Science Translational Medicine最新文献

{"title":"Erratum for the Research Article “BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure” by Q. Duan et al.","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 786","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447258","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}

{"title":"Dysfunctional CD11c − CD21 − extrafollicular memory B cells are enriched in the periphery and tumors of patients with cancer","authors":"Ayana T. Ruffin, Allison N. Casey, Sheryl R. Kunning, Ian P. MacFawn, Zhentao Liu, Charu Arora, Anjali Rohatgi, Felicia Kemp, Caleb Lampenfeld, Ashwin Somasundaram, Giovanna Rappocciolo, John M. Kirkwood, Umamaheswar Duvvuri, Raja Seethala, Riyue Bao, Yufei Huang, Anthony R. Cillo, Robert L. Ferris, Tullia C. Bruno","doi":"10.1126/scitranslmed.adh1315","DOIUrl":"https://doi.org/10.1126/scitranslmed.adh1315","url":null,"abstract":"Many patients with recurrent and metastatic cancer fail to produce a durable response to immunotherapy, highlighting the need for additional therapeutic targets to improve the immune landscape in tumors. Recent studies have highlighted the importance of B cells in the antitumor response, with memory B cells (MBCs) being prognostic in a variety of solid tumors. MBCs are a heterogenous B cell subset and can be generated through both germinal center reactions and extrafollicular (EF) responses. EF-derived MBCs have been recently linked to poor prognosis and treatment resistance in solid tumors and thus may represent candidate biomarkers or immunotherapy targets. EF-derived MBCs, termed “double-negative” (DN) MBCs may be further classified on the basis of surface expression of CD11c and CD21 into DN1, DN2, and DN3 MBCs. CD11c <jats:sup>−</jats:sup> CD21 <jats:sup>+</jats:sup> DN1 MBCs and CD11c <jats:sup>+</jats:sup> CD21 <jats:sup>−</jats:sup> DN2 MBCs have been well studied across inflammatory diseases; however, the biology and clinical relevance of CD11c <jats:sup>−</jats:sup> CD21 <jats:sup>−</jats:sup> DN3 MBCs remain unknown. Here, we report an accumulation of DN3 MBCs in the blood and tumors of patients with head and neck squamous cell carcinoma (HNSCC) and an increase in DN3 MBCs in locally advanced HNSCC tumors. Circulating and intratumoral DN3 MBCs were hyporesponsive to antigen stimulation, had low antibody production, and failed to differentiate into antibody-secreting cells. Moreover, DN3 MBCs accumulated selectively outside of tertiary lymphoid structures. Last, circulating DN3 MBCs correlated with poor therapeutic response, advanced disease, and worse outcomes in patients with HNSCC and melanoma, supporting further assessment of EF-derived MBCs as potential biomarkers and therapeutic targets.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"7 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451582","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}

