Pub Date : 2024-09-05DOI: 10.1172/jci.insight.182469
Tomas Blanco, Hayate Nakagawa, Aytan Musayeva, Mark Krauthammer, Rohan Bir Singh, Akitomo Narimatsu, Hongyan Ge, Sara I Shoushtari, Reza Dana
Post-transplantation, T helper 1 (Th1)-mediated immune rejection is the predominant cause of graft failure. Th1 cell sensitization occurs through complex and context-dependent interaction among antigen-presenting cell subsets, particularly CD11b+ dendritic cells (DC2) and CD103+ dendritic cells (DC1). This interaction necessitates further investigation in context of transplant immunity. We use a well-established pre-clinical models of corneal transplantation and identified distinct roles of migratory CD103+ DC1 in influencing the outcomes of the grafted tissue. In recipients with uninflamed corneal beds, migratory CD103+DC1 demonstrate a tolerogenic phenotype that modulate the immunogenic capacity of CD11b+DC2 primarily mediated by IL-10, suppressing alloreactive CD4+Th1 cells via the PD-L1/PD-1 pathway, and enhancing Treg-mediated tolerance via αvβ8 integrin-activated TGFβ1, thus facilitating graft survival. Conversely, in recipients with inflamed and vascularized corneal beds, IFN-γ produced by CD4+Th1 cells induces migratory CD103+DC1 to adopt an immunostimulatory phenotype, characterized by the downregulation of regulatory markers including αvβ8 integrin and IL-10 and the upregulation of IL-12 and costimulatory molecules CD80/86, resulting in graft failure. The adoptive transfer of ex-vivo induced tolerogenic CD103+DC1(iDC1) effectively inhibits Th1 polarization and preserves the tolerogenic phenotype of their physiological counterparts. Collectively, our findings underscore the essential role played by CD103+DC1 in modulating host alloimmune responses.
{"title":"Acquired Immunostimulatory Phenotype of Migratory CD103+ Dendritic Cells Promotes Alloimmunity Following Corneal Transplantation.","authors":"Tomas Blanco, Hayate Nakagawa, Aytan Musayeva, Mark Krauthammer, Rohan Bir Singh, Akitomo Narimatsu, Hongyan Ge, Sara I Shoushtari, Reza Dana","doi":"10.1172/jci.insight.182469","DOIUrl":"https://doi.org/10.1172/jci.insight.182469","url":null,"abstract":"<p><p>Post-transplantation, T helper 1 (Th1)-mediated immune rejection is the predominant cause of graft failure. Th1 cell sensitization occurs through complex and context-dependent interaction among antigen-presenting cell subsets, particularly CD11b+ dendritic cells (DC2) and CD103+ dendritic cells (DC1). This interaction necessitates further investigation in context of transplant immunity. We use a well-established pre-clinical models of corneal transplantation and identified distinct roles of migratory CD103+ DC1 in influencing the outcomes of the grafted tissue. In recipients with uninflamed corneal beds, migratory CD103+DC1 demonstrate a tolerogenic phenotype that modulate the immunogenic capacity of CD11b+DC2 primarily mediated by IL-10, suppressing alloreactive CD4+Th1 cells via the PD-L1/PD-1 pathway, and enhancing Treg-mediated tolerance via αvβ8 integrin-activated TGFβ1, thus facilitating graft survival. Conversely, in recipients with inflamed and vascularized corneal beds, IFN-γ produced by CD4+Th1 cells induces migratory CD103+DC1 to adopt an immunostimulatory phenotype, characterized by the downregulation of regulatory markers including αvβ8 integrin and IL-10 and the upregulation of IL-12 and costimulatory molecules CD80/86, resulting in graft failure. The adoptive transfer of ex-vivo induced tolerogenic CD103+DC1(iDC1) effectively inhibits Th1 polarization and preserves the tolerogenic phenotype of their physiological counterparts. Collectively, our findings underscore the essential role played by CD103+DC1 in modulating host alloimmune responses.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1172/jci.insight.180016
Lauren E Gyllenhammer, Vincent Zaegel, Allison M Duensing, Manoel Lixandrao, Dana Dabelea, Bryan C Bergman, Kristen E Boyle
Our objective was to interrogate infant mesenchymal stem cell (MSC) lipid metabolism and gestational exposures that may contribute to child obesity risk. MSCs were cultured from term infants of mothers with obesity (n=16) or normal-weight (n=15). In MSCs undergoing myogenesis in vitro, we used lipidomics to distinguish phenotypes by unbiased cluster analysis and lipid challenge (24h excess fatty acid, 24hFA). We measured MSC AMP-activated protein kinase (AMPK) activity and fatty acid oxidation (FAO), and a composite index of maternal glucose, insulin, triglycerides, free fatty acids, tumor necrosis factor-α, high density lipoprotein- and total- cholesterol in fasting blood from mid- and late-gestation (~17, ~27wks). We measured child adiposity at birth (n=29), 4-6m (n=29), and 4-6y (n=13). Three MSC clusters were distinguished by triacylglycerol (TAG) stores, with greatest TAGs in Cluster-2. All Clusters increased acylcarnitines and TAGs with 24hFA, though Cluster-2 was more pronounced and corresponded to AMPK activation and FAO. Maternal metabolic markers predicted MSC Clusters and child adiposity at 4-6y (both highest in Cluster-3). Our data supports that MSC phenotypes are predicted by comprehensive maternal metabolic milieu exposures, independent of maternal BMI, and suggest utility as an at-birth predictor for child adiposity, though validation with larger longitudinal samples is warranted.
