JCI insight最新文献_第9页

Early treatment and PD1 inhibition enhance HIV-specific functionality of follicular CD8+ T cells. 早期治疗和抑制PD1可增强滤泡CD8+ T细胞的hiv特异性功能。

IF 6.3 1区医学

JCI insight Pub Date : 2025-04-08 DOI: 10.1172/jci.insight.180309

Susanne Rueger, Eva Gruener, Danni Wang, Faiaz Shaik Abdool, Veronica Ober, Theresa Vallée, Renate Stirner, Raffaele Conca, Immanuel Andrä, Lisa Rogers, Robert Zahn, Elke Gersbacher, Joanna Eger, Ramona Pauli, Nils Postel, Christoph D Spinner, Jörg J Vehreschild, Melanie Stecher, Hans Nitschko, Josef Eberle, Johannes R Bogner, Ulrich Seybold, Rika Draenert, Al Leslie, Henrik N Kløverpris, Christof Geldmacher, Maximilian Muenchhoff, Kathrin Held, Julia Roider

{"title":"Early treatment and PD1 inhibition enhance HIV-specific functionality of follicular CD8+ T cells.","authors":"Susanne Rueger, Eva Gruener, Danni Wang, Faiaz Shaik Abdool, Veronica Ober, Theresa Vallée, Renate Stirner, Raffaele Conca, Immanuel Andrä, Lisa Rogers, Robert Zahn, Elke Gersbacher, Joanna Eger, Ramona Pauli, Nils Postel, Christoph D Spinner, Jörg J Vehreschild, Melanie Stecher, Hans Nitschko, Josef Eberle, Johannes R Bogner, Ulrich Seybold, Rika Draenert, Al Leslie, Henrik N Kløverpris, Christof Geldmacher, Maximilian Muenchhoff, Kathrin Held, Julia Roider","doi":"10.1172/jci.insight.180309","DOIUrl":"10.1172/jci.insight.180309","url":null,"abstract":"People living with HIV treated during acute infection are the group for whom achieving functional cure appears most viable. Follicular CD8+ T cells could contribute to HIV reservoir clearance by accessing B cell follicles through CXCR5 expression. This study examines peripheral follicular CD8+ T cells using flow cytometry, transcriptome analyses, and functional assays in people treated during acute (n = 37) and chronic (n = 18) infection, as well as in individuals naturally controlling HIV (n = 20) and living without HIV (n = 10). Our results reveal that early, as opposed to late, treatment initiation preserves antiviral effector functions of follicular CD8+ T cells, which are further enhanced by PD1 inhibition. We also identify a correlation between follicular CD8+ T cells and intact proviral HIV DNA levels in acute, but not chronic, infection. Longitudinal transcriptomic analysis of peripheral effector cells after 48 weeks of suppressive therapy indicated traits of recent antigen exposure, suggesting potential recirculation into lymphoid tissue. These findings underscore the pivotal role of follicular CD8+ T cells in anti-HIV responses and support investigating targeted cure strategies, such as anti-PD1 therapy, especially in individuals initiating treatment during acute infection.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803318","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}

引用次数: 0

CAR Treg synergy with anti-CD154 promotes infectious tolerance and dictates allogeneic heart transplant acceptance. CAR - Treg与抗cd154的协同作用促进了感染耐受性并决定了异体心脏移植的接受度。

IF 6.3 1区医学

JCI insight Pub Date : 2025-04-08 DOI: 10.1172/jci.insight.188624

Samarth S Durgam, Isaac Rosado-Sánchez, Dengping Yin, Madeleine Speck, Majid Mojibian, Ismail Sayin, Grace E Hynes, Maria-Luisa Alegre, Megan K Levings, Anita S Chong