{"title":"A window-of-opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma","authors":"Veronica Rendo, Eudocia Q. Lee, Connor Bossi, Nicholas Khuu, Michelle A. Rudek, Sangita Pal, Narmen Azazmeh, Rumana Rashid, Jia-Ren Lin, Margaret Cusick, Abigail R. N. Reynolds, Auriole C. R. Fassinou, Georges Ayoub, Seth Malinowski, Emily Lapinskas, William Pisano, John Jeang, Sylwia A. Stopka, Michael S. Regan, Johan Spetz, Arati Desai, Frank Lieberman, Kamalakannan Palanichamy, Joy D. Fisher, Kristine Pelton, Raymond Y. Huang, Kristopher A. Sarosiek, Louis B. Nabors, Matthias Holdhoff, Neeraja Danda, Roy Strowd, Serena Desideri, Tobias Walbert, Xiaobu Ye, Arnab Chakravarti, Peter K. Sorger, Sandro Santagata, Nathalie Y. R. Agar, Stuart A. Grossman, Brian M. Alexander, Patrick Y. Wen, Keith L. Ligon, Rameen Beroukhim","doi":"10.1126/scitranslmed.adn6274","DOIUrl":"https://doi.org/10.1126/scitranslmed.adn6274","url":null,"abstract":"Inhibitors of murine double minute homolog 2 (MDM2) represent a promising therapeutic approach for the treatment of <jats:italic>TP53</jats:italic> wild-type glioblastomas (GBMs), reactivating p53 signaling to induce cancer cell death. We conducted a surgical window-of-opportunity trial (NCT03107780) of the MDM2 inhibitor navtemadlin (KRT-232) in 21 patients with <jats:italic>TP53</jats:italic> wild-type recurrent GBM to determine achievable drug concentrations within tumor tissues and biological mechanisms of response and resistance. Participants received navtemadlin at 120 mg ( <jats:italic>n</jats:italic> = 10) or 240 mg ( <jats:italic>n</jats:italic> = 11) for 2 days before surgical resection and after surgery until progression or unacceptable toxicity. Both 120 and 240 mg daily dosing achieved a pharmacodynamic impact, but median progression-free survival was 3.1 months. DNA sequencing of three recurrent tumors revealed an absence of <jats:italic>TP53</jats:italic> -inactivating mutations, indicating alternative mechanisms of resistance. To understand the mechanisms of response and resistance associated with navtemadlin, we conducted functional and spatial analyses of human tissue and patient-derived GBM neurosphere models. Navtemadlin induced partial tumor cell death as monotherapy, and combination with temozolomide enhanced apoptosis in GBM neurospheres while sparing normal bone marrow cells in vitro. We also observed up-regulation of oligodendrocyte differentiation genes with navtemadlin treatment and enrichment of oligodendrocyte transcription factor 2 (OLIG2)–positive cells at relapse, suggesting an unexplored mechanism of navtemadlin tolerance in GBM. Overall, these results indicated that clinically achievable doses of navtemadlin exert pharmacodynamic effects on GBM and suggest that combined treatment with temozolomide may be a route to more durable survival benefits.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"2 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451583","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}

{"title":"Antibodies targeting Crimean-Congo hemorrhagic fever virus GP38 limit vascular leak and viral spread","authors":"Felix Pahmeier,&nbsp;Stephanie R. Monticelli,&nbsp;Xinyi Feng,&nbsp;Christy K. Hjorth,&nbsp;Albert Wang,&nbsp;Ana I. Kuehne,&nbsp;Russell R. Bakken,&nbsp;Thomas G. Batchelor,&nbsp;Saeyoung E. Lee,&nbsp;Marissa Middlecamp,&nbsp;Lauren Stuart,&nbsp;Amaro N. Duarte-Neto,&nbsp;Dafna M. Abelson,&nbsp;Jason S. McLellan,&nbsp;Scott B. Biering,&nbsp;Andrew S. Herbert,&nbsp;Kartik Chandran,&nbsp;Eva Harris","doi":"","DOIUrl":"","url":null,"abstract":"<div >Crimean-Congo hemorrhagic fever virus (CCHFV) is a priority pathogen transmitted by tick bites, with no vaccines or specific therapeutics approved to date. Severe disease manifestations include hemorrhage, endothelial dysfunction, and multiorgan failure. Infected cells release the viral glycoprotein GP38, whose extracellular function is presently unknown. GP38 is considered an important target for vaccine and therapeutic design because GP38-specific antibodies can protect against severe disease in animal models, albeit through an unknown mechanism of action. Here, we showed that GP38 induces endothelial barrier dysfunction in vitro by disrupting the endothelial glycocalyx layer and triggering hyperpermeability. We also demonstrated that GP38 alone can cause vascular leak in a mouse model. We found that CCHFV infection leads to vascular leak in vivo, which was exacerbated by exogenous administration of GP38, facilitating dissemination of CCHFV into target tissues such as the liver. Protective antibodies that recognized specific antigenic sites on GP38, but not a protective neutralizing antibody binding the structural protein Gc, potently inhibited endothelial hyperpermeability in vitro and vascular leak in vivo during CCHFV infection. This work uncovers a function of the circulating viral protein GP38 as a viral toxin in CCHFV pathogenesis and elucidates a potential mode of action of nonneutralizing yet protective GP38-specific antibodies.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 786","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447242","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}

