapeutic target molecules to prevent or alleviate CAR-T cell-related toxicities.

利用嵌合抗原受体(CAR)工程T细胞进行的采纳性免疫疗法可诱导针对血液系统恶性肿瘤的强大抗肿瘤反应。然而,大多数患者的疗效并不持久,因此需要进一步改善T细胞的功能。细胞因子信号转导是调节 T 细胞存活和效应功能的关键级联之一。除了使用共同的 γ 链作为受体亚基的细胞因子外,还有多种细胞因子直接或间接地调节 T 细胞功能。通过基因工程调节 CAR-T 细胞中的细胞因子信号转导是增强其疗效的一种很有前景的策略。这些策略包括异位表达细胞因子、细胞因子受体和模拟内源性细胞因子信号的合成分子。另外,还可以通过转录和表观遗传修饰对 CAR-T 细胞特性进行重编程,从而增强自分泌 IL-2 信号。另一方面,CAR-T 细胞产生的细胞因子会引发全身炎症反应,主要表现为细胞因子释放综合征(CRS)和神经毒性等不良反应。除了抑制活化巨噬细胞释放的 IL-6 和 IL-1 等直接炎症介质外,还可以通过对 CAR-T 细胞进行基因修饰来抑制与巨噬细胞引物相关的 T 细胞衍生细胞因子。在这篇综述中,我将概述最近开发的利用细胞因子信号增强 CAR-T 细胞功能的合成生物学方法。我还将讨论预防或减轻 CAR-T 细胞相关毒性的治疗靶分子。
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引用次数: 0
Metabolic advantages of regulatory T cells dictated by cancer cells. 癌症细胞决定的调节性T细胞的代谢优势。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-02-14 DOI: 10.1093/intimm/dxad035
Masaki Kondo, Shogo Kumagai, Hiroyoshi Nishikawa

Cancer cells employ glycolysis for their survival and growth (the "Warburg effect"). Consequently, surrounding cells including immune cells in the tumor microenvironment (TME) are exposed to hypoglycemic, hypoxic, and low pH circumstances. Since effector T cells depend on the glycolysis for their survival and functions, the metabolically harsh TME established by cancer cells is unfavorable, resulting in the impairment of effective antitumor immune responses. By contrast, immunosuppressive cells such as regulatory T (Treg) cells can infiltrate, proliferate, survive, and exert immunosuppressive functions in the metabolically harsh TME, indicating the different metabolic dependance between effector T cells and Treg cells. Indeed, some metabolites that are harmful for effector T cells can be utilized by Treg cells; lactic acid, a harmful metabolite for effector T cells, is available for Treg cell proliferation and functions. Deficiency of amino acids such as tryptophan and glutamine in the TME impairs effector T cell activation but increases Treg cell populations. Furthermore, hypoxia upregulates fatty acid oxidation via hypoxia-inducible factor 1α (HIF-1α) and promotes Treg cell migration. Adenosine is induced by the ectonucleotidases CD39 and CD73, which are strongly induced by HIF-1α, and reportedly accelerates Treg cell development by upregulating Foxp3 expression in T cells via A2AR-mediated signals. Therefore, this review focuses on the current views of the unique metabolism of Treg cells dictated by cancer cells. In addition, potential cancer combination therapies with immunotherapy and metabolic molecularly targeted reagents that modulate Treg cells in the TME are discussed to develop "immune metabolism-based precision medicine".