{"title":"Lipidomics of infant mesenchymal stem cells associate with the maternal milieu and child adiposity.","authors":"Lauren E Gyllenhammer, Vincent Zaegel, Allison M Duensing, Manoel Lixandrao, Dana Dabelea, Bryan C Bergman, Kristen E Boyle","doi":"10.1172/jci.insight.180016","DOIUrl":"https://doi.org/10.1172/jci.insight.180016","url":null,"abstract":"<p><p>Our objective was to interrogate infant mesenchymal stem cell (MSC) lipid metabolism and gestational exposures that may contribute to child obesity risk. MSCs were cultured from term infants of mothers with obesity (n=16) or normal-weight (n=15). In MSCs undergoing myogenesis in vitro, we used lipidomics to distinguish phenotypes by unbiased cluster analysis and lipid challenge (24h excess fatty acid, 24hFA). We measured MSC AMP-activated protein kinase (AMPK) activity and fatty acid oxidation (FAO), and a composite index of maternal glucose, insulin, triglycerides, free fatty acids, tumor necrosis factor-α, high density lipoprotein- and total- cholesterol in fasting blood from mid- and late-gestation (~17, ~27wks). We measured child adiposity at birth (n=29), 4-6m (n=29), and 4-6y (n=13). Three MSC clusters were distinguished by triacylglycerol (TAG) stores, with greatest TAGs in Cluster-2. All Clusters increased acylcarnitines and TAGs with 24hFA, though Cluster-2 was more pronounced and corresponded to AMPK activation and FAO. Maternal metabolic markers predicted MSC Clusters and child adiposity at 4-6y (both highest in Cluster-3). Our data supports that MSC phenotypes are predicted by comprehensive maternal metabolic milieu exposures, independent of maternal BMI, and suggest utility as an at-birth predictor for child adiposity, though validation with larger longitudinal samples is warranted.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1172/jci.insight.181067
Mohadeseh Hasanpourghadi, Mikhail Novikov, Robert Ambrose, Arezki Chekaoui, Dakota Newman, Zhiquan Xiang, Andrew D Luber, Sue L Currie, XiangYang Zhou, Hildegund C Ertl
In patients who progress from acute hepatitis B virus (HBV) infection to a chronic HBV (CHB) infection, CD8+ T cells fail to eliminate the virus and become impaired. A functional cure of CHB likely requires new and highly functional CD8+ T cell responses different from those induced by the infection. Here we report preclinical immunogenicity and efficacy of an HBV therapeutic vaccine that includes herpes simplex virus (HSV) glycoprotein D (gD), a checkpoint modifier of early T cell activation, that enhances, broadens, and prolongs CD8+ T cell responses. We developed a therapeutic HBV vaccine based on a chimpanzee adenovirus serotype 6 (AdC6) vector, called AdC6-gDHBV2, that targets conserved and highly immunogenic regions of the viral polymerase (pol) and core antigens fused into HSV gD. The vaccine was tested with, and without gD, in mice for immunogenicity and in an adeno-associated virus (AAV)8-1.3HBV vector model for antiviral efficacy. The vaccine encoding the HBV antigens within gD stimulates potent and broad CD8+ T cell responses. In a surrogate model of HBV infection, a single intramuscular (i.m.) injection of AdC6-gDHBV2 achieved significant and sustained declines of circulating HBV DNA copies (cps) and HBV surface antigen (HBsAg); both inversely correlated with HBV specific CD8+ T cell frequencies in spleens and livers. AdC6-gDHBV2 is the first therapeutic vaccine to show significant reductions in levels of HBV genome copies and HBsAg when used alone, even when vaccination was delayed for months from infection.