{"title":"Antisense oligonucleotide–mediated MSH3 suppression reduces somatic CAG repeat expansion in Huntington’s disease iPSC–derived striatal neurons","authors":"Emma L. Bunting, Jasmine Donaldson, Sarah A. Cumming, Jessica Olive, Elizabeth Broom, Mihai Miclăuș, Joseph Hamilton, Matthew Tegtmeyer, Hien T. Zhao, Jonathan Brenton, Won-Seok Lee, Robert E. Handsaker, Susan Li, Brittany Ford, Mina Ryten, Steven A. McCarroll, Holly B. Kordasiewicz, Darren G. Monckton, Gabriel Balmus, Michael Flower, Sarah J. Tabrizi","doi":"10.1126/scitranslmed.adn4600","DOIUrl":"https://doi.org/10.1126/scitranslmed.adn4600","url":null,"abstract":"Expanded CAG alleles in the huntingtin ( <jats:italic>HTT</jats:italic> ) gene that cause the neurodegenerative disorder Huntington’s disease (HD) are genetically unstable and continue to expand somatically throughout life, driving HD onset and progression. MSH3, a DNA mismatch repair protein, modifies HD onset and progression by driving this somatic CAG repeat expansion process. <jats:italic>MSH3</jats:italic> is relatively tolerant of loss-of-function variation in humans, making it a potential therapeutic target. Here, we show that an <jats:italic>MSH3</jats:italic> -targeting antisense oligonucleotide (ASO) effectively engaged with its RNA target in induced pluripotent stem cell (iPSC)–derived striatal neurons obtained from a patient with HD carrying <jats:italic>125 HTT</jats:italic> CAG repeats (the 125 CAG iPSC line). ASO treatment led to a dose-dependent reduction of MSH3 and subsequent stalling of CAG repeat expansion in these striatal neurons. Bulk RNA sequencing revealed a safe profile for <jats:italic>MSH3</jats:italic> reduction, even when reduced by &gt;95%. Maximal knockdown of MSH3 also effectively slowed CAG repeat expansion in striatal neurons with an otherwise accelerated expansion rate, derived from the 125 CAG iPSC line where <jats:italic>FAN1</jats:italic> was knocked out by CRISPR-Cas9 editing. Last, we created a knock-in mouse model expressing the human <jats:italic>MSH3</jats:italic> gene and demonstrated effective in vivo reduction in human <jats:italic>MSH3</jats:italic> after ASO treatment. Our study shows that ASO-mediated MSH3 reduction can prevent <jats:italic>HTT</jats:italic> CAG repeat expansion in HD 125 CAG iPSC–derived striatal neurons, highlighting the therapeutic potential of this approach.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"78 5 Pt 1 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393554","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}

{"title":"Tumor extracellular vesicle–derived PD-L1 promotes T cell senescence through lipid metabolism reprogramming","authors":"Feiya Ma,&nbsp;Xia Liu,&nbsp;Yuanqin Zhang,&nbsp;Yan Tao,&nbsp;Lei Zhao,&nbsp;Hazar Abusalamah,&nbsp;Cody Huffman,&nbsp;R. Alex Harbison,&nbsp;Sidharth V. Puram,&nbsp;Yuqi Wang,&nbsp;Guangyong Peng","doi":"","DOIUrl":"","url":null,"abstract":"<div >The limited success of cancer immunotherapy has posed challenges in treating patients with cancer. However, promising strides could be made with a deeper understanding of the factors that cause T cell dysfunction within the tumor microenvironment and by developing effective strategies to counteract tumor-induced immune suppression. Here, we report that tumor-derived extracellular vesicles (tEVs) can induce senescence and suppression in T cells. Programmed death ligand 1 (PD-L1), a key component within tEVs, induced DNA damage and hyperactive lipid metabolism in both human and mouse T cells. This caused an elevated expression of lipid metabolic enzymes and an increase in cholesterol and lipid droplet formation, leading to cellular senescence. At a molecular level, PD-L1 derived from tEVs activated the cAMP-response element binding protein (CREB) and signal transducer and activator of transcription (STAT) signaling, which promoted lipid metabolism and facilitated senescence in human and mouse T cells. Inhibiting EV synthesis in tumors or blocking CREB signaling, cholesterol synthesis, and lipid droplet formation in effector T cells averted the tEV-mediated T cell senescence in vitro and in vivo in cell adoptive transfer and melanoma mouse models. The same treatments also bolstered the antitumor efficacy of adoptive transfer T cell therapy and anti–PD-L1 checkpoint immunotherapy in both human and mouse melanoma models. These studies identified mechanistic links between tumor-mediated immune suppression and potential immunotherapy resistance, and they provide new strategies for cancer immunotherapy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 785","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adm7269","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397446","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}

