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Neonatal helminth infection and chronic type 2 inflammation promotes immune suppression through FcγRIIb 新生儿蠕虫感染和慢性2型炎症通过FcγRIIb促进免疫抑制
Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.82.04
B. Alexander, Mindy M Miller, R. Reinhardt
Allergic diseases are rising in industrialized countries. This contrasts with rural communities where decreased allergic incidence correlates with increased prevalence of intestinal helminth infections. While helminths and their byproducts can ameliorate allergic inflammation in adult mice with established disease, it remains unknown if early-life exposure can prevent or delay allergic disease onset. We utilized a neonatal infection model with the gastrointestinal helminth Heligmosomoides polygyrusand found that neonatal H. polygyruscolonization results in chronic infection and type 2 inflammation. This study investigates how chronic and systemic type 2 hallmarks IL-4 and IgG1 may be involved in the long-term suppressive mechanisms induced by neonatal helminth colonization. We hypothesize that IL-4-induced upregulation of the sole inhibitory Fc receptor, FcγRIIb, allows for sustained suppression of T cell mediated inflammation by increasing the activation threshold of antigen presenting cells. Increasing this threshold prevents allergen-specific T cells from becoming optimally activated and instead promotes T cell tolerance. In addition to IL-4 increasing expression of FcγRIIb on macrophages, it promotes the production of its ligand IgG1, completing the suppressive circuit. This model predicts that elimination of FcγRIIb and/or IL-4 will result in greater T cell activation and allergic inflammation. Our in vivoand in vitrodata show that FcγRIIb is necessary for reducing allergic airway inflammation and T cell activation after allergen challenge. Taken together, these data support a model in which chronic helminth infection naturally mimics the suppressive effects of intravenous immunoglobulin therapy. Supported by the National Institutes of Health NIAID training grant (Training Program in Immunology; T32-AI07405)
过敏性疾病在工业化国家呈上升趋势。这与农村社区形成对比,在农村社区,过敏发生率降低与肠道蠕虫感染患病率增加相关。虽然蠕虫及其副产品可以改善患有既定疾病的成年小鼠的过敏性炎症,但尚不清楚早期接触是否可以预防或延迟过敏性疾病的发生。我们利用胃肠道蠕虫多回Heligmosomoides polygyruss的新生儿感染模型,发现新生儿多回Heligmosomoides polygyruss定植导致慢性感染和2型炎症。本研究探讨了慢性和全身性2型标志物IL-4和IgG1如何参与新生儿蠕虫定殖诱导的长期抑制机制。我们假设il -4诱导的唯一抑制性Fc受体Fcγ riib的上调,可以通过增加抗原提呈细胞的激活阈值来持续抑制T细胞介导的炎症。增加这个阈值可以防止过敏原特异性T细胞被最佳激活,而不是促进T细胞的耐受性。IL-4除了增加巨噬细胞上FcγRIIb的表达外,还促进其配体IgG1的产生,完成抑制回路。该模型预测FcγRIIb和/或IL-4的消除将导致更大的T细胞活化和过敏性炎症。我们的体内和体外数据表明,fc - γ riib是减少过敏性气道炎症和过敏原攻击后T细胞活化所必需的。综上所述,这些数据支持慢性蠕虫感染自然模仿静脉注射免疫球蛋白治疗的抑制作用的模型。由美国国立卫生研究院NIAID培训补助金(免疫学培训计划)支持;T32-AI07405)
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引用次数: 0
Synergy between oxaliplatin and adenovirus initiates immunogenic cell death in human colorectal carcinoma cells 奥沙利铂和腺病毒的协同作用引发人结直肠癌细胞的免疫原性细胞死亡
Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.145.19
J. Jessup, S. Hewitt, T. Fuerst
Externalization of Calreticulin (CALR) is the critical first step in the initiation of Immunogenic Cell Death. Since Oxaliplatin (OX) cooperates with an oncolytic chimeric human adenovirus Ad5/3-NP2.ADP (ADP) to induce adaptive immunity as well as regression of established cancer, we sought to determine whether the cooperation was additive or synergistic. Methods include immunohistochemistry (IHC) for Calreticulin expression in mice 11 days after intratumoral injection of the OX-ADP mixture. In vitro assays with limiting dilutions of OX and ADP on human Clone A colorectal carcinoma cell monolayers were cultured for 3 days and cytotoxicity, viral infectivity by GFP, and the expression of externalized CALR (ectoCALR) on Clone A cells measured by static cytometry. Synergy was measured using SynergyFinder 3.0 (Ianevski et al., PMC9252834) that creates 2-D interactive surfaces to measure synergy and antagonism. Areas of synergy have mean scores > 10. IHC revealed strong CALR expression in OX-ADP treated tumors, weak expression in tumors injected with OX or ADP alone and minimal in PBS treated controls. Mean Viral Infectivity synergy score was 27.2 for the area of (Ox μM, ADP MOI): (0.12μM, 4 MOI) to (12.5μM, 100 MOI) while mean synergy score for ectoCALR expression was 29.2 for OX/ADP (0.01μM, 0.16) to (0.12μM, 20 MOI). The role of oxidative and endoplasmic reticulum stress as the basis of synergy is under study. Oxaliplatin and adenovirus are synergistic in their ability to initiate ICD which is important for vaccine development.