在从急性乙型肝炎病毒(HBV)感染发展为慢性 HBV(CHB)感染的患者中,CD8+ T 细胞无法清除病毒并受损。慢性乙型肝炎的功能性治愈可能需要与感染诱导的CD8+ T细胞反应不同的新的高功能CD8+ T细胞反应。在此,我们报告了一种 HBV 治疗性疫苗的临床前免疫原性和疗效,该疫苗包括单纯疱疹病毒 (HSV) 糖蛋白 D (gD),这是一种早期 T 细胞活化的检查点调节剂,可增强、扩大和延长 CD8+ T 细胞应答。我们开发了一种基于黑猩猩腺病毒血清型 6 (AdC6) 载体的治疗性 HBV 疫苗,称为 AdC6-gDHBV2,其靶标是病毒聚合酶 (pol) 的保守和高免疫原性区域以及融合到 HSV gD 中的核心抗原。该疫苗在小鼠体内进行了含 gD 和不含 gD 的免疫原性测试,并在腺相关病毒 (AAV)8-1.3HBV 载体模型中进行了抗病毒效力测试。在 gD 中编码 HBV 抗原的疫苗可激发强效、广泛的 CD8+ T 细胞反应。在代理 HBV 感染模型中,单次肌肉注射 AdC6-gDHBV2 可使循环 HBV DNA 拷贝(cps)和 HBV 表面抗原(HBsAg)显著持续下降;两者均与脾脏和肝脏中的 HBV 特异性 CD8+ T 细胞频率成反比。AdC6-gDHBV2 是首个单独使用就能显著降低 HBV 基因组拷贝和 HBsAg 水平的治疗性疫苗,即使在感染后数月才接种疫苗也是如此。
{"title":"A therapeutic HBV vaccine containing a checkpoint modifier enhances CD8+ T cell and antiviral responses.","authors":"Mohadeseh Hasanpourghadi, Mikhail Novikov, Robert Ambrose, Arezki Chekaoui, Dakota Newman, Zhiquan Xiang, Andrew D Luber, Sue L Currie, XiangYang Zhou, Hildegund C Ertl","doi":"10.1172/jci.insight.181067","DOIUrl":"https://doi.org/10.1172/jci.insight.181067","url":null,"abstract":"<p><p>In patients who progress from acute hepatitis B virus (HBV) infection to a chronic HBV (CHB) infection, CD8+ T cells fail to eliminate the virus and become impaired. A functional cure of CHB likely requires new and highly functional CD8+ T cell responses different from those induced by the infection. Here we report preclinical immunogenicity and efficacy of an HBV therapeutic vaccine that includes herpes simplex virus (HSV) glycoprotein D (gD), a checkpoint modifier of early T cell activation, that enhances, broadens, and prolongs CD8+ T cell responses. We developed a therapeutic HBV vaccine based on a chimpanzee adenovirus serotype 6 (AdC6) vector, called AdC6-gDHBV2, that targets conserved and highly immunogenic regions of the viral polymerase (pol) and core antigens fused into HSV gD. The vaccine was tested with, and without gD, in mice for immunogenicity and in an adeno-associated virus (AAV)8-1.3HBV vector model for antiviral efficacy. The vaccine encoding the HBV antigens within gD stimulates potent and broad CD8+ T cell responses. In a surrogate model of HBV infection, a single intramuscular (i.m.) injection of AdC6-gDHBV2 achieved significant and sustained declines of circulating HBV DNA copies (cps) and HBV surface antigen (HBsAg); both inversely correlated with HBV specific CD8+ T cell frequencies in spleens and livers. AdC6-gDHBV2 is the first therapeutic vaccine to show significant reductions in levels of HBV genome copies and HBsAg when used alone, even when vaccination was delayed for months from infection.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The prevalence of chronic kidney diseases (CKD) varies by race due to genetic and environmental factors. The Glu504Lys polymorphism in aldehyde dehydrogenase 2 (ALDH2), commonly observed among East Asians, alters the enzyme's function in detoxifying alcohol-derived aldehydes, impacting kidney function. This study investigated the association between variations in ALDH2 levels within the kidney and the progression of kidney fibrosis. Our clinical data indicates that diminished ALDH2 levels are linked to worse CKD outcomes, with correlations between ALDH2 expression, estimated glomerular filtration rate, urinary levels of acrolein, an aldehyde metabolized by ALDH2, and fibrosis severity. In mouse models of unilateral ureteral obstruction and folic acid nephropathy, reduced ALDH2 levels and elevated acrolein were observed in kidneys, especially in ALDH2 Glu504Lys knock-in mice. Mechanistically, acrolein modifies pyruvate kinase M2, leading to its nuclear translocation and co-activation of HIF-1α, shifting cellular metabolism to glycolysis, disrupting mitochondrial function, contributing to tubular damage and the progression of kidney fibrosis. Enhancing ALDH2 expression through adeno-associated virus vectors reduces acrolein and mitigates fibrosis in both wild-type and Glu504Lys knock-in mice. These findings underscore the potential therapeutic significance of targeting the dynamic interaction between ALDH2 and acrolein in CKD.
