tbuckley/cabot-search huggingface dataset:
CD154 blockade effectively controls antibody-mediated rejection in highly sensitized nonhuman primate kidney transplant recipients
Authors: Imran J. Anwar, Isabel DeLaura, Joseph M. Ladowski, Davide Schilirò, Qimeng Gao, Miriam Manook, Janghoon Yoon, Rafaela Belloni, Angela Park, Daniel J. Schuster, Mingqing Song, Lin Lin, Alton B. Farris, Diogo Magnani, Kyha Williams, Jean Kwun, Stuart J. Knechtle
Journal: Science Translational Medicine (2025)

Current desensitization and maintenance immunosuppression regimens for kidney transplantation in sensitized individuals show limited ability to control the posttransplant humoral response, resulting in high rates of antibody-mediated rejection (ABMR) and graft failure. Here, we showed that anti-CD154 monoclonal antibody (mAb)–based immunosuppression more effectively controlled allograft rejection and humoral rebound in a highly sensitized nonhuman primate kidney transplantation model compared with tacrolimus-based standard-of-care (SOC) immunosuppression. Desensitization with an anti-CD154 mAb (5C8) and a proteasome inhibitor led to decreased donor-specific antibodies (DSAs) and disruption of lymph node germinal centers with reduction of proliferating, memory, and class-switched B cells as well as T follicular helper cells. After transplant, the nonhuman primates maintained on 5C8-based immunosuppression had significantly better survival compared with those maintained on SOC immunosuppression (135.2 days versus 32.8 days, P = 0.013). The 5C8-treated group demonstrated better suppression of DSAs after transplant, more robust suppression of B cell populations, and better induction of regulatory T cells. Fewer infectious and welfare complications, including viral reactivation and weight loss, were also observed with 5C8-based immunosuppression compared with SOC immunosuppression. Therefore, anti-CD154 mAbs may improve kidney transplant outcomes through better control of posttransplant immune responses. The superior efficacy of anti-CD154 mAb–based immunosuppression over tacrolimus-based SOC seen in this highly sensitized NHP transplant model suggests that anti-CD154 mAbs could potentially be used to desensitize and treat highly sensitized patients receiving kidney transplantation.
Vaccination with different group 2 influenza subtypes alters epitope targeting and breadth of hemagglutinin stem–specific human B cells
Authors: Grace E. Mantus, Ankita J. Chopde, Jason Gorman, Lauren Y. Cominsky, Amine Ourahmane, Adrian Creanga, Geoffrey D. Shimberg, Rebecca A. Gillespie, David J. Van Wazer, Tongqing Zhou, Suprabhath R. Gajjala, Connor Williams, Emma Maestle, Douglas S. Reed, Leonid Serebryannyy, Pamela Costner, Lasonji Holman, Joseph P. Casazza, Richard A. Koup, Lesia K. Dropulic, Peter D. Kwong, Adrian B. McDermott, Masaru Kanekiyo, Sarah F. Andrews
Journal: Science Translational Medicine (2025)

The conserved influenza hemagglutinin stem, which is a target of cross-neutralizing antibodies, is now used in vaccine strategies focused on protecting against influenza pandemics. Antibody responses to group 1 stem have been extensively characterized, but little is known about group 2. Here, we characterized the stem-specific repertoire of individuals vaccinated with one of three group 2 influenza subtypes (H3, H7, or H10). Epitope mapping revealed two epitope supersites on the group 2 stem. Antibodies targeting the central epitope were broadly cross-reactive, whereas antibodies targeting the lower epitope had narrower breadth but higher potency against H3 subtypes. The ratio of B cells targeting each of the supersites varied with the vaccine subtype, leading to differences in the cross-reactivity of the B cell response. Our findings suggest that vaccine strategies targeting both group 2 stem epitopes would be complementary, eliciting broader and more potent protection against both seasonal and pandemic influenza strains.
Lipidomic profiling of mouse brain and human neuron cultures reveals a role for <i>Mboat7</i> in mTOR-dependent neuronal migration
Authors: Isaac Tang, Ashna Nisal, Alex Reed, Timothy B. Ware, Anide Johansen, Maha S. Zaki, Benjamin F. Cravatt, Joseph G. Gleeson
Journal: Science Translational Medicine (2025)