钙网蛋白(CALR)的外化是免疫原性细胞死亡开始的关键第一步。奥沙利铂(OX)与溶瘤嵌合人腺病毒Ad5/3-NP2协同作用。ADP (ADP)诱导适应性免疫和既定癌症的消退,我们试图确定这种合作是加性的还是协同的。方法采用免疫组化(IHC)法检测小鼠瘤内注射OX-ADP混合物后11天钙网蛋白的表达。用有限稀释的OX和ADP体外培养人克隆A结肠癌细胞3 d,用静态细胞术检测细胞毒性、GFP病毒感染性和外化CALR (ectoCALR)的表达。使用SynergyFinder 3.0 (Ianevski等人,PMC9252834)测量协同作用,该工具创建二维交互表面来测量协同作用和拮抗作用。协同领域的平均得分> 10。免疫组化结果显示,在OX-ADP治疗的肿瘤中CALR表达较强,单独注射OX或ADP的肿瘤中CALR表达较弱,PBS治疗的对照中CALR表达最低。(Ox μM, ADP MOI) (0.12μM, 4 MOI)至(12.5μM, 100 MOI)区域的平均病毒感染性协同评分为27.2,而Ox /ADP (0.01μM, 0.16)至(0.12μM, 20 MOI)区域ectoCALR表达的平均协同评分为29.2。氧化应激和内质网应激作为协同作用基础的作用正在研究中。奥沙利铂和腺病毒在启动ICD方面具有协同作用,这对疫苗开发非常重要。
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引用次数: 0
c-Kit signaling modulated group 3 innate lymphoid cell functions in mouse neutrophilic asthma model c-Kit信号传导调节小鼠中性粒细胞哮喘模型3组先天淋巴样细胞功能
Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.67.08
Jheng-Syuan Shao, Po-Yu Chi, Yajie Chang
Group 3 innate lymphoid cells (ILC3s) are involved in air pollution- and bacterial infection-associated neutrophilic asthma. Studies showed that asthmatic patients have higher stem cell factor (SCF) expression in airway and sera. Of note, ILC3s express SCF receptor, c-Kit, suggesting a potential role of SCF/c-Kit signaling in ILC3 functions and neutrophilic asthma. In this study, we aimed to determine whether SCF/c-Kit signaling could modulate ILC3 functions and neutrophilic asthma. Wild-type (WT) and c-Kit deficient mice (Kit w-sh) were intranasally treated with IL-1β/IL-23 or particulate matter (PM) 2.5 to induce neutrophilic asthma. While IL-1β/IL-23 or PM2.5 caused increases in neutrophil infiltration to bronchoalveolar lavage fluid (BALF) and airway hyperreactivity (AHR) in WT mice, Kit w-shmice had decreased infiltration of neutrophils and ameliorated AHR. Concomitantly, flow cytometry results showed a decreased number of IL-17+ ILC3 in the lung of Kit w-shmice compared to WT mice, which may be due to the reduced proliferation of c-Kit-deficient ILC3. In addition, we showed SCF enhanced IL-17 secretion from ILC3s in vitro. Based on re-analysis of published mouse whole lung cells scRNAseq data, we hypothesized fibroblasts are the source of SCF. Indeed, mice with SCF knockout in fibroblast exhibited decreased neutrophil infiltration and reduced IL-17+ ILC3 number in response to IL-1β/IL-23. Finally, administration of imatinib, a FDA-approved drug targeting c-Kit signaling, ameliorated AHR and ILC3 activation in the mouse neutrophilic asthma model. Taken together, our data suggested that inhibition of ILC3 activation by targeting c-Kit signaling may provide a potential therapeutic management for neutrophilic asthma.