{"title":"Aldehyde dehydrogenase 2 preserves kidney function by countering acrolein-induced metabolic and mitochondrial dysfunction.","authors":"Szu-Yuan Li, Ming-Tsun Tsai, Yu-Ming Kuo, Hui-Min Yang, Zhen-Jie Tong, Hsiao-Wei Cheng, Chih-Ching Lin, Hsiang-Tsui Wang","doi":"10.1172/jci.insight.179871","DOIUrl":"https://doi.org/10.1172/jci.insight.179871","url":null,"abstract":"<p><p>The prevalence of chronic kidney diseases (CKD) varies by race due to genetic and environmental factors. The Glu504Lys polymorphism in aldehyde dehydrogenase 2 (ALDH2), commonly observed among East Asians, alters the enzyme's function in detoxifying alcohol-derived aldehydes, impacting kidney function. This study investigated the association between variations in ALDH2 levels within the kidney and the progression of kidney fibrosis. Our clinical data indicates that diminished ALDH2 levels are linked to worse CKD outcomes, with correlations between ALDH2 expression, estimated glomerular filtration rate, urinary levels of acrolein, an aldehyde metabolized by ALDH2, and fibrosis severity. In mouse models of unilateral ureteral obstruction and folic acid nephropathy, reduced ALDH2 levels and elevated acrolein were observed in kidneys, especially in ALDH2 Glu504Lys knock-in mice. Mechanistically, acrolein modifies pyruvate kinase M2, leading to its nuclear translocation and co-activation of HIF-1α, shifting cellular metabolism to glycolysis, disrupting mitochondrial function, contributing to tubular damage and the progression of kidney fibrosis. Enhancing ALDH2 expression through adeno-associated virus vectors reduces acrolein and mitigates fibrosis in both wild-type and Glu504Lys knock-in mice. These findings underscore the potential therapeutic significance of targeting the dynamic interaction between ALDH2 and acrolein in CKD.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1172/jci.insight.179599
Scott J Bright, Mandira Manandhar, David B Flint, Rishab Kolachina, Mariam Ben Kacem, David Kj Martinus, Broderick X Turner, Ilsa Qureshi, Conor H McFadden, Poliana Camila Marinello, Simona F Shaitelman, Gabriel O Sawakuchi
Ataxia telangiectasia and Rad3-related protein (ATR) is a key DNA damage response protein that facilitates DNA damage repair and regulates cell cycle progression. As such, ATR is an important component of the cellular response to radiation, particularly in cancer cells which show altered DNA damage response and aberrant cell cycle checkpoints. Therefore, ATR's pharmacological inhibition could be an effective radiosensitization strategy to improve radiotherapy. We assessed the ability of an ATR inhibitor, AZD6738, to sensitize cancer cell lines of various histologic types to photon and proton radiotherapy. We found that radiosensitization took place through persistent DNA damage and abrogated G2 cell cycle arrest. We also found that AZD6738 increased the number of micronuclei after exposure to radiotherapy. We found that combining radiation with AZD6738 led to tumor growth delay and prolonged survival relative to radiation alone in a breast cancer model. Combining AZD6738 with photons or protons also led to increased macrophage infiltration at the tumor microenvironment. These results provide a rationale for further investigation of ATR inhibition in combination with radiotherapy and with other agents such as immune checkpoint blockade.
共济失调毛细血管扩张症和 Rad3 相关蛋白(ATR)是一种关键的 DNA 损伤反应蛋白,可促进 DNA 损伤修复并调节细胞周期的进展。因此,ATR 是细胞对辐射反应的重要组成部分,尤其是在 DNA 损伤反应发生改变和细胞周期检查点异常的癌细胞中。因此,ATR 的药理抑制可能是改善放疗的一种有效的放射增敏策略。我们评估了 ATR 抑制剂 AZD6738 使不同组织学类型的癌细胞系对光子和质子放疗敏感的能力。我们发现,放射增敏是通过持续的 DNA 损伤和 G2 细胞周期停滞来实现的。我们还发现,AZD6738 会增加接受放疗后的微核数量。我们发现,在乳腺癌模型中,放疗与 AZD6738 联合使用可延缓肿瘤生长,延长生存期,而单独使用则无法达到这一效果。将 AZD6738 与光子或质子结合使用还能增加巨噬细胞在肿瘤微环境中的浸润。这些结果为进一步研究 ATR 抑制与放疗和免疫检查点阻断等其他药物的联合应用提供了依据。
{"title":"ATR inhibition radiosensitizes cells through augmented DNA Damage and G2 cell cycle arrest abrogation.","authors":"Scott J Bright, Mandira Manandhar, David B Flint, Rishab Kolachina, Mariam Ben Kacem, David Kj Martinus, Broderick X Turner, Ilsa Qureshi, Conor H McFadden, Poliana Camila Marinello, Simona F Shaitelman, Gabriel O Sawakuchi","doi":"10.1172/jci.insight.179599","DOIUrl":"https://doi.org/10.1172/jci.insight.179599","url":null,"abstract":"<p><p>Ataxia telangiectasia and Rad3-related protein (ATR) is a key DNA damage response protein that facilitates DNA damage repair and regulates cell cycle progression. As such, ATR is an important component of the cellular response to radiation, particularly in cancer cells which show altered DNA damage response and aberrant cell cycle checkpoints. Therefore, ATR's pharmacological inhibition could be an effective radiosensitization strategy to improve radiotherapy. We assessed the ability of an ATR inhibitor, AZD6738, to sensitize cancer cell lines of various histologic types to photon and proton radiotherapy. We found that radiosensitization took place through persistent DNA damage and abrogated G2 cell cycle arrest. We also found that AZD6738 increased the number of micronuclei after exposure to radiotherapy. We found that combining radiation with AZD6738 led to tumor growth delay and prolonged survival relative to radiation alone in a breast cancer model. Combining AZD6738 with photons or protons also led to increased macrophage infiltration at the tumor microenvironment. These results provide a rationale for further investigation of ATR inhibition in combination with radiotherapy and with other agents such as immune checkpoint blockade.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1172/jci.insight.184452
Dana Danino, Yoav Kalron, Jeffrey Haspel, Guy Hazan
Background: Immune processes are influenced by circadian rhythms. We evaluate the association between varicella vaccine administration time-of-day and vaccine effectiveness.
Methods: A national cohort, children < 6 years were enrolled between January 2002 to December 2023. We compared children vaccinated during morning (7:00-10:59), late-morning to afternoon (11:00-15:59), or evening hours (16:00-19:59). A Cox proportional-hazards regression model was used to adjust for ethnicity, sex, and comorbidities. The first varicella infection occurring at least 14 days after vaccination, or a second dose administration were treated as a terminal event.