Mutations in lipid regulator genes are a frequent cause of autism spectrum disorder, including those regulating phosphatidylinositol (PI) and phosphoinositide 3-kinase signaling. MBOAT7 encodes a key acyltransferase in PI synthesis and is mutated in an autism-related condition with neurodevelopmental delay and epilepsy. Using liquid chromatography–tandem mass spectrometry, we analyzed the PI-associated glycerolipidome in mice and humans during neurodevelopment and found dynamic regulation at times corresponding to neural apoptosis in the brains of Mboat7 knockout mice. Mboat7 function was necessary for polyunsaturated lipid synthesis and cortical neural migration, and loss resulted in massive accumulation of the precursor lysophosphatidylinositol and hyperactive mTOR signaling. Inhibiting mTOR signaling rescued migration defects. Our findings demonstrate roles for lipid remodeling during neurodevelopment and implicate lipid regulation in neuronal migration, revealing potential paths to treatment for MBOAT7 deficiency.
Preexisting vaccine-primed heterosubtypic T cell immunity protects the maternal-fetal unit from adverse influenza outcomes in mice
Authors: Valeria Flores Malavet, Kunal Dhume, Ali Satchmei, Andrea C. Arvelo, Aaron J. Beaird, Siva N. Annamalai, Lauren A. Kimball, K. Kai McKinstry, Tara M. Strutt
Journal: Journal of Clinical Investigation (2025)

The risk of severe outcomes of influenza increases during pregnancy. Whether vaccine-induced T cell memory-primed prepregnancy retains the ability to mediate protection during pregnancy, when systemic levels of several hormones with putative immunomodulatory functions are increased, is unknown. Here, using murine adoptive transfer systems and a translationally relevant model of cold-adapted live-attenuated influenza A virus vaccination, we show that preexisting virus-specific memory T cell responses are largely unaltered and highly protective against heterotypic viral challenges during pregnancy. Expression of the transcription factor T-bet, which is upregulated in antiviral T cells responding in pregnant mice, is critical in preventing hormone-associated gain of detrimental T helper type 2 (TH2) attributes reported in other settings. Beyond antiviral effects, preexisting vaccine-primed T cell immunity prevents metabolic dysfunction in gravid dams and adverse neonatal outcomes often associated with maternal influenza infection. These results demonstrate robust protection of the maternal-fetal unit from severe consequences of respiratory virus infection by preexisting T cell immunity.
Mechanisms of postischemic cardiac death and protection following myocardial injury
Authors: Yusuf Mastoor, Elizabeth Murphy, Barbara Roman
Journal: Journal of Clinical Investigation (2025)

Acute myocardial infarction (MI) is a leading cause of death worldwide. Although with current treatment, acute mortality from MI is low, the damage and remodeling associated with MI are responsible for subsequent heart failure. Reducing cell death associated with acute MI would decrease the mortality associated with heart failure. Despite considerable study, the precise mechanism by which ischemia and reperfusion (I/R) trigger cell death is still not fully understood. In this Review, we summarize the changes that occur during I/R injury, with emphasis on those that might initiate cell death, such as calcium overload and oxidative stress. We review cell-death pathways and pathway crosstalk and discuss cardioprotective approaches in order to provide insight into mechanisms that could be targeted with therapeutic interventions. Finally, we review cardioprotective clinical trials, with a focus on possible reasons why they were not successful. Cardioprotection has largely focused on inhibiting a single cell-death pathway or one death-trigger mechanism (calcium or ROS). In treatment of other diseases, such as cancer, the benefit of targeting multiple pathways with a "drug cocktail" approach has been demonstrated. Given the crosstalk between cell-death pathways, targeting multiple cardiac death mechanisms should be considered.
Human intraepithelial mast cell differentiation and effector function are directed by TGF-β signaling
Authors: Tahereh Derakhshan, Eleanor Hollers, Alex Perniss, Tessa Ryan, Alanna McGill, Jonathan Hacker, Regan W Bergmark, Neil Bhattacharyya, Stella E Lee, Alice Z Maxfield, Rachel E Roditi, Lora Bankova, Kathleen M Buchheit, Tanya M Laidlaw, Joshua A Boyce, Daniel F Dwyer
Journal: Journal of Clinical Investigation (2025)

