Pub Date : 2025-10-29DOI: 10.1126/scitranslmed.adq1965
Veronica Obregon-Perko, Achal Awasthi, Richard Barfield, Stella J. Berendam, Bhrugu Yagnik, Tiffany Styles, Greg Tharp, Prachi M. Gupta, Gloria Mensah, Margaret Neja, Mithra Kumar, Emily Fray, Fan Bu, Justin Pollara, Marina Tuyishime, Guido Ferrari, Janet D. Siliciano, Robert F. Siliciano, Maud Mavigner, Guido Silvestri, Rama R. Amara, Steve Bosinger, Genevieve G. Fouda, Sallie R. Permar, Cliburn Chan, Ann Chahroudi
Evaluation of HIV cure strategies requires antiretroviral therapy (ART) interruption, but ethical and clinical considerations make this difficult in children. Here, we used a pediatric preclinical model of simian-HIV (SHIV) infection to uncover features associated with time to viral rebound (TTR) and posttreatment control (PTC) of rebound viremia after ART interruption to inform the design of studies testing cure interventions. We assessed 141 variables in SHIV-infected infant rhesus macaques in three staggered ART initiation groups and during subsequent analytical treatment interruption (ATI). Viral rebound occurred in 25 of 30 macaques within 7 to 98 days of ATI, with TTR delayed in the early ART group compared with the intermediate and late ART groups. Peak plasma viral load pre-ART was the most important correlate of TTR, with increased model performance through the successive inclusion of six additional viral and immune variables. The odds of PTC were reduced with higher SHIV RNA in rectal CD4+ T cells pre-ATI; conversely, higher frequencies of Ki67+ effector memory CD8+ T cells in lymph nodes increased the likelihood of PTC. RNA sequencing of CD4+ T cells pre-ATI revealed a down-regulated metabolic and immune gene signature in macaques with PTC. Analysis of the early ART group alone implicated transforming growth factor–β signaling genes in lack of viral rebound off ART. This comprehensive investigation reveals major determinants of viral rebound dynamics after ART interruption that should be validated and explored as potential biomarkers to screen children with HIV being considered for ATI.
{"title":"Identifying correlates of viral rebound timing and viral control in SHIV-infected infant macaques after ART interruption","authors":"Veronica Obregon-Perko, Achal Awasthi, Richard Barfield, Stella J. Berendam, Bhrugu Yagnik, Tiffany Styles, Greg Tharp, Prachi M. Gupta, Gloria Mensah, Margaret Neja, Mithra Kumar, Emily Fray, Fan Bu, Justin Pollara, Marina Tuyishime, Guido Ferrari, Janet D. Siliciano, Robert F. Siliciano, Maud Mavigner, Guido Silvestri, Rama R. Amara, Steve Bosinger, Genevieve G. Fouda, Sallie R. Permar, Cliburn Chan, Ann Chahroudi","doi":"10.1126/scitranslmed.adq1965","DOIUrl":"10.1126/scitranslmed.adq1965","url":null,"abstract":"<div >Evaluation of HIV cure strategies requires antiretroviral therapy (ART) interruption, but ethical and clinical considerations make this difficult in children. Here, we used a pediatric preclinical model of simian-HIV (SHIV) infection to uncover features associated with time to viral rebound (TTR) and posttreatment control (PTC) of rebound viremia after ART interruption to inform the design of studies testing cure interventions. We assessed 141 variables in SHIV-infected infant rhesus macaques in three staggered ART initiation groups and during subsequent analytical treatment interruption (ATI). Viral rebound occurred in 25 of 30 macaques within 7 to 98 days of ATI, with TTR delayed in the early ART group compared with the intermediate and late ART groups. Peak plasma viral load pre-ART was the most important correlate of TTR, with increased model performance through the successive inclusion of six additional viral and immune variables. The odds of PTC were reduced with higher SHIV RNA in rectal CD4<sup>+</sup> T cells pre-ATI; conversely, higher frequencies of Ki67<sup>+</sup> effector memory CD8<sup>+</sup> T cells in lymph nodes increased the likelihood of PTC. RNA sequencing of CD4<sup>+</sup> T cells pre-ATI revealed a down-regulated metabolic and immune gene signature in macaques with PTC. Analysis of the early ART group alone implicated transforming growth factor–β signaling genes in lack of viral rebound off ART. This comprehensive investigation reveals major determinants of viral rebound dynamics after ART interruption that should be validated and explored as potential biomarkers to screen children with HIV being considered for ATI.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 822","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145385227","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 : 2025-10-29DOI: 10.1126/scitranslmed.adx2652
Josef Shin, Paul Götz, Nesrin Sharif, Noemi Sola-Sevilla, Camille Grasmuck, Muriel Schraad, Katrin Pape, Muthuraman Muthuraman, Vinzenz Fleischer, Stephanie EJ Zandee, Stefan Bittner, Christina Francisca Vogelaar, Alexandre Prat, Nicholas Hanuscheck, Frauke Zipp
Although B cell depletion slows disability accrual in people with multiple sclerosis (pwMS), the role of B cells in MS-associated neuronal injury remains elusive. B cells release cytokines such as lymphotoxin-α (LTα), and this proinflammatory protein is also present in the cerebrospinal fluid (CSF) and meninges of pwMS. B cell–specific ablation of LTα alleviates disease severity in a preclinical model of MS. To further study the impact of B cell–derived cytokines on neuronal function, we performed patch-clamp recordings on human iPSC-derived neurons. Coculture with proinflammatory human B cells led to depolarization and aberrant firing. Pretreatment of proinflammatory B cells with a Bruton’s tyrosine kinase inhibitor (BTKi), reported in patients to beneficially affect disability progression even in the absence of inflammatory relapse activity, prevented neuronal impairment and inhibited LTα release from B cells. Blocking LTα, tumor necrosis factor receptor 1 (TNFR1), or receptor-interacting protein kinase 1 or 3 also prevented neuronal impairment, but blocking TNFα or LTβ had no such effect. Neuronal impairment was reversible by BTKi or blockage of LTα, and this reversibility was dependent on the activity of acid sphingomyelinase. In pwMS, LTα correlated with elevated neurofilament light chain (NfL) abundance in CSF, and anti-CD20 B cell–depletion therapy led to a reduction in circulating LTα, supporting the role of B cells as a regulator for LTα. These findings highlight the negative impact of B cell–derived LTα on neurons and suggest potential treatment avenues for MS-associated neuronal injury.