癌症细胞利用糖酵解进行生存和生长(“Warburg效应”)。因此,包括肿瘤微环境(TME)中的免疫细胞在内的周围细胞暴露于低血糖、缺氧和低pH的环境中。由于效应T细胞的生存和功能依赖于糖酵解,癌症细胞建立的代谢苛刻的TME是不利的,导致有效的抗肿瘤免疫反应受损。相反,免疫抑制细胞如调节性T(Treg)细胞可以在代谢苛刻的TME中浸润、增殖、存活并发挥免疫抑制功能,这表明效应T细胞和Treg细胞之间的代谢依赖性不同。事实上,一些对效应T细胞有害的代谢产物可以被Treg细胞利用;乳酸是效应T细胞的有害代谢产物,可用于Treg细胞的增殖和功能。TME中色氨酸和谷氨酰胺等氨基酸的缺乏损害了效应T细胞的活化,但增加了Treg细胞群。此外,缺氧通过缺氧诱导因子1α(HIF-1α)上调脂肪酸氧化,并促进Treg细胞迁移。腺苷由HIF-1α强烈诱导的外核肽酶CD39和CD73诱导,据报道,腺苷通过A2AR介导的信号上调T细胞中Foxp3的表达,从而加速Treg细胞的发育。因此,这篇综述的重点是目前对癌症细胞所决定的Treg细胞独特代谢的看法。此外,还讨论了潜在的癌症联合疗法,包括免疫疗法和调节TME中Treg细胞的代谢分子靶向试剂,以开发“基于免疫代谢的精准医学”。
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引用次数: 0
Identification of immune-related gene signatures for chronic obstructive pulmonary disease with metabolic syndrome: evidence from integrated bulk and single-cell RNA sequencing data. 慢性阻塞性肺病代谢综合征免疫相关基因特征的鉴定:来自整合的大量和单细胞RNA测序数据的证据。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-01-29 DOI: 10.1093/intimm/dxad043
Yueren Wu, Mengyu Ma, Wenglam Choi, Weifang Xu, Jingcheng Dong

Chronic obstructive pulmonary disease (COPD) is closely related to innate and adaptive inflammatory immune responses. It is increasingly becoming evident that metabolic syndrome (MetS) affects a significant portion of COPD patients. Through this investigation, we identify shared immune-related candidate biological markers. The Weighted Gene Co-Expression Network Analysis (WGCNA) was utilized to reveal the co-expression modules linked to COPD and MetS. The commonly expressed genes in the COPD and MetS were utilized to conduct an enrichment analysis. We adopted machine-learning to screen and validate hub genes. We also assessed the relationship between hub genes and immune cell infiltration in COPD and MetS, respectively. Moreover, associations across hub genes and metabolic pathways were also explored. Finally, we chose a single-cell RNA sequencing (scRNA-seq) dataset to investigate the hub genes and shared mechanisms at the level of the cells. We also applied cell trajectory analysis and cell-cell communication analysis to focus on the vital immune cell we were interested in. As a result, we selected and validated 13 shared hub genes for COPD and MetS. The enrichment analysis and immune infiltration analysis illustrated strong associations between hub genes and immunology. Additionally, we applied metabolic pathway enrichment analysis, indicating the significant role of reactive oxygen species (ROS) in COPD with MetS. Through scRNA-seq analysis, we found that ROS might accumulate the most in the alveolar macrophages. In conclusion, the 13 hub genes related to the immune response and metabolism may serve as diagnostic biomarkers and treatment targets of COPD with MetS.