3组先天淋巴样细胞(ILC3s)参与空气污染和细菌感染相关的中性粒细胞哮喘。研究表明,哮喘患者气道和血清中有较高的干细胞因子(SCF)表达。值得注意的是,ILC3表达SCF受体c-Kit,提示SCF/c-Kit信号传导在ILC3功能和中性粒细胞哮喘中的潜在作用。在这项研究中,我们旨在确定SCF/c-Kit信号是否可以调节ILC3功能和中性粒细胞哮喘。野生型(WT)和c-Kit缺陷小鼠(Kit w-sh)经鼻注射IL-1β/IL-23或颗粒物质(PM) 2.5诱导中性粒细胞哮喘。虽然IL-1β/IL-23或PM2.5引起WT小鼠支气管肺泡灌洗液(BALF)中性粒细胞浸润和气道高反应性(AHR)增加,但Kit w-shmice减少中性粒细胞浸润,改善AHR。同时,流式细胞术结果显示,与WT小鼠相比,Kit w- sh小鼠肺中IL-17+ ILC3的数量减少,这可能是由于c-Kit缺陷ILC3的增殖减少。此外,我们发现SCF在体外增强了ILC3s分泌IL-17。基于对已发表的小鼠全肺细胞scRNAseq数据的重新分析,我们假设成纤维细胞是SCF的来源。事实上,在成纤维细胞中敲除SCF的小鼠,在IL-1β/IL-23的作用下,表现出中性粒细胞浸润减少和IL-17+ ILC3数量减少。最后,给药伊马替尼(一种fda批准的靶向c-Kit信号的药物)可以改善小鼠中性粒细胞哮喘模型中的AHR和ILC3激活。综上所述,我们的数据表明,通过靶向c-Kit信号通路抑制ILC3激活可能为中性粒细胞性哮喘提供潜在的治疗管理。
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引用次数: 0
Programming of checkpoint blockade responsive exhausted T cells by rheostatic IL-2 signals during priming by dendritic cells 在树突状细胞启动过程中,通过变阻性IL-2信号编程检查点封锁反应性耗尽T细胞
Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.83.16
S. Sarkar, R. Toumi, Hanxi Xiao, T. Pulliam, J. Reed, P. Nghiem, V. Kalia
Stem-like progenitor exhausted CD8 T cells are critical for maintaining long-term resistance during chronic infections and cancer, and represent an important checkpoint blockade immunotherapy target for functional reinvigoration and disease control. Here, we show a fate-deterministic role of rheostatic IL-2 signals and differential DC priming in programming the development of stem-like progenitor exhausted CD8 T cells during chronic viral infection. In vivo fate-tracking studies reveal that strong IL-2 signals during priming drive terminal differentiation. In contrast, tempered IL-2 signals are associated with TCF-1 Histem-like precursors, which give rise to progenitor exhausted CD8 T cells, capable of long-term persistence and potent responsiveness to anti-PD-1 therapy in later stages of chronic viral infection. In the context of human tumors as well, single cell RNA-seq analyses of total or antigen-specific tumor infiltrating lymphocytes show an inverse relationship of IL-2 signaling signature with T cell stemness, as well as checkpoint blockade therapy outcomes in melanoma. Our studies further show that the rheostatic control of exhausted T cell fates by differential IL-2 signals is physiologically mediated through differential cell surface expression of IL-2Rα during early stages of T cell activation, which in turn is pioneered during priming by distinct dendritic cell subsets. Notably, moderation of in vivo IL-2 signals during priming promotes the development of stem-like TCF-1 Hilineage, thus supporting a unique strategy for improving clinical immunotherapy outcomes by enhancing the development of long-lived, therapy-responsive stem-like cells with vigorous effector expansion capabilities. Pediatric Cancer Research Foundation to SS, the Rachel Lynn Henley Foundation to VK, the Hopes and Smiles For Children Foundation to VK, In Concert for Cancer Foundation to VK and the National Institutes of Health (CA254168 to TP; CA225517 to PN; AI132819, AI103748 to SS; 5P30CA015704; AI154363 to VK)