{"title":"Bruton’s tyrosine kinase inhibitors rescue neuronal impairment caused by B cell–mediated lymphotoxin-α release","authors":"Josef Shin, Paul Götz, Nesrin Sharif, Noemi Sola-Sevilla, Camille Grasmuck, Muriel Schraad, Katrin Pape, Muthuraman Muthuraman, Vinzenz Fleischer, Stephanie EJ Zandee, Stefan Bittner, Christina Francisca Vogelaar, Alexandre Prat, Nicholas Hanuscheck, Frauke Zipp","doi":"10.1126/scitranslmed.adx2652","DOIUrl":"10.1126/scitranslmed.adx2652","url":null,"abstract":"<div >Although B cell depletion slows disability accrual in people with multiple sclerosis (pwMS), the role of B cells in MS-associated neuronal injury remains elusive. B cells release cytokines such as lymphotoxin-α (LTα), and this proinflammatory protein is also present in the cerebrospinal fluid (CSF) and meninges of pwMS. B cell–specific ablation of LTα alleviates disease severity in a preclinical model of MS. To further study the impact of B cell–derived cytokines on neuronal function, we performed patch-clamp recordings on human iPSC-derived neurons. Coculture with proinflammatory human B cells led to depolarization and aberrant firing. Pretreatment of proinflammatory B cells with a Bruton’s tyrosine kinase inhibitor (BTKi), reported in patients to beneficially affect disability progression even in the absence of inflammatory relapse activity, prevented neuronal impairment and inhibited LTα release from B cells. Blocking LTα, tumor necrosis factor receptor 1 (TNFR1), or receptor-interacting protein kinase 1 or 3 also prevented neuronal impairment, but blocking TNFα or LTβ had no such effect. Neuronal impairment was reversible by BTKi or blockage of LTα, and this reversibility was dependent on the activity of acid sphingomyelinase. In pwMS, LTα correlated with elevated neurofilament light chain (NfL) abundance in CSF, and anti-CD20 B cell–depletion therapy led to a reduction in circulating LTα, supporting the role of B cells as a regulator for LTα. These findings highlight the negative impact of B cell–derived LTα on neurons and suggest potential treatment avenues for MS-associated neuronal injury.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 822","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145385228","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 : 2025-10-29DOI: 10.1126/scitranslmed.adk0627
Xin Du, Pei K. Goh, Chenkai Ma, Eamon Coughlan, Spencer Greatorex, Laura H. Porter, Brendan Russ, Katherine D. Cummins, Kevin Sek, Clare Y. Slaney, Andrew M. Scott, Jane Oliaro, Paul J. Neeson, Gail P. Risbridger, Renea A. Taylor, Joseph A. Trapani, Stephen J. Turner, Phillip K. Darcy, Florian Wiede, Tony Tiganis
Chimeric antigen receptor (CAR) T cells have been ineffective against solid tumors, where the hostile tumor microenvironment limits CAR T cell function and persistence. Protein tyrosine phosphatase N2 (PTPN2) attenuates T cell receptor and cytokine signaling to maintain T cell tolerance. Here, we used CRISPR-Cas9 gene editing or an inhibitor to target PTPN2 in human CAR T cells specific for the Lewis Y (LeY) neoantigen, which is expressed in most epithelial tumors. Targeting PTPN2 increased CAR and cytokine signaling, including interferon signaling, and enhanced the antigen-induced expansion, activation, and cytotoxicity of anti-LeY CAR T cells in vitro and in vivo. The deletion of PTPN2 in CAR T cells repressed the growth of human tumor and patient-derived xenografts in mice, when compared with unedited CAR T cells, and prolonged mouse survival. The administration of inhibitor also enhanced the ability of α-LeY CAR T cells to repress tumor growth. Cellular indexing of transcriptomes and epitopes by sequencing analysis of splenic PTPN2-deficient CD8+ CAR T cells in tumor-bearing mice revealed that PTPN2 deficiency favored the generation of CD45RA+ CAR T cells expressing markers of long-lived stem cell memory (SCM) CAR T cells. Flow cytometric analysis reaffirmed that the deletion or inhibition of PTPN2 promoted the intratumoral accumulation of SCM CD8+ CAR T cells and the overall persistence of CD8+ CAR T cells. These data support the use of gene editing or small-molecule inhibitors targeting PTPN2 in human CAR T cells to treat solid tumors.
