[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-413886-105":59,"doc-detail-413886-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","fanning-the-flames-ifn-fuels-car-t-inflammation-and-cytopenia","Fanning the flames: IFN-γ fuels CAR-T inflammation and cytopenia","","Chimeric antigen receptor T (CAR-T) therapy reshapes treatment of hematologic malignancies but still faces severe inflammatory toxicities and prolonged cytopenias that restrict broader use. In this JCI commentary, the work links IFN-γ-driven inflammation to disrupted neutrophil homeostasis, proposing a shared pathway for cytokine release syndrome and immune cell–associated hematologic toxicity. Using IL-2Ra–deficient mice and patient samples, the study shows IFN-γ suppresses IL-17A and G-CSF, impairing granulopoiesis and neutrophil survival.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/fanning-the-flames-ifn-fuels-car-t-inflammation-and-cytopenia/413886/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/fanning-the-flames-ifn-fuels-car-t-inflammation-and-cytopenia/413886.png","ImageObject",300,407,{"name":92,"@type":93},"Patrick","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-28",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What mechanism connects IFN-γ to CAR-T–related inflammation and blood toxicity?","Question",{"text":112,"@type":113},"IFN-γ–driven inflammation disrupts neutrophil homeostasis, linking cytokine release syndrome and immune cell–associated hematologic toxicity through a shared biological pathway.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does IFN-γ affect neutrophil production and survival in the described study?",{"text":117,"@type":113},"Excess IFN-γ suppresses IL-17A and G-CSF, which reduces granulopoiesis and neutrophil survival, contributing to neutropenia.",{"name":119,"@type":110,"acceptedAnswer":120},"What is the effect of blocking IFN-γ in the CAR-T toxicity model?",{"text":121,"@type":113},"IFN-γ blockade alleviates both CRS and neutropenia without diminishing CAR-T efficacy, suggesting a route toward safer cell therapies.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},413886,1790812990,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":81,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":39,"preview_page_count":4},549758146520,"https://ap-avatar.wpscdn.com/avatar/80002397d8c0411e94?_k=1775819394049821470","The Journal of Clinical Investigation COMMENTARY  \nFanning the flames: IFN-γ fuels CAR-T inflammation and cytopenia  \nStefanie R. Bailey1 and Marcela V. Maus2  \n1Division of Pediatric Hematology/Oncology, Department of Pediatrics, Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA. 2Cellular Immunotherapy Program, Mass General Cancer Center, Krantz Family Center for Cancer Research, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, Masschusetts, USA.  \nChimeric antigen receptor T cell (CAR-T) therapy has transformed the treatment of hematologic malignancies, yet, severe inflammatory toxicities continue to limit its broader use. In this issue of the JCI, Goala et al. uncovered a mechanistic link between IFN-γ–driven inflammation and disrupted neutrophil homeostasis, revealing that cytokine release syndrome (CRS) and immune cell–associated hematologic toxicity (ICAHT) stem from a shared biological pathway. Using IL-2Ra–deficient mice and patient samples, they showed that IFN-γ suppressed IL-17A and granulocyte colony-stimulating factor (G-CSF), disrupting granulopoiesisand neutrophil survival. Strikingly, IFN-γ blockade eased both CRS and neutropenia without diminishing CAR-T efficacy, suggesting a path toward safer, better-tolerated cell therapies.  \nSystemic toxicity and cytopenia arise from CAR-T therapy  \nCAR-T therapy has changed what ispossible for patients with blood cancer, offering durable remissions in otherwise refractory disease. However, cytokine release syndrome (CRS) and immune cell–associated neurotoxicity (ICANS), which are typically managed through IL-6R or IL-1R antagonists, remain prevalent complications, especially in patients with high burdens of disease (1) . In addition, prolonged cytopenias can occur, especially in patients who experienced severe CRS (2) . Prolonged and severe neutropenia increases the risk for infection, extends hospital stays, and accounts for much of the nonrelapse mortality observed after CAR-T infusion (3) . Collectively termed immune cell– associated hematologic toxicity (ICAHT),  \nthese cytopenias frequently appear alongside severe CRS, hinting at shared inflammatory triggers that have remained poorly defined. Prior to the publication of a study by Goala et al. (4) in this issue of the JCI, the biological connection between CRSand bone-marrow suppression has been largely speculative, limited by the absence of immune-competent animal models that replicate both phenomena.  \nAn IL-2Ra–deficient mouse model recapitulates CAR-T toxicities  \nGoala and colleagues fill this experimental gap by leveraging an IL-2Ra–deficient mouse model to recapitulate the dual pathology of CAR-T–mediated CRS and neutropenia (4). The choice of an IL-2Ra–deficient background was strategic, as impaired IL-2 signaling results  \nRelated Article: [https://doi.org/10.1172/JCI194631](https://doi.org/10.1172/JCI194631)  \nConflict of interest: MVM is an inventor on patents related to adoptive cell therapies, held by Massachusetts General Hospital (some licensed to Promab and Luminary) and University of Pennsylvania (some licensed to Novartis)(patent numbers are available in the Supplemental Materials. Supplemental material available online with this article: [https://doi.org/10.1172/JCI201161DS1). MVM receives Grant/Research support from Kite Pharma and Sobi. MVM](https://doi.org/10.1172/JCI201161DS1). MVM receives Grant/Research support from Kite Pharma and Sobi. MVM)[ ](https://doi.org/10.1172/JCI201161DS1). MVM receives Grant/Research support from Kite Pharma and Sobi. MVM)[holds Equity in Model T bio. MVM is a compensated Consultant for A2Bio](holds Equity in Model T bio. MVM is a compensated Consultant for A2Bio), Adaptimmune, Astellas, AstraZeneca, BMS, Cabaletta Bio, In8bio, KSQ, Lumicks.  \nCopyright: © 2026, Bailey et al. This is an open access article published under the terms of the Creative Commons Attrib","cbCaiaosnuxg4PMi","https://ap.wps.com/l/cbCaiaosnuxg4PMi","pdf",559904,"English","# Systemic toxicity and cytopenia arise from CAR-T therapy\n# An IL-2Ra–deficient mouse model recapitulates CAR-T toxicities\n# IFN-γ blockade reduces CAR-T–mediated toxicity and neutropenia","[{\"question\":\"What mechanism connects IFN-γ to CAR-T–related inflammation and blood toxicity?\",\"answer\":\"IFN-γ–driven inflammation disrupts neutrophil homeostasis, linking cytokine release syndrome and immune cell–associated hematologic toxicity through a shared biological pathway.\"},{\"question\":\"How does IFN-γ affect neutrophil production and survival in the described study?\",\"answer\":\"Excess IFN-γ suppresses IL-17A and G-CSF, which reduces granulopoiesis and neutrophil survival, contributing to neutropenia.\"},{\"question\":\"What is the effect of blocking IFN-γ in the CAR-T toxicity model?\",\"answer\":\"IFN-γ blockade alleviates both CRS and neutropenia without diminishing CAR-T efficacy, suggesting a route toward safer cell therapies.\"}]","Fanning the flames: IFN-γ fuels CAR-T inflammation and cytopenia | PDF",1790596092]