慢性阻塞性肺病(COPD)与先天性和适应性炎症免疫反应密切相关。代谢综合征(MetS)对COPD患者的影响越来越明显。通过这项研究,我们确定了共享的免疫相关候选生物标志物。加权基因共表达网络分析(WGCNA)用于揭示与COPD和MetS相关的共表达模块。利用COPD和MetS中常见表达的基因进行富集分析。我们采用机器学习来筛选和验证中枢基因。我们还分别评估了中枢基因与COPD和MetS免疫细胞浸润之间的关系。此外,还探讨了中枢基因和代谢途径之间的关联。最后,我们选择了一个单细胞RNA测序(scRNA-seq)数据集来研究细胞水平上的枢纽基因和共享机制。我们还应用细胞轨迹分析和细胞间通讯分析来关注我们感兴趣的重要免疫细胞。因此,我们选择并验证了13个COPD和MetS的共享枢纽基因。富集分析和免疫浸润分析表明中枢基因与免疫学之间有很强的相关性;此外,我们应用了代谢途径富集分析,表明活性氧(ROS)在患有代谢综合征的COPD中的重要作用。通过scRNA-seq分析,我们发现ROS可能在肺泡巨噬细胞中积累最多。总之,与免疫反应和代谢相关的13个枢纽基因可以作为COPD合并代谢综合征的诊断生物标志物和治疗靶点。
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引用次数: 0
Alcaligenes lipid A functions as a superior mucosal adjuvant to monophosphoryl lipid A via the recruitment and activation of CD11b+ dendritic cells in nasal tissue. 碱性脂质A通过募集和激活鼻组织中CD11b+树突状细胞作为单磷酰脂质A的优越粘膜佐剂。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-01-29 DOI: 10.1093/intimm/dxad045
Xiao Sun, Koji Hosomi, Atsushi Shimoyama, Ken Yoshii, Azusa Saika, Haruki Yamaura, Takahiro Nagatake, Hiroshi Kiyono, Koichi Fukase, Jun Kunisawa

We previously demonstrated that Alcaligenes-derived lipid A (ALA), which is produced from an intestinal lymphoid tissue-resident commensal bacterium, is an effective adjuvant for inducing antigen-specific immune responses. To understand the immunologic characteristics of ALA as a vaccine adjuvant, we here compared the adjuvant activity of ALA with that of a licensed adjuvant (monophosphoryl lipid A, MPLA) in mice. Although the adjuvant activity of ALA was only slightly greater than that of MPLA for subcutaneous immunization, ALA induced significantly greater IgA antibody production than did MPLA during nasal immunization. Regarding the underlying mechanism, ALA increased and activated CD11b+ CD103- CD11c+ dendritic cells in the nasal tissue by stimulating chemokine responses. These findings revealed the superiority of ALA as a mucosal adjuvant due to the unique immunologic functions of ALA in nasal tissue.

我们之前已经证明,Alcaligenes-derived脂质A (ALA)是一种有效的佐剂,可以诱导抗原特异性免疫反应,这种脂质A是由肠道淋巴组织中的共生细菌产生的。为了了解ALA作为疫苗佐剂的免疫学特性,我们在这里比较了ALA与一种许可佐剂(单磷酰脂质a, MPLA)在小鼠中的佐剂活性。虽然ALA在皮下免疫时的佐剂活性仅略高于MPLA,但在鼻腔免疫时,ALA诱导的IgA抗体产生明显高于MPLA。至于其潜在机制,ALA通过刺激趋化因子反应增加和激活鼻腔组织中的CD11b+ CD103- CD11c+树突状细胞。由于ALA在鼻组织中具有独特的免疫功能,这些发现揭示了ALA作为粘膜佐剂的优越性。
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引用次数: 0
Peripheral helper T cells, mavericks of peripheral immune responses. 外周辅助性T细胞,外周免疫反应的特立独行者。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-01-29 DOI: 10.1093/intimm/dxad041
Hiroyuki Yoshitomi

Peripheral helper T (Tph) cells have been established, through intensive efforts to elucidate local immune responses in human rheumatoid arthritis (RA), as a CD4 subset intimately involved in acquired immunity in peripheral tissues. Initially, Tph cells were noted as a CD4 population that produces high levels of CXCL13 in RA synovial tissues, followed by a demonstration of their ability to help B cells. In contrast to follicular helper T (Tfh) cells, Tph cells do not express the transcription factor BCL6 but express molecules such as CXCL13, interleukin (IL)-21, and inducible T-cell costimulator (ICOS) to help B cells in peripheral tissues. Subsequent studies showed that Tph cells are associated with various diseases, including autoimmune diseases, infections, and malignancies, and with the development of early life immunity. This review summarizes the phenotype and function of Tph cells in RA and discusses their differentiation and diversity in various conditions.