干细胞样祖细胞耗竭的CD8 T细胞对于慢性感染和癌症期间维持长期耐药性至关重要,并且代表了功能恢复和疾病控制的重要检查点阻断免疫治疗靶点。在这里,我们展示了在慢性病毒感染期间,变阻性IL-2信号和差异DC启动在编程干细胞样祖耗尽CD8 T细胞发育中的命运决定性作用。体内命运跟踪研究表明,在启动过程中强烈的IL-2信号驱动终端分化。相比之下,缓和的IL-2信号与TCF-1组织样前体相关,后者产生祖细胞耗尽的CD8 T细胞,能够长期持续存在,并在慢性病毒感染的后期对抗pd -1治疗产生有效的反应。在人类肿瘤的背景下,对总或抗原特异性肿瘤浸润淋巴细胞的单细胞RNA-seq分析显示,在黑色素瘤中,IL-2信号信号与T细胞干细胞性以及检查点阻断治疗结果呈负相关。我们的研究进一步表明,在T细胞激活的早期阶段,不同IL-2信号对衰竭T细胞命运的流变控制是通过IL-2Rα的差异细胞表面表达进行生理介导的,而这反过来又在不同树突状细胞亚群的启动过程中率先实现。值得注意的是,在启动过程中,体内IL-2信号的调节促进了干细胞样TCF-1细胞的发展,从而支持了一种独特的策略,通过增强具有强大效应扩增能力的长寿命、治疗反应性干细胞的发展来改善临床免疫治疗结果。儿童癌症研究基金会捐赠给SS,雷切尔·林恩·亨利基金会捐赠给VK,儿童希望与微笑基金会捐赠给VK,癌症基金会捐赠给VK和美国国立卫生研究院(CA254168捐赠给TP;CA225517到PN;AI132819、AI103748至SS;5 p30ca015704;AI154363转VK)
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引用次数: 0
Intramuscular mRNA prime plus intranasal adenoviral vector booster elicit robust respiratory mucosal IgA responses against SARS-CoV-2 肌内mRNA引物加鼻内腺病毒载体增强剂可引起呼吸道黏膜对SARS-CoV-2的强效IgA反应
Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.253.14
Jinyi Tang, Yue Wu, C. Zeng, Justin J. Taylor, Guizhi Zhu, D. Weissman, Shan-Lu Liu, Jie Sun
Current SARS-CoV-2 mRNA vaccines induce robust humoral and cellular immunity in the circulation, but its ability in eliciting respiratory mucosal immunity is less characterized. Here, we demonstrated that systemic mRNA expressing ancestral spike (mRNA-S) vaccination alone induced weak respiratory mucosal neutralizing antibody and cellular immunity, particularly against SARS-CoV-2 Omicron strain. In contrast, an immunization strategy combining systemic mRNA-S administration plus mucosal adenoviral vector expressing ancestral spike (Ad5-S) booster induced strong T cell, B cell, and antibody responses in the respiratory tract, which can last for a long time. Furthermore, we found that Ad5-S mucosal booster promoted robust IgA-producing B cells in the respiratory tract, which were correlated with the levels of mucosal S-specific IgA levels. Strikingly, these local IgA-producing B cells were more cross-reactive to the Delta and Omicron Spike proteins compared to those IgG-producing B cells. We further showed that CD4 T cell help was required for the development of IgA-producing B cell in the respiratory mucosa. Taken together, our study identified a vaccination strategy and its associated mechanisms for the induction of strong cross-reactive IgA responses, which were shown to correlate with optimal protection against breakthrough infection, especially by Omicron sub-lineages. Hence, our data provide insights into the rational design of next-generation SARS-CoV-2 mucosal vaccines required for the protection against infection by SARS-CoV-2 Omicron sub-lineages or future variants.