嵌合抗原受体（CAR） T细胞对实体肿瘤无效，其中敌对的肿瘤微环境限制了CAR T细胞的功能和持久性。蛋白酪氨酸磷酸酶N2 （PTPN2）减弱T细胞受体和细胞因子信号以维持T细胞耐受性。在这里，我们使用CRISPR-Cas9基因编辑或抑制剂靶向人类CAR - T细胞中特异性Lewis Y （LeY）新抗原的PTPN2，该抗原在大多数上皮肿瘤中表达。靶向PTPN2增加了CAR和细胞因子信号传导，包括干扰素信号传导，并增强了抗原诱导的抗ley CAR - T细胞在体外和体内的扩增、活化和细胞毒性。与未编辑的CAR - T细胞相比，CAR - T细胞中PTPN2的缺失抑制了小鼠体内人类肿瘤和患者来源的异种移植物的生长，并延长了小鼠的生存期。抑制剂的使用也增强了α-LeY CAR - T细胞抑制肿瘤生长的能力。通过测序分析肿瘤小鼠脾PTPN2缺陷CD8+ CAR - T细胞的转录组和表位的细胞索引显示，PTPN2缺陷有利于产生表达长寿命干细胞记忆（SCM） CAR - T细胞标志物的CD45RA+ CAR - T细胞。流式细胞分析再次证实，PTPN2的缺失或抑制促进了SCM CD8+ CAR - T细胞在瘤内的蓄积和CD8+ CAR - T细胞的整体持久性。这些数据支持在人类CAR - T细胞中使用基因编辑或靶向PTPN2的小分子抑制剂来治疗实体肿瘤。
{"title":"Targeting PTPN2 enhances human CAR T cell efficacy and the development of long-term memory in mouse xenograft models","authors":"Xin Du, Pei K. Goh, Chenkai Ma, Eamon Coughlan, Spencer Greatorex, Laura H. Porter, Brendan Russ, Katherine D. Cummins, Kevin Sek, Clare Y. Slaney, Andrew M. Scott, Jane Oliaro, Paul J. Neeson, Gail P. Risbridger, Renea A. Taylor, Joseph A. Trapani, Stephen J. Turner, Phillip K. Darcy, Florian Wiede, Tony Tiganis","doi":"10.1126/scitranslmed.adk0627","DOIUrl":"10.1126/scitranslmed.adk0627","url":null,"abstract":"<div >Chimeric antigen receptor (CAR) T cells have been ineffective against solid tumors, where the hostile tumor microenvironment limits CAR T cell function and persistence. Protein tyrosine phosphatase N2 (PTPN2) attenuates T cell receptor and cytokine signaling to maintain T cell tolerance. Here, we used CRISPR-Cas9 gene editing or an inhibitor to target PTPN2 in human CAR T cells specific for the Lewis Y (LeY) neoantigen, which is expressed in most epithelial tumors. Targeting PTPN2 increased CAR and cytokine signaling, including interferon signaling, and enhanced the antigen-induced expansion, activation, and cytotoxicity of anti-LeY CAR T cells in vitro and in vivo. The deletion of <i>PTPN2</i> in CAR T cells repressed the growth of human tumor and patient-derived xenografts in mice, when compared with unedited CAR T cells, and prolonged mouse survival. The administration of inhibitor also enhanced the ability of α-LeY CAR T cells to repress tumor growth. Cellular indexing of transcriptomes and epitopes by sequencing analysis of splenic PTPN2-deficient CD8<sup>+</sup> CAR T cells in tumor-bearing mice revealed that PTPN2 deficiency favored the generation of CD45RA<sup>+</sup> CAR T cells expressing markers of long-lived stem cell memory (SCM) CAR T cells. Flow cytometric analysis reaffirmed that the deletion or inhibition of PTPN2 promoted the intratumoral accumulation of SCM CD8<sup>+</sup> CAR T cells and the overall persistence of CD8<sup>+</sup> CAR T cells. These data support the use of gene editing or small-molecule inhibitors targeting PTPN2 in human CAR T cells to treat solid tumors.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 822","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145385224","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 : 2025-10-29DOI: 10.1126/scitranslmed.ady5288
Miriam M. Fonseca, Oriana Gelblung, Sarah D. Pennypacker, Taylor Brooks, Michael Limia, James W. Morgan, Xuewei Zhu, Luis C. Tovias-Sanchez, Alejandro Pluma-Pluma, Ruth Elena Martinez, Mathew R. Eber, Sun H. Park, Cristina M. Furdui, Deepika Awasthi, Alexander Emmanuelli, Byuri A. Cho, Chen Tan, David I. Shalowitz, Samuel S. Lentz, Michael Kelly, Anderson O’Brien Cox, Lindsay Macnamara, Fang-Chi Hsu, Yusuke Shiozawa, Wesley Hsu, Takao Iwawaki, Lance D. Miller, Glenn J. Lesser, Roy Strowd, Juan R. Cubillos-Ruiz, E. Alfonso Romero-Sandoval
Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent and limiting side effect of paclitaxel treatment in patients with cancer. CIPN affects sensory neurons through neuroinflammatory mechanisms, but how immune cells sense and interpret systemic paclitaxel exposure during treatment is unclear. Here, we found that paclitaxel administration activated the endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) in circulating and dorsal root ganglion–resident myeloid cells, engendering an inflammatory milieu that promotes CIPN. Mechanistically, paclitaxel induced the overproduction of mitochondria-derived reactive oxygen species (ROS) that provoked ER stress and IRE1α hyperactivation in macrophages. This process reprogrammed macrophages toward an inflammatory state characterized by IRE1α-dependent production of TNF-α, IL-1β, PGE2, IL-6, IL-5, GM-CSF, MCP-1, and MIP-2. Ablation of IRE1α in leukocytes, or treatment with a selective IRE1α pharmacological inhibitor, prevented dorsal root ganglion neuroinflammation and CIPN-related pain behaviors in mice. Furthermore, the development and severity of CIPN in patients with gynecological cancer were associated with the status of IRE1α activation in their circulating leukocytes. Our study uncovers leukocyte-intrinsic IRE1α as a key mediator of CIPN and suggests that targeting its dysregulated activation could help mitigate CIPN in patients with cancer who are receiving paclitaxel.