{"title":"CAR Treg synergy with anti-CD154 promotes infectious tolerance and dictates allogeneic heart transplant acceptance.","authors":"Samarth S Durgam, Isaac Rosado-Sánchez, Dengping Yin, Madeleine Speck, Majid Mojibian, Ismail Sayin, Grace E Hynes, Maria-Luisa Alegre, Megan K Levings, Anita S Chong","doi":"10.1172/jci.insight.188624","DOIUrl":"10.1172/jci.insight.188624","url":null,"abstract":"Successful allograft-specific tolerance induction would eliminate the need for daily immunosuppression and improve posttransplant quality of life. Adoptive cell therapy with regulatory T cells expressing donor-specific chimeric antigen receptors (CAR Tregs) is a promising strategy but, as monotherapy, cannot prolong survival with allografts with multiple MHC mismatches. Using an HLA-A2-transgenic haplo-mismatched heart transplantation model in immunocompetent C57BL/6 recipients, we showed that HLA-A2-specific CAR (A2.CAR) Tregs were able to synergize with a low dose of anti-CD154 to enhance graft survival. Using haplo-mismatched grafts expressing the 2W-OVA transgene and tetramer-based tracking of 2W- and OVA-specific T cells, we showed that in mice with accepted grafts, A2.CAR Tregs inhibited donor-specific T cell, B cell, and antibody responses and promoted a substantial increase in endogenous FOXP3+ Tregs with indirect donor specificity. By contrast, in mice where A2.CAR Tregs failed to prolong graft survival, FOXP3- A2.CAR T cells preferentially accumulated in rejecting allografts, and endogenous donor-specific responses were not controlled. This study therefore provides evidence for synergy between A2.CAR Tregs and CD154 blockade to promote infectious tolerance in immunocompetent recipients of haplo-mismatched heart grafts and defines features of A2.CAR Tregs when they fail to reshape host immunity toward allograft tolerance.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803315","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}

引用次数: 0

Increased fatty acid delivery by tumor endothelium promotes metastatic outgrowth. 增加的脂肪酸通过肿瘤内皮传递促进转移性生长。

IF 6.3 1区医学

JCI insight Pub Date : 2025-04-08 eCollection Date: 2025-05-08 DOI: 10.1172/jci.insight.187531

Deanna N Edwards, Shan Wang, Kelby Kane, Wenqiang Song, Laura C Kim, Verra M Ngwa, Yoonha Hwang, Kevin Ess, Mark R Boothby, Jin Chen

{"title":"Increased fatty acid delivery by tumor endothelium promotes metastatic outgrowth.","authors":"Deanna N Edwards, Shan Wang, Kelby Kane, Wenqiang Song, Laura C Kim, Verra M Ngwa, Yoonha Hwang, Kevin Ess, Mark R Boothby, Jin Chen","doi":"10.1172/jci.insight.187531","DOIUrl":"10.1172/jci.insight.187531","url":null,"abstract":"Metastatic outgrowth in distant microscopic niches requires sufficient nutrients, including fatty acids (FAs), to support tumor growth and to generate an immunosuppressive tumor microenvironment (TME). However, despite the important role of FAs in metastasis, the regulation of FA supply in metastatic niches has not been defined. In this report, we show that tumor endothelium actively promotes outgrowth and restricts antitumor cytolysis by transferring FAs into developing metastatic tumors. We describe a process of transendothelial FA delivery via endosomes that requires mTORC1 activity. Thus, endothelial cell-specific targeted deletion of Raptor (RptorECKO), a unique component of the mTORC1 complex, significantly reduced metastatic tumor burden that was associated with improved markers of T cell cytotoxicity. Low-dose everolimus that selectively inhibited endothelial mTORC1 improves immune checkpoint responses in metastatic disease models. This work reveals the importance of transendothelial nutrient delivery to the TME, highlighting a future target for therapeutic development.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803283","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}

引用次数: 0

A study of MD-PhD pre-health advising identifies challenges to building a robust MD-PhD applicant pool. 一项针对医学博士前健康咨询的研究发现，建立一个强大的医学博士申请人才库面临着挑战。

IF 6.3 1区医学

JCI insight Pub Date : 2025-04-08 DOI: 10.1172/jci.insight.185839

Amara L Plaza-Jennings, Christie B Ryba, Jessica Tan, Jennifer El Diaz, Grace E Mosley, Talia H Swartz, Margaret H Baron, Robert Fallar, Valerie Parkas

{"title":"A study of MD-PhD pre-health advising identifies challenges to building a robust MD-PhD applicant pool.","authors":"Amara L Plaza-Jennings, Christie B Ryba, Jessica Tan, Jennifer El Diaz, Grace E Mosley, Talia H Swartz, Margaret H Baron, Robert Fallar, Valerie Parkas","doi":"10.1172/jci.insight.185839","DOIUrl":"10.1172/jci.insight.185839","url":null,"abstract":"MD-PhD programs provide interdisciplinary training in medicine and research. Undergraduate pre-health advisors (PHAs) play a critical role in counseling prospective applicants, yet there have been no studies to our knowledge of MD-PhD pre-health advising. Here we surveyed 280 PHAs from US colleges and universities using both qualitative and quantitative measures that assessed their real-world advising behaviors as well as standardized evaluation of 1 of 2 fictional MD-PhD applicants, identical except for gender. We identified 3 factors that influenced advising behaviors: experience advising MD-PhD applicants, attitudes toward MD-PhD programs, and gender bias. Those PHAs with less experience and who held negative attitudes toward MD-PhD programs were less likely to initiate discussions about MD-PhD programs with qualified applicants and less likely to recommend the fictional applicants apply to MD-PhD programs. Finally, there was subtle gender bias that favored the male applicant. PHAs face challenges in advising MD-PhD applicants because there are relatively few MD-PHD applicants overall and there is a lack of resources to guide them. Addressing these challenges by strengthening collaborations with PHAs and providing comprehensive information about the value of and applicant qualifications for MD-PhD programs is crucial to enhancing MD-PhD advising, mitigating effects of bias, and expanding the pool of qualified applicants.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803298","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}