目前的SARS-CoV-2 mRNA疫苗在循环中诱导了强大的体液和细胞免疫,但其诱导呼吸道黏膜免疫的能力尚不清楚。在这里,我们证明了单独接种表达祖先spike (mRNA- s)的系统性mRNA可诱导弱呼吸道粘膜中和抗体和细胞免疫,特别是针对SARS-CoV-2 Omicron菌株。相比之下,结合全身mRNA-S给药和表达祖先刺突(Ad5-S)增强剂的粘膜腺病毒载体的免疫策略在呼吸道诱导强烈的T细胞、B细胞和抗体反应,这种反应可以持续很长时间。此外,我们发现Ad5-S粘膜增强剂促进呼吸道中产生IgA的B细胞的增强,这与粘膜s特异性IgA水平相关。引人注目的是,与那些产生igg的B细胞相比,这些局部产生iga的B细胞对Delta和Omicron刺突蛋白的交叉反应更强。我们进一步表明,在呼吸道粘膜中,CD4 T细胞的帮助对于产生iga的B细胞的发育是必需的。综上所述,我们的研究确定了一种疫苗接种策略及其诱导强交叉反应性IgA反应的相关机制,这被证明与针对突破性感染的最佳保护相关,特别是由欧米克隆亚谱系。因此,我们的数据为合理设计下一代SARS-CoV-2粘膜疫苗提供了见解,这些疫苗是防止SARS-CoV-2 Omicron亚谱系或未来变体感染所需的。
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引用次数: 0
Tumor infiltrating natural killer cells in soft tissue sarcoma are predominantly CD56 dim: Implications for outcomes 软组织肉瘤中浸润性自然杀伤细胞以CD56暗淡为主:对预后的影响
Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.237.07
Cyrus J. Sholevar, Sylvia M Cruz, Khurshid R. Iranpur, S. Judge, Alicia A. Gingrich, Lauren E Farley, Aryana M. Razmara, M. Lammers, S. Thorpe, A. Monjazeb, W. Murphy, R. Canter
Natural killer (NK) cells have been shown to be important mediators of anti-tumor responses, including in soft tissue sarcomas (STS). NK cells show significant heterogeneity, depending on maturation, tissue residency, and inflammatory environment. As previous studies have suggested that tumor-infiltrating NK cells (TiNKs) acquire a less cytotoxic CD56 brighttissue resident phenotype, we sought to compare blood versus tumor NK cell phenotype in STS and evaluate any association with survival. Blood and tumor from 27 STS patients undergoing surgery from 2018–2022 were collected prospectively for flow cytometry and retrospectively analyzed. 52% were female, the mean age was 59, and 74% were AJCC stage 3. Increasing absolute number of NK cells in the blood correlated with longer survival (P<0.005, r=0.6). As expected, CD56 dimNK cells predominated in the blood (91.5±5.8% of CD3-CD56+ lymphocytes compared to 80.1±13% in tumor, P<0.005). In contrast, CD56 brightcells were enriched in tumor representing 18.5±13% compared to 8.4±5.8% in blood (P<0.005). Although CD56 brightNK cells were approximately 2.4±3-fold higher in tumor compared to blood, CD56 dimNK cells still represented the majority of TiNKs. Higher proportions of both overall NK cells and CD56 dimNK cells in STS tumors were associated with better metastasis-free survival on Kaplan-Meier analysis (P<0.05). CD56 dimTiNKs had higher NKp46 expression than CD56 brights. In conclusion, both blood and intra-tumoral NK cells appear prognostic in STS. Although the proportion of CD56 brightTiNKs in STS is higher than blood the majority of TiNKs are CD56 dimconsistent with a cytotoxic phenotype. Better characterization of NK subsets in STS is likely to have translational significance.
自然杀伤(NK)细胞已被证明是抗肿瘤反应的重要介质,包括在软组织肉瘤(STS)中。NK细胞表现出显著的异质性,这取决于成熟度、组织驻留和炎症环境。由于先前的研究表明,肿瘤浸润NK细胞(TiNKs)获得更低的细胞毒性CD56亮组织常驻表型,我们试图比较STS中血液和肿瘤NK细胞表型,并评估其与生存率的关系。前瞻性采集2018-2022年27例STS手术患者的血液和肿瘤进行流式细胞术分析,并进行回顾性分析。52%为女性,平均年龄59岁,74%为AJCC 3期。血液中NK细胞的绝对数量增加与存活时间延长相关(P<0.005, r=0.6)。正如预期的那样,CD56暗nk细胞在血液中占主导地位(CD3-CD56+淋巴细胞占91.5±5.8%,而肿瘤中为80.1±13%,P<0.005)。相比之下,CD56亮细胞在肿瘤中富集18.5±13%,而在血液中富集8.4±5.8% (P<0.005)。尽管在肿瘤中CD56亮nk细胞比血液中高出约2.4±3倍,但CD56暗nk细胞仍占TiNKs的大多数。Kaplan-Meier分析显示,STS肿瘤中总NK细胞和CD56 dimNK细胞比例较高与较好的无转移生存率相关(P<0.05)。CD56 dimTiNKs的NKp46表达量高于CD56 brights。总之,血液和肿瘤内NK细胞对STS的预后都有影响。尽管STS中CD56亮蛋白的比例高于血液,但大多数TiNKs是CD56暗蛋白,与细胞毒性表型一致。更好地表征STS中NK亚群可能具有翻译意义。
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引用次数: 0
Does the upper respiratory tract microbiome change in dairy calves fed milk replacer containing probiotics? 饲喂含有益生菌的代乳剂后,犊牛上呼吸道微生物群是否发生变化?
Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.225.01
C. Chitko-McKown, T. McDaneld, J. Kritchevsky, K. A. Bryan, S. Eicher
Our overall hypothesis is that feeding probiotics to dairy calves will alter overall immunity and may additionally change the microbiome in the respiratory tract as well as the gut. A group of 20 dairy calves were split into two treatment groups: Control (N=10, milk replacer), and Probiotic (N=10, milk replacer + 0.5 g/day Bovamine Dairy). On day 0 birth weight was obtained and the calves were provided colostrum as per the dairy SOP. On day 2, probiotics were added to the milk replacer of the treated group. Blood was collected along with nasal and tonsil swabs on days 0, 7, 14, 21, 28, 42, and 48. Calves were monitored daily for fecal, nasal, and ocular discharge scores. Our preliminary data showed no significant differences (P<0.5) between the Control and Probiotic groups in immune cell populations in peripheral blood. DNA was extracted from nasal and tonsil swabs to evaluate the bacterial populations in the upper respiratory microbiome. Hypervariable regions 1 through 3 along the 16S ribosomal RNA gene were amplified by PCR and sequenced by Illumina MiSeq to determine the bacterial taxa present. Evaluation of these samples revealed a greater percentage of operational taxonomy units (OTU) were classified at the genus level in the tonsil compared to the nasal samples. The microbiome of the tonsils was more stable over time points compared to the nasal samples. Evaluation of each timepoint for nasal and tonsil samples identified bacterial taxa that changed in relative abundance with the addition of the probiotic compared to the control diet. Addition of probiotic changed the relative abundance of OTU (P<0.01) in the nasal and tonsil sampling sites and at multiple timepoints. Analyses are ongoing. Project supported by fund from the USDA Agricultural Research Service.
我们的总体假设是,给奶牛喂食益生菌会改变整体免疫力,并可能额外改变呼吸道和肠道中的微生物群。将20头犊牛分为对照组(N=10,使用代乳剂)和益生菌组(N=10,使用代乳剂+ 0.5 g/d的牛胺乳)。在第0天获得初生体重,并按照乳制品SOP提供初乳。第2天,处理组在代乳中添加益生菌。在第0、7、14、21、28、42和48天采集血液和鼻腔和扁桃体拭子。每天监测犊牛的粪便、鼻分泌物和眼分泌物评分。我们的初步数据显示,对照组和益生菌组之间外周血免疫细胞群无显著差异(P<0.5)。从鼻腔和扁桃体拭子中提取DNA以评估上呼吸道微生物群中的细菌种群。通过PCR扩增16S核糖体RNA基因的高变区1 ~ 3,并用Illumina MiSeq测序确定存在的细菌分类群。这些样本的评估显示,与鼻样本相比,扁桃体中更大比例的操作分类单位(OTU)被分类在属水平。与鼻腔样本相比,扁桃体的微生物组随着时间点的变化更加稳定。对鼻腔和扁桃体样本的每个时间点进行评估,发现与对照组相比,添加益生菌后细菌分类群的相对丰度发生了变化。添加益生菌改变了鼻、扁桃体取样部位和多个时间点OTU的相对丰度(P<0.01)。分析正在进行中。该项目由美国农业部农业研究局资助。
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引用次数: 0
CpG therapeutic efficacy in a murine model of metastatic Lymphangioleiomyomatosis (LAM) is mediated by plasmacytoid dendritic cell and T cell immune responses CpG在小鼠转移性淋巴管平滑肌瘤病(LAM)模型中的治疗效果是由浆细胞样树突状细胞和T细胞免疫反应介导的
Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.226.19
M. Amosu, Jacob McCright, Kaitlyn Moore, K. Maisel
LAM is a slow growing, metastasizing neoplasm affecting women of reproductive age, marked by abnormal growth of smooth muscle-like cells leading to cystic lung destruction. LAM has hallmarks of cancer, like expression of immune checkpoint receptors. Effective cancer therapies promote robust T cell responses through activated dendritic cells (DCs). Anti-cancer strategies, like toll like receptor (TLR) activation and immune checkpoint inhibition could work as LAM therapy. In this study, we examine the effect of CpG, a TLR9 agonist, on