{"title":"In vivo expansion of gene-targeted hepatocytes through transient inhibition of an essential gene","authors":"Marco De Giorgi, So Hyun Park, Adam Castoreno, Mingming Cao, Ayrea Hurley, Lavanya Saxena, Marcel A. Chuecos, Christopher J. Walkey, Alexandria M. Doerfler, Mia N. Furgurson, M. Cecilia Ljungberg, Kalyani R. Patel, Sarah Hyde, Tyler Chickering, Stephanie Lefebvre, Kelly Wassarman, Patrick Miller, June Qin, Mark K. Schlegel, Ivan Zlatev, Jun Han, Christine Beeton, Rich Gang Li, Jong Kim, James F. Martin, Karl-Dimiter Bissig, Vasant Jadhav, Gang Bao, William R. Lagor","doi":"10.1126/scitranslmed.adk3920","DOIUrl":"https://doi.org/10.1126/scitranslmed.adk3920","url":null,"abstract":"Homology-directed repair (HDR)–based genome editing is an approach that could permanently correct a broad range of genetic diseases. However, its utility is limited by inefficient and imprecise DNA repair mechanisms in terminally differentiated tissues. Here, we tested Repair Drive, a platform technology for selectively expanding HDR-corrected hepatocytes in adult mice in vivo. Repair Drive involves transient conditioning of the liver by knocking down an essential gene, <jats:italic>fumarylacetoacetate hydrolase</jats:italic> ( <jats:italic>Fah</jats:italic> ), and delivering an untargetable version of the essential gene in cis with a therapeutic transgene. We show that Repair Drive increased the percentage of correctly targeted hepatocytes in healthy wild-type mice up to 25%, which resulted in a fivefold increased expression of a therapeutic transgene, <jats:italic>human factor IX</jats:italic> ( <jats:italic>FIX</jats:italic> ). Repair Drive was well tolerated and did not induce toxicity or tumorigenesis during a 1-year follow-up. This approach may broaden the range of liver diseases that can be treated with somatic genome editing.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393553","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}

{"title":"Antisense oligonucleotide–mediated MSH3 suppression reduces somatic CAG repeat expansion in Huntington’s disease iPSC–derived striatal neurons","authors":"Emma L. Bunting,&nbsp;Jasmine Donaldson,&nbsp;Sarah A. Cumming,&nbsp;Jessica Olive,&nbsp;Elizabeth Broom,&nbsp;Mihai Miclăuș,&nbsp;Joseph Hamilton,&nbsp;Matthew Tegtmeyer,&nbsp;Hien T. Zhao,&nbsp;Jonathan Brenton,&nbsp;Won-Seok Lee,&nbsp;Robert E. Handsaker,&nbsp;Susan Li,&nbsp;Brittany Ford,&nbsp;Mina Ryten,&nbsp;Steven A. McCarroll,&nbsp;Holly B. Kordasiewicz,&nbsp;Darren G. Monckton,&nbsp;Gabriel Balmus,&nbsp;Michael Flower,&nbsp;Sarah J. Tabrizi","doi":"","DOIUrl":"","url":null,"abstract":"<div >Expanded CAG alleles in the huntingtin (<i>HTT</i>) gene that cause the neurodegenerative disorder Huntington’s disease (HD) are genetically unstable and continue to expand somatically throughout life, driving HD onset and progression. MSH3, a DNA mismatch repair protein, modifies HD onset and progression by driving this somatic CAG repeat expansion process. <i>MSH3</i> is relatively tolerant of loss-of-function variation in humans, making it a potential therapeutic target. Here, we show that an <i>MSH3</i>-targeting antisense oligonucleotide (ASO) effectively engaged with its RNA target in induced pluripotent stem cell (iPSC)–derived striatal neurons obtained from a patient with HD carrying <i>125 HTT</i> CAG repeats (the 125 CAG iPSC line). ASO treatment led to a dose-dependent reduction of MSH3 and subsequent stalling of CAG repeat expansion in these striatal neurons. Bulk RNA sequencing revealed a safe profile for <i>MSH3</i> reduction, even when reduced by &gt;95%. Maximal knockdown of MSH3 also effectively slowed CAG repeat expansion in striatal neurons with an otherwise accelerated expansion rate, derived from the 125 CAG iPSC line where <i>FAN1</i> was knocked out by CRISPR-Cas9 editing. Last, we created a knock-in mouse model expressing the human <i>MSH3</i> gene and demonstrated effective in vivo reduction in human <i>MSH3</i> after ASO treatment. Our study shows that ASO-mediated MSH3 reduction can prevent <i>HTT</i> CAG repeat expansion in HD 125 CAG iPSC–derived striatal neurons, highlighting the therapeutic potential of this approach.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 785","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397457","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}