引用次数: 0

The physician-scientist: looking back, looking forward. 医生兼科学家：回顾过去，展望未来。

IF 6.3 1区医学

JCI insight Pub Date : 2025-04-08 DOI: 10.1172/jci.insight.192637

Gary Koretzky

引用次数: 0

AMPK activator ATX-304 reduces oxidative stress and improves MASLD via metabolic switching. AMPK激活剂ATX-304通过代谢转换减少氧化应激，改善MASLD。

IF 6.3 1区医学

JCI insight Pub Date : 2025-04-08 DOI: 10.1172/jci.insight.179990

Emanuel Holm, Isabeau Vermeulen, Saba Parween, Ana López-Pérez, Berta Cillero-Pastor, Michiel Vandenbosch, Silvia Remeseiro, Andreas Hörnblad

{"title":"AMPK activator ATX-304 reduces oxidative stress and improves MASLD via metabolic switching.","authors":"Emanuel Holm, Isabeau Vermeulen, Saba Parween, Ana López-Pérez, Berta Cillero-Pastor, Michiel Vandenbosch, Silvia Remeseiro, Andreas Hörnblad","doi":"10.1172/jci.insight.179990","DOIUrl":"10.1172/jci.insight.179990","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide for which there is only one approved treatment. Adenosine monophosphate-activated protein kinase (AMPK) is an interesting therapeutic target since it acts as a central regulator of cellular metabolism. Despite efforts to target AMPK, no direct activators have yet been approved for treatment of this disease. This study investigated the effect of the AMPK activator ATX-304 in a preclinical mouse model of progressive fatty liver disease. The data demonstrated that ATX-304 diminishes body fat mass, lowers blood cholesterol levels, and mitigates general liver steatosis and the development of liver fibrosis, but with pronounced local heterogeneities. The beneficial effects of ATX-304 treatment were accompanied by a shift in the liver metabolic program, including increased fatty acid oxidation, reduced lipid synthesis, as well as remodeling of cholesterol and lipid transport. We also observed variations in lipid distribution among liver lobes in response to ATX-304, and a shift in the zonal distribution of lipid droplets upon treatment. Taken together, our data suggested that ATX-304 holds promise as a potential treatment for MASLD.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803311","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}

引用次数: 0

Residence of mice in metabolic cages reduces experimental kidney inflammation through stress-induced glucocorticoids. 在代谢笼中居住的小鼠通过应激诱导的糖皮质激素减少实验性肾脏炎症。

IF 6.3 1区医学

JCI insight Pub Date : 2025-04-08 eCollection Date: 2025-05-08 DOI: 10.1172/jci.insight.189794

Junping Yin, Melanie Eichler, Clivia Lisowski, Jian Li, Sibylle von Vietinghoff, Natalio Garbi, Qi Mei, Anne-Kathrin Gellner, Christian Kurts

引用次数: 0

Unique and shared transcriptomic signatures underlying localized scleroderma pathogenesis identified using interpretable machine learning. 使用可解释的机器学习确定的局部硬皮病发病机制的独特和共享的转录组特征。

IF 6.3 1区医学

JCI insight Pub Date : 2025-04-08 DOI: 10.1172/jci.insight.185758

Aaron Bi Rosen, Anwesha Sanyal, Theresa Hutchins, Giffin Werner, Jacob S Berkowitz, Tracy Tabib, Robert Lafyatis, Heidi Jacobe, Jishnu Das, Kathryn S Torok