Mast cells (MCs) expressing a distinctive protease phenotype (MCTs) selectively expand within the epithelium of human mucosal tissues during type 2 (T2) inflammation. While MCTs are phenotypically distinct from subepithelial MCs (MCTCs), signals driving human MCT differentiation and this subset's contribution to inflammation remain unexplored. Here, we have identified TGF-β as a key driver of the MCT transcriptome in nasal polyps. We found that short-term TGF-β signaling alters MC cell surface receptor expression and partially recapitulated the in vivo MCT transcriptome, while TGF-β signaling during MC differentiation upregulated a larger number of MCT-associated transcripts. TGF-β inhibited the hallmark MCTC proteases chymase and cathepsin G at both the transcript and protein level, allowing selective in vitro differentiation of MCTs for functional study. We identified discrete differences in effector phenotype between in vitro-derived MCTs and MCTCs, with MCTs exhibiting enhanced proinflammatory lipid mediator generation and a distinct cytokine, chemokine, and growth factor production profile in response to both innate and adaptive stimuli, recapitulating functional features of their tissue-associated counterpart MC subsets. Thus, our findings support a role for TGF-β in promoting human MCT differentiation and identified a discrete contribution of this cell type to T2 inflammation.
ATRX silences Cartpt expression in osteoblastic cells during skeletal development
Authors: Yi-Ting Chen, Ming-Ming Jiang, Carolina Leynes, Mary Adeyeye, Camilla F Majano, Barakat Ibrahim, Urszula Polak, George Hung, Zixue Jin, Denise G Lanza, Lan Liao, Brian Dawson, Yuqing Chen-Evenson, Oscar E Ruiz, Richard J Gibbons, Jason D Heaney, Yangjin Bae, Brendan Lee
Journal: Journal of Clinical Investigation (2025)

ATP-dependent chromatin remodeling protein ATRX is an essential regulator involved in maintenance of DNA structure and chromatin state and regulation of gene expression during development. ATRX was originally identified as the monogenic cause of X-linked α-thalassemia mental retardation (ATR-X) syndrome. Affected individuals display a variety of developmental abnormalities and skeletal deformities. Studies from others investigated the role of ATRX in skeletal development by tissue-specific Atrx knockout. However, the impact of ATRX during early skeletal development has not been examined. Using preosteoblast-specific Atrx conditional knockout mice, we observed increased trabecular bone mass and decreased osteoclast number in bone. In vitro coculture of Atrx conditional knockout bone marrow stromal cells (BMSCs) with WT splenocytes showed impaired osteoclast differentiation. Additionally, Atrx deletion was associated with decreased receptor activator of nuclear factor κ-B ligand (Rankl)/ osteoprotegerin (Opg) expression ratio in BMSCs. Notably, Atrx-deficient osteolineage cells expressed high levels of the neuropeptide cocaine- and amphetamine-regulated transcript prepropeptide (Cartpt). Mechanistically, ATRX suppresses Cartpt transcription by binding to the promoter, which is otherwise poised for Cartpt expression by RUNX2 binding to the distal enhancer. Finally, Cartpt silencing in Atrx conditional knockout BMSCs rescued the molecular phenotype by increasing the Rankl/Opg expression ratio. Together, our data show a potent repressor function of ATRX in restricting Cartpt expression during skeletal development.
Type 2 immunity to the rescue: enhancing antitumor immunity for skin cancer prevention
Authors: Matthew D Vesely, Sean R Christensen
Journal: Journal of Clinical Investigation (2025)

Cutaneous squamous cell carcinoma (cSCC) incidence and deaths continue to rise, underscoring the need for improved cSCC prevention. Elimination of actinic keratosis (AK) precursor lesions is a major strategy to prevent cSCC. Topical calcipotriol and 5-fluorouracil (5-FU) have been shown to eliminate AKs and reduce the risk of cSCC development, but the mechanism was undefined. In this issue of the JCI, Oka et al. demonstrate that type 2 immunity is necessary and sufficient for the elimination of premalignant keratinocytes and cSCC prevention. Paired biopsies from AK lesions and unaffected skin revealed that only keratinocytes from AKs produced thymic stromal lymphopoietin (TSLP) and damage-associated molecular patterns, resulting in selective recruitment of Th2 cells to the AK lesion. In mouse models of skin carcinogenesis, TSLP was necessary to recruit Th2 cells and trigger IL-24-mediated keratinocyte cell death. These findings suggest that the TSLP/Th2/IL-24 axis is a potential therapeutic target for SCC prevention.
Neonatal T cells unleash innate powers to combat congenital cytomegalovirus infection
Authors: Simon Grassmann
Journal: Journal of Clinical Investigation (2025)