通过深入研究人类类风湿性关节炎(RA)的局部免疫反应,已经建立了外周辅助T细胞(Tph),作为与外周组织获得性免疫密切相关的CD4亚群。最初,Tph细胞被认为是在RA滑膜组织中产生高水平CXCL13的CD4群体,随后证明了它们帮助B细胞的能力。与滤泡辅助性T(Tfh)细胞相比,Tph细胞不表达转录因子BCL6,但表达CXCL13、IL-21和ICOS等分子,以帮助外周组织中的B细胞。随后的研究表明,Tph细胞与各种疾病有关,包括自身免疫性疾病、感染和恶性肿瘤,并与早期生命免疫的发展有关。本文综述了RA中Tph细胞的表型和功能,并讨论了它们在各种条件下的分化和多样性。
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引用次数: 0
Highlights from International Immunology in 2023 2023 年国际免疫学要点
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-01-10 DOI: 10.1093/intimm/dxad044
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引用次数: 0
Systemic immunometabolism and responses to vaccines: insights from T and B cell perspectives. 全身免疫代谢和对疫苗的反应:从 T 细胞和 B 细胞的角度看问题。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2023-12-23 DOI: 10.1093/intimm/dxad021
Sam Nettelfield, Di Yu, Pablo F Cañete

Vaccination stands as the cornerstone in the battle against infectious diseases, and its efficacy hinges on several host-related factors like genetics, age, and metabolic status. Vulnerable populations, such as malnourished individuals, the obese, and the elderly, commonly exhibit diminished vaccine responses and efficacy. While the specific factors contributing to this impairment may vary, these individuals typically display a degree of metabolic dysregulation, thereby underscoring its potential significance as a fundamental determinant of suboptimal vaccine responses. The emerging field of immunometabolism aims to unravel the intricate interplay between immune regulation and metabolic pathways, and recent research has revealed diverse metabolic signatures linked to various vaccine responses and outcomes. In this review, we summarize the major metabolic pathways utilized by B and T cells during vaccine responses, their complex and varied metabolic requirements, and the impact of micronutrients and metabolic hormones on vaccine outcomes. Furthermore, we examine how systemic metabolism influences vaccine responses and the evidence suggesting that metabolic dysregulation in vulnerable populations can lead to impaired vaccine responses. Lastly, we reflect on the challenge of proving causality with respect to the contribution of metabolic dysregulation to poor vaccine outcomes, and highlight the need for a systems biology approach that combines multimodal profiling and mathematical modelling to reveal the underlying mechanisms of such complex interactions.

疫苗接种是抗击传染病的基石,其效果取决于与宿主相关的几个因素,如遗传、年龄和新陈代谢状况。营养不良者、肥胖者和老年人等易感人群对疫苗的反应和效力通常会减弱。虽然导致这种损害的具体因素可能各不相同,但这些人通常会表现出一定程度的代谢失调,从而突出了代谢失调作为次优疫苗反应基本决定因素的潜在意义。新兴的免疫代谢领域旨在揭示免疫调节与代谢途径之间错综复杂的相互作用,最近的研究揭示了与各种疫苗反应和结果相关的各种代谢特征。在这篇综述中,我们总结了 B 细胞和 T 细胞在疫苗反应过程中利用的主要代谢途径、它们复杂多样的代谢需求以及微量营养素和代谢激素对疫苗结果的影响。此外,我们还研究了全身代谢如何影响疫苗应答,以及有证据表明易感人群的代谢失调会导致疫苗应答受损。最后,我们反思了证明代谢失调对疫苗不良反应的因果关系所面临的挑战,并强调了系统生物学方法的必要性,该方法结合了多模态分析和数学建模,以揭示这种复杂相互作用的内在机制。
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引用次数: 0
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International immunology
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