{"title":"Unique and shared transcriptomic signatures underlying localized scleroderma pathogenesis identified using interpretable machine learning.","authors":"Aaron Bi Rosen, Anwesha Sanyal, Theresa Hutchins, Giffin Werner, Jacob S Berkowitz, Tracy Tabib, Robert Lafyatis, Heidi Jacobe, Jishnu Das, Kathryn S Torok","doi":"10.1172/jci.insight.185758","DOIUrl":"10.1172/jci.insight.185758","url":null,"abstract":"Using transcriptomic profiling at single-cell resolution, we investigated cell-intrinsic and cell-extrinsic signatures associated with pathogenesis and inflammation-driven fibrosis in both adult and pediatric patients with localized scleroderma (LS). We performed single-cell RNA-Seq on adult and pediatric patients with LS and healthy controls. We then analyzed the single-cell RNA-Seq data using an interpretable factor analysis machine learning framework, significant latent factor interaction discovery and exploration (SLIDE), which moves beyond predictive biomarkers to infer latent factors underlying LS pathophysiology. SLIDE is a recently developed latent factor regression-based framework that comes with rigorous statistical guarantees regarding identifiability of the latent factors, corresponding inference, and FDR control. We found distinct differences in the characteristics and complexity in the molecular signatures between adult and pediatric LS. SLIDE identified cell type-specific determinants of LS associated with age and severity and revealed insights into signaling mechanisms shared between LS and systemic sclerosis (SSc), as well as differences in onset of the disease in the pediatric compared with adult population. Our analyses recapitulate known drivers of LS pathology and identify cellular signaling modules that stratify LS subtypes and define a shared signaling axis with SSc.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803356","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}

引用次数: 0

Science: our past, our present, and always our future. 科学：我们的过去，我们的现在，永远是我们的未来。

IF 6.3 1区医学

JCI insight Pub Date : 2025-04-08 DOI: 10.1172/jci.insight.193355

Oliver Eickelberg, Christopher S Williams, Kyu Y Rhee

引用次数: 0

ICOS+CD4+ T cells define a high susceptibility to anti-PD-1 therapy-induced lung pathogenesis. ICOS+CD4 T细胞对抗pd -1治疗诱导的肺部发病机制具有高度易感性。

IF 6.3 1区医学

JCI insight Pub Date : 2025-04-08 eCollection Date: 2025-05-22 DOI: 10.1172/jci.insight.186483

Mari Yokoi, Kosaku Murakami, Tomonori Yaguchi, Kenji Chamoto, Hiroaki Ozasa, Hironori Yoshida, Mirei Shirakashi, Katsuhiro Ito, Yoshihiro Komohara, Yukio Fujiwara, Hiromu Yano, Tatsuya Ogimoto, Daiki Hira, Tomohiro Terada, Toyohiro Hirai, Hirotake Tsukamoto

{"title":"ICOS+CD4+ T cells define a high susceptibility to anti-PD-1 therapy-induced lung pathogenesis.","authors":"Mari Yokoi, Kosaku Murakami, Tomonori Yaguchi, Kenji Chamoto, Hiroaki Ozasa, Hironori Yoshida, Mirei Shirakashi, Katsuhiro Ito, Yoshihiro Komohara, Yukio Fujiwara, Hiromu Yano, Tatsuya Ogimoto, Daiki Hira, Tomohiro Terada, Toyohiro Hirai, Hirotake Tsukamoto","doi":"10.1172/jci.insight.186483","DOIUrl":"10.1172/jci.insight.186483","url":null,"abstract":"Managing immune-related adverse events (irAEs) caused by cancer immunotherapy is essential for developing effective and safer therapies. However, cellular mechanism(s) underlying organ toxicity during anti-PD-(L)1 therapy remain unclear. Here, we investigated the effect of chronological aging on anti-PD-(L)1 therapy-induced irAE-like lung toxicity, utilizing tumor-bearing aged mice. Anti-PD-(L)1 therapy facilitated ectopic infiltration of T and B cells, and antibody deposition in lungs of aged but not young mice. Adoptive transfer of aged lung-derived CD4+ T cells into TCR-deficient mice revealed that both pathogenic CD4+ T cells and an aged host environment were necessary for the irAE-inducible responses. Single-cell transcriptomics of lung-infiltrating cells in aged mice demonstrated that anti-PD-(L)1 therapy elicited ICOS+CD4+ T cell activation. Disruption of the ICOS-ICOSL interaction attenuated germinal center B cell differentiation and subsequent lung damage, which were overcome by local administration of IL-21 in the lungs of anti-PD-1 therapy-treated aged mice. Therefore, ICOS+CD4+ T cells elicited under an aged environment exacerbated aberrant immune responses and the subsequent lung dysfunction. Consistent with the findings from the mouse model, ICOS upregulation in CD4+ T cells was associated with later irAE incidence in patients with cancer. These finding will help development of useful strategies for irAE management in patients with cancer, many of whom are elderly.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803280","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}

引用次数: 0