Results: 4,501 (1.8%), of 251,141 vaccinated children, experienced breakthrough infections. Infection rates differed based on vaccination time, with the lowest rates associated with late-morning to afternoon (11:00-15:59), HR 0.88, 95% CI 0.82-0.95, P < 0.001, and the highest rates with evening vaccination (16:00-19:59), HR 1.41, 95% CI 1.32-1.52, P < 0.001. Vaccination timing remained significant after adjustment for ethnicity, sex, and comorbidities. The association between immunization time and infection risk followed a sinusoidal pattern, consistent with a diurnal rhythm in vaccine effectiveness.
Conclusions: We report a significant association between the time of varicella vaccination and its clinical effectiveness. Similar association was observed with the COVID-19 vaccine, providing proof of concept consistent with a diurnal rhythm in vaccine effectiveness.
{"title":"Diurnal rhythms in varicella vaccine effectiveness.","authors":"Dana Danino, Yoav Kalron, Jeffrey Haspel, Guy Hazan","doi":"10.1172/jci.insight.184452","DOIUrl":"https://doi.org/10.1172/jci.insight.184452","url":null,"abstract":"<p><strong>Background: </strong>Immune processes are influenced by circadian rhythms. We evaluate the association between varicella vaccine administration time-of-day and vaccine effectiveness.</p><p><strong>Methods: </strong>A national cohort, children < 6 years were enrolled between January 2002 to December 2023. We compared children vaccinated during morning (7:00-10:59), late-morning to afternoon (11:00-15:59), or evening hours (16:00-19:59). A Cox proportional-hazards regression model was used to adjust for ethnicity, sex, and comorbidities. The first varicella infection occurring at least 14 days after vaccination, or a second dose administration were treated as a terminal event.</p><p><strong>Results: </strong>4,501 (1.8%), of 251,141 vaccinated children, experienced breakthrough infections. Infection rates differed based on vaccination time, with the lowest rates associated with late-morning to afternoon (11:00-15:59), HR 0.88, 95% CI 0.82-0.95, P < 0.001, and the highest rates with evening vaccination (16:00-19:59), HR 1.41, 95% CI 1.32-1.52, P < 0.001. Vaccination timing remained significant after adjustment for ethnicity, sex, and comorbidities. The association between immunization time and infection risk followed a sinusoidal pattern, consistent with a diurnal rhythm in vaccine effectiveness.</p><p><strong>Conclusions: </strong>We report a significant association between the time of varicella vaccination and its clinical effectiveness. Similar association was observed with the COVID-19 vaccine, providing proof of concept consistent with a diurnal rhythm in vaccine effectiveness.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1172/jci.insight.177775
Georgina Gyarmati, Urvi Nikhil Shroff, Audrey K Izuhara, Sachin Deepak, Radko Komers, Patricia W Bedard, Janos Peti-Peterdi
Dual endothelin-1 (ET-1) and angiotensin II (AngII) receptor antagonism with sparsentan has strong antiproteinuric actions via multiple potential mechanisms that are more pronounced, or additive compared to current standard of care using angiotensin receptor blockers (ARB). Considering the many actions of ET-1 and AngII on multiple cell types, this study aimed to determine glomeruloprotective mechanisms of sparsentan compared to the ARB losartan by direct visualization of its effects in the intact kidney in focal segmental glomerulosclerosis (FSGS) using intravital multiphoton microscopy. In both healthy and FSGS models, sparsentan treatment increased afferent/efferent arteriole diameters, increased or preserved blood flow and single nephron glomerular filtration rate, attenuated acute ET-1+AngII-induced increases in podocyte calcium, reduced proteinuria, preserved podocyte number, increased both endothelial and renin lineage cells and clones in vasculature, glomeruli and tubules, restored glomerular endothelial glycocalyx, attenuated mitochondrial stress and immune cell homing. These effects were either not observed or of smaller magnitude with losartan. The pleiotropic nephroprotective effects of sparsentan included improved hemodynamics, podocyte and endothelial cell functions, and tissue repair. Compared to losartan, sparsentan was more effective in the sustained preservation of kidney structure and function, which underscores the importance of the ET-1 component in FSGS pathogenesis and therapy.