Approximately 1 in 200 newborns worldwide are affected by congenital cytomegalovirus (CMV). Most of these cases are asymptomatic due to successful control of the infection by the newborn's immune system. In this issue of the JCI, Semmes et al. characterized the cellular immune response in cord blood of neonates with CMV infection. The authors found that conventional T cells with NK-like features expanded during congenital CMV infection. To exert their antiviral function, these cells relied on Fc receptors, recognizing virus-infected cells bound by IgG. Thereby, the fetal and maternal immune system can optimally cooperate to control CMV infection: maternal IgG crossing the placenta opsonizes virus-infected cells subsequently lysed by neonatal NK-like T cells. This finding suggests that innate-like programming of conventional T cells may have evolved to combat congenital CMV infection, offering insights that could inform the development of future therapies.
Clonal hematopoiesis JAKs up plaque formation
Authors: Koral Campbell, Qing Li
Journal: Journal of Clinical Investigation (2025)

Clonal hematopoiesis (CH) is a condition in which hematopoietic stem cells (HSCs) acquire mutations seen in leukemia. While individuals with CH generally do not show signs of hematologic disease, the condition becomes more common with age and correlates with age-related diseases, especially cardiovascular disease (CVD). JAK2 mutations in HSCs can lead to CH and correlate with atherosclerosis, but the condition has been difficult to study because of challenges modeling the mutant cells at very low frequency. In this issue of the JCI, Liu et al. developed a low-allele-burden (LAB) mouse model in which a small number of bone marrow cells carrying the Jak2VF mutation were transplanted into mice predisposed to hyperlipidemia. Along with recapitulating features of plaque development, the authors identified the phagocytic receptors MERTK and TREM2 in WT cells as downstream of the inflammatory cytokine IL-1. These findings provide potential targets for preventing or treating patients at risk for CH-associated CVD.
A vaccine against cytomegalovirus: how close are we?
Authors: Sallie R Permar, Mark R Schleiss, Stanley A Plotkin
Journal: Journal of Clinical Investigation (2025)

The pursuit of a vaccine against the human cytomegalovirus (HCMV) has been ongoing for more than 50 years. HCMV is the leading infectious cause of birth defects, including damage to the brain, and is a common cause of complications in organ transplantation. The complex biology of HCMV has made vaccine development difficult, but a recent meeting sponsored by the National Institute of Allergy and Infectious Diseases in September of 2023 brought together experts from academia, industry, and federal agencies to discuss progress in the field. The meeting reviewed the status of candidate HCMV vaccines under study and the challenges in clinical trial design in demonstrating efficacy against congenital CMV infection or the reduction of HCMV disease following solid organ transplantation or hematopoietic stem cell transplantation. Discussion in the meeting revealed that, with the numerous candidate vaccines that are under study, it is clear that a safe and effective HCMV vaccine is within reach. Meeting attendees achieved a consensus opinion that even a partially effective vaccine would have a major effect on the global health consequences of HCMV infection.
TGF-β drives differentiation of intraepithelial mast cells in inflamed airway mucosa
Authors: Axel Roers
Journal: Journal of Clinical Investigation (2025)

Similarly to acute intestinal helminth infection, several conditions of chronic eosinophilic type 2 inflammation of mucosal surfaces, including asthma and eosinophilic esophagitis, feature robust expansions of intraepithelial mast cells (MCs). Also the hyperplastic mucosa of nasal polyposis in the context of chronic rhinosinusitis, with or without COX1 inhibitor intolerance, contains impressive numbers of intraepithelial MCs. In this issue of the JCI, Derakhshan et al. elucidate the heterogeneity of MCs in nasal polyposis and identify a transcriptional signature of TGF-β target genes expressed by the intraepithelial MC population. These MCs displayed effector functions that implicate them as pathogenetic contributors. TGF-β directed differentiation of similar MC populations also in vitro. These findings extend the emerging concept of TGF-β as a driver of type 2 inflammation at barrier surfaces.
T helper 2 cell–directed immunotherapy eliminates precancerous skin lesions
Authors: Tomonori Oka, Sabrina S Smith, Heehwa G Son, Truelian Lee, Valeria S Oliver-Garcia, Mahsa Mortaja, Kathryn E Trerice, Lily S Isakoff, Danielle N Conrad, Marjan Azin, Neel S Raval, Mary Tabacchi, Luni Emdad, Swadesh K Das, Paul B Fisher, Lynn A Cornelius, Shadmehr Demehri
Journal: Journal of Clinical Investigation (2025)