{"title":"Leukocyte-intrinsic ER stress responses contribute to chemotherapy-induced peripheral neuropathy","authors":"Miriam M. Fonseca, Oriana Gelblung, Sarah D. Pennypacker, Taylor Brooks, Michael Limia, James W. Morgan, Xuewei Zhu, Luis C. Tovias-Sanchez, Alejandro Pluma-Pluma, Ruth Elena Martinez, Mathew R. Eber, Sun H. Park, Cristina M. Furdui, Deepika Awasthi, Alexander Emmanuelli, Byuri A. Cho, Chen Tan, David I. Shalowitz, Samuel S. Lentz, Michael Kelly, Anderson O’Brien Cox, Lindsay Macnamara, Fang-Chi Hsu, Yusuke Shiozawa, Wesley Hsu, Takao Iwawaki, Lance D. Miller, Glenn J. Lesser, Roy Strowd, Juan R. Cubillos-Ruiz, E. Alfonso Romero-Sandoval","doi":"10.1126/scitranslmed.ady5288","DOIUrl":"10.1126/scitranslmed.ady5288","url":null,"abstract":"<div >Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent and limiting side effect of paclitaxel treatment in patients with cancer. CIPN affects sensory neurons through neuroinflammatory mechanisms, but how immune cells sense and interpret systemic paclitaxel exposure during treatment is unclear. Here, we found that paclitaxel administration activated the endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) in circulating and dorsal root ganglion–resident myeloid cells, engendering an inflammatory milieu that promotes CIPN. Mechanistically, paclitaxel induced the overproduction of mitochondria-derived reactive oxygen species (ROS) that provoked ER stress and IRE1α hyperactivation in macrophages. This process reprogrammed macrophages toward an inflammatory state characterized by IRE1α-dependent production of TNF-α, IL-1β, PGE<sub>2</sub>, IL-6, IL-5, GM-CSF, MCP-1, and MIP-2. Ablation of IRE1α in leukocytes, or treatment with a selective IRE1α pharmacological inhibitor, prevented dorsal root ganglion neuroinflammation and CIPN-related pain behaviors in mice. Furthermore, the development and severity of CIPN in patients with gynecological cancer were associated with the status of IRE1α activation in their circulating leukocytes. Our study uncovers leukocyte-intrinsic IRE1α as a key mediator of CIPN and suggests that targeting its dysregulated activation could help mitigate CIPN in patients with cancer who are receiving paclitaxel.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 822","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145385225","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 : 2025-10-29DOI: 10.1126/scitranslmed.adu3759
Seblewongel Asrat, Wei Keat Lim, Subhashini Srivatsan, Sivan Harel, Kaitlyn Gayvert, Dylan Birchard, Matthew F. Wipperman, Dave Singh, Andrea T. Hooper, George Scott, Julie E. Horowitz, Jonas S. Erjefält, Caroline Sanden, Kirsten Nagashima, Brianna Buonagurio, Li-Hong Ben, Erica Chio, Audrey Le Floc’h, Jeanne Allinne, Jennifer Maloney, George D. Kalliolias, Marcella Ruddy, Sara C. Hamon, Gary A. Herman, Andrew J. Murphy, Helene Goulaouic, Matthew A. Sleeman, Jennifer D. Hamilton, Jamie M. Orengo
Biologics targeting interleukin-4 receptor subunit α (IL-4Rα) and interleukin-33 (IL-33) have demonstrated clinical efficacy in asthma, highlighting the importance of IL-4, IL-13, and IL-33 in respiratory diseases. Despite this, few studies have linked preclinical models to human diseases or evaluated disease biology in clinical trials. To address these gaps, we evaluated transcriptional, cellular, and pathophysiological processes driven by IL-4/IL-13 and IL-33 using human innate cells in vitro, a mouse model of airway inflammation, and a bronchial allergen challenge (BAC) in house dust mite (HDM)–sensitized individuals with mild asthma. Our findings in mice revealed that the prophylactic blockade of IL-4/IL-13, but not IL-33, prevented the initiation of HDM-induced type 2 inflammation, whereas blocking IL-4Rα or IL-33 during peak inflammation ameliorated airway inflammation and remodeling. Each pathway had unique and overlapping effects on airway inflammation and remodeling, with combination blockade showing no additional benefit. Initiating either monotherapy during severe, mixed inflammation resulted in partial efficacy, whereas a combination of these two treatments led to a substantial reduction in airway inflammation and remodeling in sensitized mice. Some of these mechanistic observations translated to a human BAC model, where blocking IL-4Rα or IL-33 alone suppressed gene expression in sputum and circulating biomarkers. As observed in mice, combination treatment in individuals with allergic asthma did not provide additional benefit compared to monotherapy. Overall, these results provide insight into the differences in targeting IL-4Rα or IL-33 pathways in asthma independently or in combination.