{"title":"Sparsentan improves glomerular hemodynamics, cell functions and tissue repair in a mouse model of FSGS.","authors":"Georgina Gyarmati, Urvi Nikhil Shroff, Audrey K Izuhara, Sachin Deepak, Radko Komers, Patricia W Bedard, Janos Peti-Peterdi","doi":"10.1172/jci.insight.177775","DOIUrl":"https://doi.org/10.1172/jci.insight.177775","url":null,"abstract":"<p><p>Dual endothelin-1 (ET-1) and angiotensin II (AngII) receptor antagonism with sparsentan has strong antiproteinuric actions via multiple potential mechanisms that are more pronounced, or additive compared to current standard of care using angiotensin receptor blockers (ARB). Considering the many actions of ET-1 and AngII on multiple cell types, this study aimed to determine glomeruloprotective mechanisms of sparsentan compared to the ARB losartan by direct visualization of its effects in the intact kidney in focal segmental glomerulosclerosis (FSGS) using intravital multiphoton microscopy. In both healthy and FSGS models, sparsentan treatment increased afferent/efferent arteriole diameters, increased or preserved blood flow and single nephron glomerular filtration rate, attenuated acute ET-1+AngII-induced increases in podocyte calcium, reduced proteinuria, preserved podocyte number, increased both endothelial and renin lineage cells and clones in vasculature, glomeruli and tubules, restored glomerular endothelial glycocalyx, attenuated mitochondrial stress and immune cell homing. These effects were either not observed or of smaller magnitude with losartan. The pleiotropic nephroprotective effects of sparsentan included improved hemodynamics, podocyte and endothelial cell functions, and tissue repair. Compared to losartan, sparsentan was more effective in the sustained preservation of kidney structure and function, which underscores the importance of the ET-1 component in FSGS pathogenesis and therapy.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1172/jci.insight.172286
Hongshuai Liu, Lin Chen, Chuangchuang Zhang, Chang Liu, Yuguo Li, Liam Cheng, Yuxiao Ouyang, Catherine Rutledge, John Anderson, Zhiliang Wei, Ziqin Zhang, Hanzhang Lu, Peter Cm Van Zijl, Jeffrey J Iliff, Jiadi Xu, Wenzhen Duan
The accumulation of mutant huntingtin protein aggregates in neurons is a pathological hallmark of Huntington's disease (HD). The glymphatic system, a brain-wide perivascular network, facilitates the exchange of interstitial fluid (ISF) and cerebrospinal fluid (CSF), supporting interstitial solute clearance of brain wastes. In this study, we employed dynamic glucose-enhanced (DGE) MRI to measure D-glucose clearance from CSF as a tool to predict glymphatic function in a mouse model of HD. We found significantly diminished CSF clearance efficiency in HD mice prior to phenotypic onset. The impairment of CSF clearance efficiency worsened with disease progression. These DGE MRI findings in compromised glymphatic function were further confirmed with fluorescence-based imaging of CSF tracer influx, suggesting an impaired glymphatic function in premanifest HD. Moreover, expression of the astroglial water channel aquaporin-4 (AQP4) in the perivascular compartment, a key mediator of glymphatic function, was significantly diminished in both HD mouse brain and human HD brain. Our data, acquired using a clinically translatable MRI, indicate a perturbed glymphatic network in the HD brain. Further validation of these findings in clinical studies will provide insights into the potential of glymphatic clearance as a therapeutic target as well as an early biomarker in HD.
突变亨廷汀蛋白聚集体在神经元中的积聚是亨廷顿氏病(HD)的病理特征。淋巴系统是一个全脑血管周围网络,可促进脑间质(ISF)和脑脊液(CSF)的交换,支持脑间质溶质清除脑废物。在这项研究中,我们采用动态葡萄糖增强(DGE)核磁共振成像技术测量脑脊液中 D-葡萄糖的清除率,以此来预测 HD 小鼠模型的血糖功能。我们发现,HD 小鼠在表型发病前的 CSF 清除率明显降低。随着病情的发展,CSF清除效率的损害会进一步恶化。基于荧光成像的脑脊液示踪剂流入进一步证实了DGE磁共振成像发现的甘液功能受损,这表明HD发病前的甘液功能受损。此外,在HD小鼠和人类HD大脑中,星形胶质细胞水通道aquaporin-4(AQP4)在血管周围的表达明显减少,而AQP4是血气功能的关键介质。我们使用可用于临床的核磁共振成像获得的数据表明,HD 大脑中的血糖网络受到了干扰。在临床研究中进一步验证这些发现将有助于深入了解甘液清除作为治疗目标和 HD 早期生物标志物的潜力。
{"title":"Glymphatic influx and clearance are perturbed in Huntington's disease.","authors":"Hongshuai Liu, Lin Chen, Chuangchuang Zhang, Chang Liu, Yuguo Li, Liam Cheng, Yuxiao Ouyang, Catherine Rutledge, John Anderson, Zhiliang Wei, Ziqin Zhang, Hanzhang Lu, Peter Cm Van Zijl, Jeffrey J Iliff, Jiadi Xu, Wenzhen Duan","doi":"10.1172/jci.insight.172286","DOIUrl":"https://doi.org/10.1172/jci.insight.172286","url":null,"abstract":"<p><p>The accumulation of mutant huntingtin protein aggregates in neurons is a pathological hallmark of Huntington's disease (HD). The glymphatic system, a brain-wide perivascular network, facilitates the exchange of interstitial fluid (ISF) and cerebrospinal fluid (CSF), supporting interstitial solute clearance of brain wastes. In this study, we employed dynamic glucose-enhanced (DGE) MRI to measure D-glucose clearance from CSF as a tool to predict glymphatic function in a mouse model of HD. We found significantly diminished CSF clearance efficiency in HD mice prior to phenotypic onset. The impairment of CSF clearance efficiency worsened with disease progression. These DGE MRI findings in compromised glymphatic function were further confirmed with fluorescence-based imaging of CSF tracer influx, suggesting an impaired glymphatic function in premanifest HD. Moreover, expression of the astroglial water channel aquaporin-4 (AQP4) in the perivascular compartment, a key mediator of glymphatic function, was significantly diminished in both HD mouse brain and human HD brain. Our data, acquired using a clinically translatable MRI, indicate a perturbed glymphatic network in the HD brain. Further validation of these findings in clinical studies will provide insights into the potential of glymphatic clearance as a therapeutic target as well as an early biomarker in HD.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1172/jci.insight.183158
Hannah E Bergom, Ella Boytim, Sean McSweeney, Negar Sadeghipour, Andrew Elliott, Rachel Passow, Eamon Toye, Xiuxiu Li, Pornlada Likasitwatanakul, Daniel M Geynisman, Scott M Dehm, Susan Halabi, Nima Sharifi, Emmanuel S Antonarakis, Charles J Ryan, Justin Hwang
Background: Prostate cancer (PC) is driven by aberrant signaling of the androgen receptor (AR) or its ligands, and androgen deprivation therapies (ADT) are a cornerstone of treatment. ADT responsiveness may be associated with germline alterations in genes that regulate androgen production, uptake, and conversion (APUC).