the DC and T cell responses in murine LAM. We used a mouse model of metastatic LAM to determine survival after biweekly intranasal CpG therapy (10μg/ 5μg) with/ without systemic α-PD-1, rapamycin, or α-CD317 therapy. We used ELISA to measure the cytokine profile and flow cytometry to quantify cell populations between CpG-treated and untreated LAM lungs. We found that CpG treatment enhances median survival from 32 to 60 days in murine LAM (p <0.0001). Efficacy of CpG treatment in LAM is facilitated by plasmacytoid DCs. pDC depletion in CpG-treated mice decreases survival from 60 to 52 days (p=0.028). CpG-treated LAM lungs also produce more IFN-α (p=0.031). CpG-treated LAM lungs have increased IFN-γ (p= 0.012) and IL-12 (p= 0.005), cytokines secreted by cytotoxic T cells. CpG-treatment is synergistic with α-PD-1 checkpoint inhibition (p=0.004) and can be administered with rapamycin without adverse effects on median survival. In LAM, CpG therapy is mediated by pDC dependent immune responses and cytotoxic T cells. This suggests that adjuvant immunotherapy, like CpG, may offer new treatment options for LAM compatible with the current standard of care, rapamycin. The LAM Foundation Research Grant Award
LAM是一种生长缓慢的转移性肿瘤,影响育龄妇女,其特征是平滑肌样细胞异常生长,导致囊性肺破坏。LAM有癌症的特征,比如免疫检查点受体的表达。有效的癌症治疗通过激活树突状细胞(dc)促进强大的T细胞反应。抗癌策略,如toll样受体(TLR)激活和免疫检查点抑制可以作为LAM治疗。在这项研究中,我们研究了CpG(一种TLR9激动剂)对小鼠LAM中DC和T细胞反应的影响。我们使用转移性LAM小鼠模型来测定两周鼻内CpG治疗(10μg/ 5μg)联合/不全身α-PD-1、雷帕霉素或α-CD317治疗后的生存率。我们用ELISA法测定细胞因子谱,用流式细胞术量化cpg处理和未处理的LAM肺之间的细胞群。我们发现CpG治疗提高了小鼠LAM的中位生存期(从32天到60天)(p <0.0001)。浆细胞样dc促进了CpG治疗LAM的疗效。cpg处理小鼠的pDC耗竭降低了60至52天的存活率(p=0.028)。cpg处理的LAM肺产生更多的IFN-α (p=0.031)。cpg处理的LAM肺中细胞毒性T细胞分泌的IFN-γ (p= 0.012)和IL-12 (p= 0.005)细胞因子增加。cpg治疗与α-PD-1检查点抑制具有协同作用(p=0.004),可与雷帕霉素联合使用,对中位生存期无不良影响。在LAM中,CpG治疗是由pDC依赖性免疫反应和细胞毒性T细胞介导的。这表明,辅助免疫治疗,如CpG,可能为LAM提供新的治疗选择,与当前的护理标准雷帕霉素兼容。林郑月娥基金研究资助奖
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引用次数: 0
Cell-Intrinsic Effects of TGF-b Signaling in Mast Cell Effector Function that Modulate Allergic Inflammation TGF-b信号在肥大细胞效应功能中调节过敏性炎症的细胞内在作用
Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.151.05
T. Haque, Leshawna Leak, K. Laky, Pamela Guererrio
IgE mediated mast cell activation is a key feature of allergic disease, although the mechanisms that govern mast cell homeostasis are not fully understood. The TGFb signaling pathway has been shown to regulate mast cell effector function. Furthermore, variants in the TGFb signaling pathway are associated with allergic diseases; TGFb mediated mast cell regulation is likely involved in the allergy diathesis. Patients with Loeys Dietz Syndrome (LDS), a disorder caused by loss of function variants in TGFBR1and TGFBR2, are predisposed to develop allergic diseases, thus provide an opportunity to study the role of mast cell TGFb signaling in allergic diseases. Mast cells are activated through the high affinity IgE receptor FcERI causing the release of granules containing mediators that are directly involved in anaphylaxis and other allergic symptoms. IgE mediated activation can be modulated by other co-stimulatory signals such as the type 2 alarmin IL-33. We examined murine mast cells carrying an LDS mutation, or with conditional deletion of Tgfbr1, and found that they degranulated less in response to IgE/antigen, in vivo and in vitro. This phenotype was not tied to changes in the IgE and