{"title":"The IL-33 and IL-4Rα blocking antibodies itepekimab and dupilumab modulate both distinct and common inflammatory mediators in asthma","authors":"Seblewongel Asrat, Wei Keat Lim, Subhashini Srivatsan, Sivan Harel, Kaitlyn Gayvert, Dylan Birchard, Matthew F. Wipperman, Dave Singh, Andrea T. Hooper, George Scott, Julie E. Horowitz, Jonas S. Erjefält, Caroline Sanden, Kirsten Nagashima, Brianna Buonagurio, Li-Hong Ben, Erica Chio, Audrey Le Floc’h, Jeanne Allinne, Jennifer Maloney, George D. Kalliolias, Marcella Ruddy, Sara C. Hamon, Gary A. Herman, Andrew J. Murphy, Helene Goulaouic, Matthew A. Sleeman, Jennifer D. Hamilton, Jamie M. Orengo","doi":"10.1126/scitranslmed.adu3759","DOIUrl":"10.1126/scitranslmed.adu3759","url":null,"abstract":"<div >Biologics targeting interleukin-4 receptor subunit α (IL-4Rα) and interleukin-33 (IL-33) have demonstrated clinical efficacy in asthma, highlighting the importance of IL-4, IL-13, and IL-33 in respiratory diseases. Despite this, few studies have linked preclinical models to human diseases or evaluated disease biology in clinical trials. To address these gaps, we evaluated transcriptional, cellular, and pathophysiological processes driven by IL-4/IL-13 and IL-33 using human innate cells in vitro, a mouse model of airway inflammation, and a bronchial allergen challenge (BAC) in house dust mite (HDM)–sensitized individuals with mild asthma. Our findings in mice revealed that the prophylactic blockade of IL-4/IL-13, but not IL-33, prevented the initiation of HDM-induced type 2 inflammation, whereas blocking IL-4Rα or IL-33 during peak inflammation ameliorated airway inflammation and remodeling. Each pathway had unique and overlapping effects on airway inflammation and remodeling, with combination blockade showing no additional benefit. Initiating either monotherapy during severe, mixed inflammation resulted in partial efficacy, whereas a combination of these two treatments led to a substantial reduction in airway inflammation and remodeling in sensitized mice. Some of these mechanistic observations translated to a human BAC model, where blocking IL-4Rα or IL-33 alone suppressed gene expression in sputum and circulating biomarkers. As observed in mice, combination treatment in individuals with allergic asthma did not provide additional benefit compared to monotherapy. Overall, these results provide insight into the differences in targeting IL-4Rα or IL-33 pathways in asthma independently or in combination.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 822","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145385226","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 : 2025-10-22DOI: 10.1126/scitranslmed.adn6047
Giulia De Rossi, Ao-wang Qiu, Maxime Berg, Thomas Burgoyne, Andrea Martello, Marlene E. Da Vitoria Lobo, Matteo Rizzi, Sophie Mueller, Jack Blackburn, Yuxuan Meng, Simon Walker-Samuel, Rebecca Shipley, Colin J. Chu, Sobha Sivaprasad, John Greenwood, Stephen E. Moss
Diabetic retinopathy (DR) is a common complication of diabetes mellitus and a leading cause of visual impairment and blindness in the working-age population. The early stage of the disease is characterized by retinal capillary dysfunction, but the mechanisms whereby hyperglycemia disturbs capillary homeostasis at this initiating stage are poorly understood, posing a barrier to the development of effective early treatments. We used two mouse models of type I diabetes that replicate early features of human retinal vascular pathology. In both the streptozotocin (STZ) model, where hypoinsulinemia is chemically induced, and in the Ins2Akita model, which develops it spontaneously because of a mutation in the insulin gene, we observed early induction of the secreted glycoprotein gene leucine-rich α-2-glycoprotein 1 (Lrg1). Using the Ins2Akita mice, we showed that Lrg1 induction preceded that of vascular endothelial growth factor A (Vegfa). LRG1 initiated retinal microvascular dysfunction by modifying transforming growth factor–β (TGFβ) signaling in pericytes, driving transdifferentiation to a more contractile fibrotic phenotype, resulting in narrower capillaries and thickened basement membrane. Using computational modeling, we showed that these early vascular changes impaired retinal blood flow and oxygen delivery, consistent with a defect in visual transduction observed in both models. This early retinal phenotype could be rescued by Lrg1 knockout or by treatment with an LRG1 function–blocking antibody in both the STZ and Ins2Akita mice. These results demonstrate that LRG1 is a driver of vascular dysfunction that contributes to the onset of DR and presents itself as a potential preemptive therapeutic target.