{"title":"Tumor extracellular vesicle–derived PD-L1 promotes T cell senescence through lipid metabolism reprogramming","authors":"Feiya Ma, Xia Liu, Yuanqin Zhang, Yan Tao, Lei Zhao, Hazar Abusalamah, Cody Huffman, R. Alex Harbison, Sidharth V. Puram, Yuqi Wang, Guangyong Peng","doi":"10.1126/scitranslmed.adm7269","DOIUrl":"https://doi.org/10.1126/scitranslmed.adm7269","url":null,"abstract":"The limited success of cancer immunotherapy has posed challenges in treating patients with cancer. However, promising strides could be made with a deeper understanding of the factors that cause T cell dysfunction within the tumor microenvironment and by developing effective strategies to counteract tumor-induced immune suppression. Here, we report that tumor-derived extracellular vesicles (tEVs) can induce senescence and suppression in T cells. Programmed death ligand 1 (PD-L1), a key component within tEVs, induced DNA damage and hyperactive lipid metabolism in both human and mouse T cells. This caused an elevated expression of lipid metabolic enzymes and an increase in cholesterol and lipid droplet formation, leading to cellular senescence. At a molecular level, PD-L1 derived from tEVs activated the cAMP-response element binding protein (CREB) and signal transducer and activator of transcription (STAT) signaling, which promoted lipid metabolism and facilitated senescence in human and mouse T cells. Inhibiting EV synthesis in tumors or blocking CREB signaling, cholesterol synthesis, and lipid droplet formation in effector T cells averted the tEV-mediated T cell senescence in vitro and in vivo in cell adoptive transfer and melanoma mouse models. The same treatments also bolstered the antitumor efficacy of adoptive transfer T cell therapy and anti–PD-L1 checkpoint immunotherapy in both human and mouse melanoma models. These studies identified mechanistic links between tumor-mediated immune suppression and potential immunotherapy resistance, and they provide new strategies for cancer immunotherapy.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"70 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393511","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}

{"title":"Intestinal epithelium–derived IL-34 reprograms macrophages to mitigate gastrointestinal tract graft-versus-host disease","authors":"Aditya Rayasam,&nbsp;Alison Moe,&nbsp;Matthew Kudek,&nbsp;Ravi K. Shah,&nbsp;Cheng-Yin Yuan,&nbsp;James M. Miller,&nbsp;Mary Rau,&nbsp;Mollie Patton,&nbsp;Karolyn Wanat,&nbsp;Marco Colonna,&nbsp;Anthony E. Zamora,&nbsp;William R. Drobyski","doi":"","DOIUrl":"","url":null,"abstract":"<div >Gastrointestinal (GI) tract graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation and is attributable to dysregulation that occurs between the effector and regulatory arms of the immune system. Whereas regulatory T cells have a primary role in counterbalancing GVHD-induced inflammation, identifying and harnessing other pathways that promote immune tolerance remain major goals in this disease. Herein, we identified interleukin-34 (IL-34) as an intestinal epithelium–derived cytokine that was able to mitigate the severity of GVHD within the GI tract. Specifically, we observed that the absence of recipient IL-34 production exacerbated GVHD lethality, promoted intestinal epithelial cell death, and compromised barrier integrity. Mechanistically, the absence of host IL-34 skewed donor macrophages toward a proinflammatory phenotype and augmented the accumulation of pathogenic CD4⁺ granulocyte-macrophage colony-stimulating factor (GM-CSF)⁺ T cells within the colon. Conversely, the administration of recombinant IL-34 substantially reduced GVHD mortality and inflammation, which was dependent on the expression of apolipoprotein E in donor macrophages. Complementary genetic and imaging approaches in mice demonstrated that intestinal epithelial cells were the relevant source of IL-34. These results were supported by colonic biopsies from patients with GVHD, which displayed IL-34 expression in intestinal epithelial cells and apolipoprotein E in lamina propria macrophages, validating similar cellular localization in humans. These studies indicate that IL-34 acts as a tissue-intrinsic cytokine that regulates GVHD severity in the GI tract and could serve as a potential therapeutic target for amelioration of this disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 785","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397463","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}