SCF receptor expression or mast cell tissue distribution in mice and was recapitulated in human LDS mast cells, in vitro. Additionally, LDS mice responded more to IL-33 stimulation. Mechanistically, the LDS anaphylaxis phenotype was linked to IL-33, as the reduction of anaphylaxis in LDS mice was partially restored in IL-33RKO LDS mice. Thus, the TGFb-IL-33R axis likely plays a major role in controlling IgE mediated mast cell functions. Taken together, TGFb signaling upregulates mast cell effector function by disrupting an IL-33/ST2 mediated regulatory pathway. Intramural NIAID Support
IgE介导的肥大细胞活化是过敏性疾病的一个关键特征,尽管控制肥大细胞稳态的机制尚不完全清楚。TGFb信号通路已被证明可调节肥大细胞效应物功能。此外,TGFb信号通路的变异与过敏性疾病有关;TGFb介导的肥大细胞调节可能参与过敏体质的形成。Loeys Dietz综合征(LDS)是一种由tgfbr1和TGFBR2功能变异缺失引起的疾病,患者易患过敏性疾病,因此为研究肥大细胞TGFb信号通路在过敏性疾病中的作用提供了机会。肥大细胞通过高亲和力的IgE受体FcERI被激活,引起含有介质的颗粒的释放,这些介质直接参与过敏反应和其他过敏症状。IgE介导的激活可以被其他共刺激信号调节,如2型警报蛋白IL-33。我们检测了携带LDS突变或Tgfbr1条件缺失的小鼠肥大细胞,发现它们在体内和体外对IgE/抗原的反应中脱颗粒较少。这种表型与小鼠的IgE和SCF受体表达或肥大细胞组织分布的变化无关,并且在体外的人类LDS肥大细胞中重现。此外,LDS小鼠对IL-33刺激的反应更强。在机制上,LDS过敏表型与IL-33有关,因为LDS小鼠的过敏反应减少在IL-33RKO LDS小鼠中部分恢复。因此,TGFb-IL-33R轴可能在控制IgE介导的肥大细胞功能中起主要作用。综上所述,TGFb信号通过破坏IL-33/ST2介导的调控途径上调肥大细胞效应功能。校内NIAID支持
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引用次数: 0
Improved control of SARS-CoV-2 infection with nucleocapsid-specific antibodies 核衣壳蛋白特异性抗体改善对SARS-CoV-2感染的控制
Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.235.26
P. Penaloza-MacMaster, Tanushree Dangi, Sarah Sanchez, Jacob Class, M. Richner, L. Visvabharathy, Young Rock Chung, Kirsten Bentley, R. Stanton, I. Koralnik, Justin M. Richner, P. Penaloza-MacMaster
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main antigen in all approved COVID-19 vaccines and is also the only target for monoclonal antibody (mAb) therapies. Immune responses to other viral antigens are generated after SARS-CoV-2 infection, but their contribution to the antiviral response remains unclear. Here, we interrogated whether nucleocapsid-specific antibodies can improve protection against SARS-CoV-2. We first immunized mice with a nucleocapsid-based vaccine and then transferred sera from these mice into naive mice, followed by challenge with SARS-CoV-2. We show that mice that received nucleocapsid-specific sera or a nucleocapsid-specific mAb exhibited enhanced control of SARS-CoV-2. Nucleocapsid-specific antibodies elicited NK-mediated, antibody-dependent cellular cytotoxicity (ADCC) against infected cells. To our knowledge, these findings provide the first demonstration in the coronavirus literature that antibody responses specific to the nucleocapsid protein can improve viral clearance, providing a rationale for the clinical evaluation of nucleocapsid-based mAb therapies to treat COVID-19. NIH (DP2DA051912)
严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)刺突蛋白是所有已批准的COVID-19疫苗中的主要抗原,也是单克隆抗体(mAb)治疗的唯一靶点。对其他病毒抗原的免疫反应在SARS-CoV-2感染后产生,但它们对抗病毒反应的贡献尚不清楚。在这里,我们询问核衣壳特异性抗体是否可以提高对SARS-CoV-2的保护。我们首先用基于核衣壳的疫苗对小鼠进行免疫,然后将这些小鼠的血清转移到幼稚小鼠体内,然后用SARS-CoV-2攻击。我们发现,接受核衣壳蛋白特异性血清或核衣壳蛋白特异性单抗的小鼠表现出对SARS-CoV-2的增强控制。核衣壳蛋白特异性抗体引发了针对感染细胞的nk介导的抗体依赖性细胞毒性(ADCC)。据我们所知,这些发现首次证明了针对核衣壳蛋白的抗体反应可以提高病毒的清除能力,为临床评估基于核衣壳蛋白的单克隆抗体治疗COVID-19提供了依据。国家卫生研究院(DP2DA051912)
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引用次数: 0
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The Journal of Immunology
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