{"title":"Leucine-rich α-2-glycoprotein 1 initiates the onset of diabetic retinopathy in mice","authors":"Giulia De Rossi, Ao-wang Qiu, Maxime Berg, Thomas Burgoyne, Andrea Martello, Marlene E. Da Vitoria Lobo, Matteo Rizzi, Sophie Mueller, Jack Blackburn, Yuxuan Meng, Simon Walker-Samuel, Rebecca Shipley, Colin J. Chu, Sobha Sivaprasad, John Greenwood, Stephen E. Moss","doi":"10.1126/scitranslmed.adn6047","DOIUrl":"10.1126/scitranslmed.adn6047","url":null,"abstract":"<div >Diabetic retinopathy (DR) is a common complication of diabetes mellitus and a leading cause of visual impairment and blindness in the working-age population. The early stage of the disease is characterized by retinal capillary dysfunction, but the mechanisms whereby hyperglycemia disturbs capillary homeostasis at this initiating stage are poorly understood, posing a barrier to the development of effective early treatments. We used two mouse models of type I diabetes that replicate early features of human retinal vascular pathology. In both the streptozotocin (STZ) model, where hypoinsulinemia is chemically induced, and in the Ins2Akita model, which develops it spontaneously because of a mutation in the insulin gene, we observed early induction of the secreted glycoprotein gene leucine-rich α-2-glycoprotein 1 (<i>Lrg1</i>). Using the Ins2Akita mice, we showed that <i>Lrg1</i> induction preceded that of vascular endothelial growth factor A (<i>Vegfa</i>). LRG1 initiated retinal microvascular dysfunction by modifying transforming growth factor–β (TGFβ) signaling in pericytes, driving transdifferentiation to a more contractile fibrotic phenotype, resulting in narrower capillaries and thickened basement membrane. Using computational modeling, we showed that these early vascular changes impaired retinal blood flow and oxygen delivery, consistent with a defect in visual transduction observed in both models. This early retinal phenotype could be rescued by <i>Lrg1</i> knockout or by treatment with an LRG1 function–blocking antibody in both the STZ and Ins2Akita mice. These results demonstrate that LRG1 is a driver of vascular dysfunction that contributes to the onset of DR and presents itself as a potential preemptive therapeutic target.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 821","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339220","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}
One strategy for antigen-specific immunosuppression is to convert antigen-specific conventional T (Tconv) cells into Foxp3+ regulatory T (Treg) cells that are as stably suppressive as naturally occurring Treg (nTreg) cells. To achieve the conversion in vitro for mice and humans, we induced high Foxp3 expression in antigen- and interleukin-2 (IL-2)–stimulated Tconv cells by CDK8/19 inhibition. We further established Treg cell–specific epigenetic changes by depriving CD28 costimulation during in vitro Treg cell induction to specifically promote the expression of Treg cell signature genes, especially Foxp3. Repeating this process, with intermittent resting cultures containing IL-2 only, enabled efficient conversion of naïve as well as effector/memory CD4+ Tconv cells, including T helper 1 (TH1), TH2, and TH17 cells, into Foxp3+ Treg cells. These induced Treg (iTreg) cells were similar to nTreg cells in transcription and epigenetic modification and were functionally and phenotypically stable in vivo. Moreover, they effectively suppressed inflammatory bowel disease and graft-versus-host disease in mouse models. Adoptive cell therapy with such effector/memory Tconv cell–derived, functionally stable, iTreg cells may represent a strategy to achieve antigen- and disease-specific treatment of immunological diseases.
{"title":"Generating functionally stable and antigen-specific Treg cells from effector T cells for cell therapy of inflammatory diseases","authors":"Norihisa Mikami, Ryoji Kawakami, Atsushi Sugimoto, Masaya Arai, Shimon Sakaguchi","doi":"10.1126/scitranslmed.adr6049","DOIUrl":"10.1126/scitranslmed.adr6049","url":null,"abstract":"<div >One strategy for antigen-specific immunosuppression is to convert antigen-specific conventional T (T<sub>conv</sub>) cells into Foxp3<sup>+</sup> regulatory T (T<sub>reg</sub>) cells that are as stably suppressive as naturally occurring T<sub>reg</sub> (nT<sub>reg</sub>) cells. To achieve the conversion in vitro for mice and humans, we induced high Foxp3 expression in antigen- and interleukin-2 (IL-2)–stimulated T<sub>conv</sub> cells by CDK8/19 inhibition. We further established T<sub>reg</sub> cell–specific epigenetic changes by depriving CD28 costimulation during in vitro T<sub>reg</sub> cell induction to specifically promote the expression of T<sub>reg</sub> cell signature genes, especially <i>Foxp3</i>. Repeating this process, with intermittent resting cultures containing IL-2 only, enabled efficient conversion of naïve as well as effector/memory CD4<sup>+</sup> T<sub>conv</sub> cells, including T helper 1 (T<sub>H</sub>1), T<sub>H</sub>2, and T<sub>H</sub>17 cells, into Foxp3<sup>+</sup> T<sub>reg</sub> cells. These induced T<sub>reg</sub> (iT<sub>reg</sub>) cells were similar to nT<sub>reg</sub> cells in transcription and epigenetic modification and were functionally and phenotypically stable in vivo. Moreover, they effectively suppressed inflammatory bowel disease and graft-versus-host disease in mouse models. Adoptive cell therapy with such effector/memory T<sub>conv</sub> cell–derived, functionally stable, iT<sub>reg</sub> cells may represent a strategy to achieve antigen- and disease-specific treatment of immunological diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 821","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339222","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}
Nonalcoholic steatohepatitis (NASH) is a chronic, inflammatory form of nonalcoholic fatty liver disease (NAFLD) that frequently progresses to cirrhosis and hepatocellular carcinoma (HCC). However, the role of various immune cells in switching from NAFLD to NASH remains elusive. Here, we took an unbiased single-cell assay for transposase accessible chromatin sequencing (scATAC-seq) approach to investigate the cellular composition, gene expression profiling, and causative roles of immune cells in NASH development. T helper 17 (TH17) cells were identified as the most abundant subpopulation of immune cells in mouse livers with NASH. Further analysis of scATAC-seq data and single-cell RNA sequencing (scRNA-seq) data from the GEO database showed that human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1) is a critical transcription factor (TF) regulating TH17 cell differentiation and cytokine production. Specific knockout of Hivep1 in IL-17A+ and CD4+ T cells in mice showed impairment of TH17 cell differentiation and alleviation of NASH development. Mechanistically, HIVEP1 transcriptionally regulated ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme of polyamine metabolism, to modulate TH17 cell differentiation and cytokine production. Consequently, pharmacological inhibition of ODC1 decreased cytokine production, alleviated inflammation, and prevented the NAFLD-to-NASH transition. Together, our findings elucidate the role of polyamine metabolism in TH17 cell–mediated NASH development and identify potential therapeutic targets for the effective treatment of NASH.