Methods: We analyzed whole-exome sequencing (WES) and whole transcriptome sequencing (WTS) data from prostate tissues (SU2C/PCF, TCGA, GETx). We also interrogated the Caris POA DNA (592-gene/whole exome) and RNA (whole transcriptome) NGS databases. Algorithm for Linking Activity Networks (ALAN) was used to quantify all pairwise gene-to-gene associations. Real-world overall survival (OS) was determined from insurance claims data using Kaplan-Meier estimates.
Results: Six APUC genes (HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, CYP17A1) exhibited coalescent gene behavior in a cohort of metastatic tumors (n = 208). In the Caris POA dataset, the 6 APUC genes (APUC-6) exhibited robust clustering in primary prostate (n = 4,490) and metastatic (n = 2,593) biopsies. Surprisingly, tumors with elevated APUC-6 expression had statically lower expression of AR, AR-V7, and AR signaling scores suggesting ligand-driven disease biology. APUC-6 genes instead associated with the expression of alternative steroid hormone receptors, ESR1/2 and PGR. We used RNA expression of AR or APUC-6 genes to define two subgroups of tumors with differential association with hallmark pathways and cell surface targets.
Conclusions: The APUC-6 high/AR-low tumors represented a subgroup of patients with good clinical outcomes in contrast to the AR-high or neuroendocrine prostate cancers. Altogether, measuring the aggregate expression of APUC-6 genes in current genomic tests identifies PCs that are ligand- (rather than AR-) driven and require distinct therapeutic strategies.
Funding: NCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.
背景:前列腺癌(PC)由雄激素受体(AR)或其配体的异常信号驱动,雄激素剥夺疗法(ADT)是治疗的基础。ADT反应性可能与调节雄激素产生、摄取和转换(APUC)的基因的种系改变有关:我们分析了前列腺组织(SU2C/PCF、TCGA、GETx)的全外显子组测序(WES)和全转录组测序(WTS)数据。我们还查询了 Caris POA DNA(592 个基因/全外显子组)和 RNA(全转录组)NGS 数据库。连接活动网络算法(ALAN)用于量化所有基因对基因之间的配对关联。使用 Kaplan-Meier 估计法从保险理赔数据中确定真实世界的总生存期(OS):六个 APUC 基因(HSD3B1、HSD3B2、CYP3A43、CYP11A1、CYP11B1、CYP17A1)在一组转移性肿瘤(n = 208)中表现出基因凝聚行为。在 Caris POA 数据集中,6 个 APUC 基因(APUC-6)在原发性前列腺(n = 4,490 个)和转移性前列腺(n = 2,593 个)活检中表现出强大的聚类。令人惊讶的是,APUC-6表达量升高的肿瘤,其AR、AR-V7和AR信号转导评分的表达量呈静态降低趋势,这表明配体驱动的疾病生物学特性。APUC-6基因反而与替代类固醇激素受体ESR1/2和PGR的表达有关。我们利用AR或APUC-6基因的RNA表达来定义与标志性通路和细胞表面靶点有不同关联的两个肿瘤亚组:结论:APUC-6高/AR低肿瘤代表了临床预后良好的患者亚群,与AR高或神经内分泌性前列腺癌形成鲜明对比。总之,在目前的基因组测试中测量APUC-6基因的总表达量可以确定配体(而不是AR)驱动的PC,需要不同的治疗策略:NCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.