The continuous rise in skin cancer incidence highlights an imperative for improved skin cancer prevention. Topical calcipotriol-plus-5-fluorouracil (calcipotriol-plus-5-FU) immunotherapy effectively eliminates precancerous skin lesions and prevents squamous cell carcinoma (SCC) in patients. However, its mechanism of action remains unclear. Herein, we demonstrate that calcipotriol-plus-5-FU immunotherapy induces T helper type 2 (Th2) immunity, eliminating premalignant keratinocytes in humans. CD4+ Th2 cells were required and were sufficient downstream of thymic stromal lymphopoietin cytokine induction by calcipotriol to suppress skin cancer development. Th2-associated cytokines induced IL-24 expression in cancer cells, resulting in toxic autophagy and anoikis followed by apoptosis. Calcipotriol-plus-5-FU immunotherapy was dependent on IL-24 to suppress skin carcinogenesis in vivo. Collectively, our findings establish a critical role for Th2 immunity in cancer immunoprevention and highlight the Th2/IL-24 axis as an innovative target for skin cancer prevention and therapy.
A single-cell compendium of human cerebrospinal fluid identifies disease-associated immune cell populations
Authors: Claudia Cantoni, Roman A Smirnov, Maria Firulyova, Prabhakar S Andhey, Tara R Bradstreet, Ekaterina Esaulova, Marina Terekhova, Elizabeth A Schwarzkopf, Nada M Abdalla, Maksim Kleverov, Joseph J Sabatino, Kang Liu, Nicholas Schwab, Gerd Meyer Zu Hörste, Anne H Cross, Maxim N Artyomov, Brian T Edelson, Gregory F Wu
Journal: Journal of Clinical Investigation (2025)

Single-cell transcriptomics applied to cerebrospinal fluid (CSF) for elucidating the pathophysiology of neurologic diseases has produced only a preliminary characterization of CSF immune cells. CSF derives from and borders central nervous system (CNS) tissue, allowing for comprehensive accounting of cell types along with their relative abundance and immunologic profiles relevant to CNS diseases. Using integration techniques applied to publicly available datasets in combination with our own studies, we generated a compendium with 139 subjects encompassing 135 CSF and 58 blood samples. Healthy subjects and individuals across a wide range of diseases, such as multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease, COVID-19, and autoimmune encephalitis, were included. We found differences in lymphocyte and myeloid subset frequencies across different diseases as well as in their distribution between blood and CSF. We identified what we believe to be a new subset of AREG+ dendritic cells exclusive to the CSF that was more abundant in subjects with MS compared with healthy controls. Finally, transcriptional cell states in CSF microglia-like cells and lymphoid subsets were elucidated. Altogether, we have created a reference compendium for single-cell transcriptional profiling encompassing CSF immune cells useful to the scientific community for future studies on neurologic diseases.
Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium
Authors: James P Bridges, Eszter K Vladar, Jonathan S Kurche, Andrei Krivoi, Ian T Stancil, Evgenia Dobrinskikh, Yan Hu, Sarah K Sasse, Joyce S Lee, Rachel Z Blumhagen, Ivana V Yang, Anthony N Gerber, Anna L Peljto, Christopher M Evans, Elizabeth F Redente, David Wh Riches, David A Schwartz
Journal: Journal of Clinical Investigation (2025)

Idiopathic pulmonary fibrosis (IPF) is etiologically complex, with well-documented genetic and nongenetic origins. In this Review, we speculate that the development of IPF requires two hits: the first establishes a vulnerable bronchoalveolar epithelium, and the second triggers mechanisms that reprogram distal epithelia to initiate and perpetuate a profibrotic phenotype. While vulnerability of the bronchoalveolar epithelia is most often driven by common or rare genetic variants, subsequent injury of the bronchoalveolar epithelia results in persistent changes in cell biology that disrupt tissue homeostasis and activate fibroblasts. The dynamic biology of IPF can best be contextualized etiologically and temporally, including stages of vulnerability, early disease, and persistent and progressive lung fibrosis. These dimensions of IPF highlight critical mechanisms that adversely disrupt epithelial function, activate fibroblasts, and lead to lung remodeling. Together with better recognition of early disease, this conceptual approach should lead to the development of novel therapeutics directed at the etiologic and temporal drivers of lung fibrosis that will ultimately transform the care of patients with IPF from palliative to curative.