{"title":"HIVEP1 aggravates NASH by reprogramming polyamine metabolism in TH17 cells","authors":"Yidan Ren, Xiaoyan Liu, Maoxiao Feng, Jianxiong Zhao, Yangmiao Duan, Guoying Dong, Huiru Gao, Xiaodong Hao, Qin Wang, Jiaying Yao, Zan Yuan, Xu Jing, Jing Wu, Yihai Cao, Yunshan Wang","doi":"10.1126/scitranslmed.adn1150","DOIUrl":"10.1126/scitranslmed.adn1150","url":null,"abstract":"<div >Nonalcoholic steatohepatitis (NASH) is a chronic, inflammatory form of nonalcoholic fatty liver disease (NAFLD) that frequently progresses to cirrhosis and hepatocellular carcinoma (HCC). However, the role of various immune cells in switching from NAFLD to NASH remains elusive. Here, we took an unbiased single-cell assay for transposase accessible chromatin sequencing (scATAC-seq) approach to investigate the cellular composition, gene expression profiling, and causative roles of immune cells in NASH development. T helper 17 (T<sub>H</sub>17) cells were identified as the most abundant subpopulation of immune cells in mouse livers with NASH. Further analysis of scATAC-seq data and single-cell RNA sequencing (scRNA-seq) data from the GEO database showed that human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1) is a critical transcription factor (TF) regulating T<sub>H</sub>17 cell differentiation and cytokine production. Specific knockout of <i>Hivep1</i> in IL-17A<sup>+</sup> and CD4<sup>+</sup> T cells in mice showed impairment of T<sub>H</sub>17 cell differentiation and alleviation of NASH development. Mechanistically, HIVEP1 transcriptionally regulated ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme of polyamine metabolism, to modulate T<sub>H</sub>17 cell differentiation and cytokine production. Consequently, pharmacological inhibition of ODC1 decreased cytokine production, alleviated inflammation, and prevented the NAFLD-to-NASH transition. Together, our findings elucidate the role of polyamine metabolism in T<sub>H</sub>17 cell–mediated NASH development and identify potential therapeutic targets for the effective treatment of NASH.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 821","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adn1150","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-22DOI: 10.1126/scitranslmed.adu4879
Meichun Deng, Shao-Rui Chen, Meng-Hua Zhou, Jixiang Zhang, Yuying Huang, Hong Chen, Fernando Benavides, Rajan Sah, Hui-Lin Pan
Amplification of nociceptive transmission due to aberrant N-methyl-d-aspartate receptor (NMDAR) hyperactivity in the spinal cord is a key characteristic of neuropathic pain. However, under normal conditions, both presynaptic and postsynaptic NMDARs in the spinal dorsal horn are largely inactive. The mechanisms restraining synaptic NMDAR activity remain enigmatic. Leucine-rich repeat-containing protein 8A (LRRC8A or SWELL1) is an essential component of volume-regulated anion channels typically involved in regulating cell volume. Here, we report that LRRC8A was highly expressed in dorsal root ganglion (DRG) and spinal dorsal horn neurons of rats. Nerve injury persistently reduced LRRC8A expression in the DRG. siRNA-mediated Lrrc8a knockdown in rats or conditional Lrrc8a knockout in DRG neurons in mice consistently caused a pain hypersensitivity phenotype that was readily reversed by NMDAR antagonists. Correspondingly, Lrrc8a knockdown or conditional Lrrc8a knockout in DRG neurons markedly augmented synaptic localization and activity of NMDARs in the spinal cord. LRRC8A interacted with NMDARs in both rat and human spinal cord tissues primarily through its C-terminal LRR domain, restricting the synaptic trafficking and activity of NMDARs. Furthermore, Lrrc8aebo/ebo mutant mice, which lack the LRR domain, exhibited NMDAR-dependent pain hypersensitivity and synaptic NMDAR hyperactivity in the spinal cord. Additionally, intrathecal Lrrc8a gene delivery eliminated nerve injury–induced pain hypersensitivity and synaptic NMDAR hyperactivity in rats. These findings reveal that LRRC8A physically interacts with NMDARs and constitutively restricts their synaptic expression in the spinal cord. Reduced LRRC8A-NMDAR interactions increase synaptic expression of “unleashed” NMDARs, contributing to NMDAR hyperactivity and neuropathic pain in rodent models.