{"title":"Androgen production, uptake, and conversion (APUC) genes define prostate cancer patients with distinct clinical outcomes.","authors":"Hannah E Bergom, Ella Boytim, Sean McSweeney, Negar Sadeghipour, Andrew Elliott, Rachel Passow, Eamon Toye, Xiuxiu Li, Pornlada Likasitwatanakul, Daniel M Geynisman, Scott M Dehm, Susan Halabi, Nima Sharifi, Emmanuel S Antonarakis, Charles J Ryan, Justin Hwang","doi":"10.1172/jci.insight.183158","DOIUrl":"https://doi.org/10.1172/jci.insight.183158","url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer (PC) is driven by aberrant signaling of the androgen receptor (AR) or its ligands, and androgen deprivation therapies (ADT) are a cornerstone of treatment. ADT responsiveness may be associated with germline alterations in genes that regulate androgen production, uptake, and conversion (APUC).</p><p><strong>Methods: </strong>We analyzed whole-exome sequencing (WES) and whole transcriptome sequencing (WTS) data from prostate tissues (SU2C/PCF, TCGA, GETx). We also interrogated the Caris POA DNA (592-gene/whole exome) and RNA (whole transcriptome) NGS databases. Algorithm for Linking Activity Networks (ALAN) was used to quantify all pairwise gene-to-gene associations. Real-world overall survival (OS) was determined from insurance claims data using Kaplan-Meier estimates.</p><p><strong>Results: </strong>Six APUC genes (HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, CYP17A1) exhibited coalescent gene behavior in a cohort of metastatic tumors (n = 208). In the Caris POA dataset, the 6 APUC genes (APUC-6) exhibited robust clustering in primary prostate (n = 4,490) and metastatic (n = 2,593) biopsies. Surprisingly, tumors with elevated APUC-6 expression had statically lower expression of AR, AR-V7, and AR signaling scores suggesting ligand-driven disease biology. APUC-6 genes instead associated with the expression of alternative steroid hormone receptors, ESR1/2 and PGR. We used RNA expression of AR or APUC-6 genes to define two subgroups of tumors with differential association with hallmark pathways and cell surface targets.</p><p><strong>Conclusions: </strong>The APUC-6 high/AR-low tumors represented a subgroup of patients with good clinical outcomes in contrast to the AR-high or neuroendocrine prostate cancers. Altogether, measuring the aggregate expression of APUC-6 genes in current genomic tests identifies PCs that are ligand- (rather than AR-) driven and require distinct therapeutic strategies.</p><p><strong>Funding: </strong>NCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1172/jci.insight.179525
Ruth D Azaria, Adele B Correia, Kylie J Schache, Manuela Zapata, Koralege C Pathmasiri, Varshasnata Mohanty, Dharma T Nannapaneni, Brandon L Ashfeld, Paul Helquist, Olaf Wiest, Kenji Ohgane, Qingqing Li, Ross A Fredenburg, Brian Sj Blagg, Stephanie M Cologna, Mark L Schultz, Andrew P Lieberman
Therapeutics that rescue folding, trafficking, and function of disease-causing missense mutants are sought for a host of human diseases, but efforts to leverage model systems to test emerging strategies have met with limited success. Such is the case for Niemann-Pick type C1 disease, a lysosomal disorder characterized by impaired intracellular cholesterol trafficking, progressive neurodegeneration, and early death. NPC1, a multipass transmembrane glycoprotein, is synthesized in the endoplasmic reticulum and traffics to late endosomes/lysosomes, but this process is often disrupted in disease. We sought to identify small molecules that promote folding and enable lysosomal localization and functional recovery of mutant NPC1. We leveraged a panel of isogenic human induced neurons expressing distinct NPC1 missense mutations. We used this panel to rescreen compounds that were reported previously to correct NPC1 folding and trafficking. We established mo56-hydroxycholesterol (mo56Hc) as a potent pharmacological chaperone for several NPC1 mutants. Furthermore, we generated mice expressing human I1061T NPC1, a common mutation in patients. We demonstrated that this model exhibited disease phenotypes and recapitulated the protein trafficking defects, lipid storage, and response to mo56Hc exhibited by human cells expressing I1061T NPC1. These tools established a paradigm for testing and validation of proteostatic therapeutics as an important step towards the development of disease-modifying therapies.
{"title":"Mutant induced neurons and humanized mice enable identification of Niemann-Pick C1 proteostatic therapies.","authors":"Ruth D Azaria, Adele B Correia, Kylie J Schache, Manuela Zapata, Koralege C Pathmasiri, Varshasnata Mohanty, Dharma T Nannapaneni, Brandon L Ashfeld, Paul Helquist, Olaf Wiest, Kenji Ohgane, Qingqing Li, Ross A Fredenburg, Brian Sj Blagg, Stephanie M Cologna, Mark L Schultz, Andrew P Lieberman","doi":"10.1172/jci.insight.179525","DOIUrl":"https://doi.org/10.1172/jci.insight.179525","url":null,"abstract":"<p><p>Therapeutics that rescue folding, trafficking, and function of disease-causing missense mutants are sought for a host of human diseases, but efforts to leverage model systems to test emerging strategies have met with limited success. Such is the case for Niemann-Pick type C1 disease, a lysosomal disorder characterized by impaired intracellular cholesterol trafficking, progressive neurodegeneration, and early death. NPC1, a multipass transmembrane glycoprotein, is synthesized in the endoplasmic reticulum and traffics to late endosomes/lysosomes, but this process is often disrupted in disease. We sought to identify small molecules that promote folding and enable lysosomal localization and functional recovery of mutant NPC1. We leveraged a panel of isogenic human induced neurons expressing distinct NPC1 missense mutations. We used this panel to rescreen compounds that were reported previously to correct NPC1 folding and trafficking. We established mo56-hydroxycholesterol (mo56Hc) as a potent pharmacological chaperone for several NPC1 mutants. Furthermore, we generated mice expressing human I1061T NPC1, a common mutation in patients. We demonstrated that this model exhibited disease phenotypes and recapitulated the protein trafficking defects, lipid storage, and response to mo56Hc exhibited by human cells expressing I1061T NPC1. These tools established a paradigm for testing and validation of proteostatic therapeutics as an important step towards the development of disease-modifying therapies.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}