{"title":"LRRC8A constitutively inhibits pain hypersensitivity in rodent models by restraining NMDA receptor activity at spinal cord synapses","authors":"Meichun Deng, Shao-Rui Chen, Meng-Hua Zhou, Jixiang Zhang, Yuying Huang, Hong Chen, Fernando Benavides, Rajan Sah, Hui-Lin Pan","doi":"10.1126/scitranslmed.adu4879","DOIUrl":"10.1126/scitranslmed.adu4879","url":null,"abstract":"<div >Amplification of nociceptive transmission due to aberrant <i>N</i>-methyl-<span>d</span>-aspartate receptor (NMDAR) hyperactivity in the spinal cord is a key characteristic of neuropathic pain. However, under normal conditions, both presynaptic and postsynaptic NMDARs in the spinal dorsal horn are largely inactive. The mechanisms restraining synaptic NMDAR activity remain enigmatic. Leucine-rich repeat-containing protein 8A (LRRC8A or SWELL1) is an essential component of volume-regulated anion channels typically involved in regulating cell volume. Here, we report that LRRC8A was highly expressed in dorsal root ganglion (DRG) and spinal dorsal horn neurons of rats. Nerve injury persistently reduced LRRC8A expression in the DRG. siRNA-mediated <i>Lrrc8a</i> knockdown in rats or conditional <i>Lrrc8a</i> knockout in DRG neurons in mice consistently caused a pain hypersensitivity phenotype that was readily reversed by NMDAR antagonists. Correspondingly, <i>Lrrc8a</i> knockdown or conditional <i>Lrrc8a</i> knockout in DRG neurons markedly augmented synaptic localization and activity of NMDARs in the spinal cord. LRRC8A interacted with NMDARs in both rat and human spinal cord tissues primarily through its C-terminal LRR domain, restricting the synaptic trafficking and activity of NMDARs. Furthermore, <i>Lrrc8a<sup>ebo/ebo</sup></i> mutant mice, which lack the LRR domain, exhibited NMDAR-dependent pain hypersensitivity and synaptic NMDAR hyperactivity in the spinal cord. Additionally, intrathecal <i>Lrrc8a</i> gene delivery eliminated nerve injury–induced pain hypersensitivity and synaptic NMDAR hyperactivity in rats. These findings reveal that LRRC8A physically interacts with NMDARs and constitutively restricts their synaptic expression in the spinal cord. Reduced LRRC8A-NMDAR interactions increase synaptic expression of “unleashed” NMDARs, contributing to NMDAR hyperactivity and neuropathic pain in rodent models.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 821","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339221","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}
Antigen-specific immunotherapy represents one candidate strategy for treating autoimmune diseases such as pemphigus vulgaris, a skin autoimmune disorder mediated by anti–desmoglein 3 (Dsg3) autoantibodies. We developed a therapeutic strategy by which Dsg3-specific pathogenic autoreactive CD4+ T cells were converted in vitro into functionally stable Foxp3+ regulatory T (Treg) cells, designated stable and functional induced Treg (S/F-iTreg) cells. The conversion was achieved by pharmacological induction of Foxp3 and costimulation-dependent installation of Treg cell–specific epigenetic changes. In an animal model of pemphigus vulgaris, the Dsg3-specific S/F-iTreg cells expanded specifically in the skin-draining lymph nodes through recognition of endogenous Dsg3. They selectively inhibited Dsg3-specific T follicular helper cell and B cell proliferation and, consequently, anti-Dsg3 autoantibody formation, without affecting the total B cell population, thereby mitigating disease progression without inducing systemic immunosuppression. Human S/F-iTreg cells with similar functions could also be efficiently generated from peripheral blood T cells of patients with pemphigus vulgaris. This study demonstrates that pathogenic autoreactive T cells can be converted into disease-specific Treg cells retaining antigen specificity, enabling antigen- and disease-specific treatment of autoimmune disease.
{"title":"Conversion of pathogenic T cells into functionally stabilized Treg cells for antigen-specific immunosuppression in pemphigus vulgaris","authors":"Miho Mukai, Hayato Takahashi, Yoko Kubo, Yasuhiko Asahina, Hisato Iriki, Hisashi Nomura, Aki Kamata, Hiromi Ito, Yutaka Kurebayashi, Jun Yamagami, Norihisa Mikami, Shimon Sakaguchi, Masayuki Amagai","doi":"10.1126/scitranslmed.adq9913","DOIUrl":"10.1126/scitranslmed.adq9913","url":null,"abstract":"<div >Antigen-specific immunotherapy represents one candidate strategy for treating autoimmune diseases such as pemphigus vulgaris, a skin autoimmune disorder mediated by anti–desmoglein 3 (Dsg3) autoantibodies. We developed a therapeutic strategy by which Dsg3-specific pathogenic autoreactive CD4<sup>+</sup> T cells were converted in vitro into functionally stable Foxp3<sup>+</sup> regulatory T (T<sub>reg</sub>) cells, designated stable and functional induced T<sub>reg</sub> (S/F-iT<sub>reg</sub>) cells. The conversion was achieved by pharmacological induction of Foxp3 and costimulation-dependent installation of T<sub>reg</sub> cell–specific epigenetic changes. In an animal model of pemphigus vulgaris, the Dsg3-specific S/F-iT<sub>reg</sub> cells expanded specifically in the skin-draining lymph nodes through recognition of endogenous Dsg3. They selectively inhibited Dsg3-specific T follicular helper cell and B cell proliferation and, consequently, anti-Dsg3 autoantibody formation, without affecting the total B cell population, thereby mitigating disease progression without inducing systemic immunosuppression. Human S/F-iT<sub>reg</sub> cells with similar functions could also be efficiently generated from peripheral blood T cells of patients with pemphigus vulgaris. This study demonstrates that pathogenic autoreactive T cells can be converted into disease-specific T<sub>reg</sub> cells retaining antigen specificity, enabling antigen- and disease-specific treatment of autoimmune disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 821","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339223","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}
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