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Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in infants, the immunocompromised, and the elderly. RSV infects the airway epithelium via the apical membrane and almost exclusively sheds progeny virions back into the airway mucus (AM), making RSV difficult to target by systemically administered therapies. An inhalable "muco-trapping" variant of motavizumab (Mota-MT), a potent neutralizing mAb against RSV F is engineered. Mota-MT traps RSV in AM via polyvalent Fc-mucin bonds, reducing the fraction of fast-moving RSV particles in both fresh pediatric and adult AM by ≈20-30-fold in a Fc-glycan dependent manner, and facilitates clearance from the airways of mice within minutes. Intranasal dosing of Mota-MT eliminated viral load in cotton rats within 2 days. Daily nebulized delivery of Mota-MT to RSV-infected neonatal lambs, beginning 3 days after infection when viral load is at its maximum, led to a 10 000-fold and 100 000-fold reduction in viral load in bronchoalveolar lavage and lung tissues relative to placebo control, respectively. Mota-MT-treated lambs exhibited reduced bronchiolitis, neutrophil infiltration, and airway remodeling than lambs receiving placebo or intramuscular palivizumab. The findings underscore inhaled delivery of muco-trapping mAbs as a promising strategy for the treatment of RSV and other acute respiratory infections., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Objective: Liver metastases are often resistant to immune checkpoint inhibitor therapy (ICI) and portend a worse prognosis compared with metastases to other locations. Regulatory T cells (Tregs) are one of several immunosuppressive cells implicated in ICI resistance of liver tumours, but the role played by Tregs residing within the liver surrounding a tumour is unknown., Design: Flow cytometry and single-cell RNA sequencing were used to characterise hepatic Tregs before and after ICI therapy., Results: We found that the murine liver houses a Treg population that, unlike those found in other organs, is both highly proliferative and apoptotic at baseline. On administration of αPD-1, αPD-L1 or αCTLA4, the liver Treg population doubled regardless of the presence of an intrahepatic tumour. Remarkably, this change was not due to the preferential expansion of the subpopulation of Tregs that express PD-1. Instead, a subpopulation of CD29 + ( Itgb1 , integrin β1) Tregs, that were highly proliferative at baseline, doubled its size in response to αPD-1. Partial and full depletion of Tregs identified CD29 + Tregs as the prominent niche-filling subpopulation in the liver, and CD29 + Tregs demonstrated enhanced suppression in vitro when derived from the liver but not the spleen. We identified IL2 as a critical modulator of both CD29 + and CD29 - hepatic Tregs, but expansion of the liver Treg population with αPD-1 driven by CD29 + Tregs was in part IL2-independent., Conclusion: We propose that CD29 + Tregs constitute a unique subpopulation of hepatic Tregs that are primed to respond to ICI agents and mediate resistance., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The presentation of eosinophilic esophagitis (EoE) is heterogeneous, but trends over time are not known., Aim: To determine whether clinical and endoscopic phenotypes at EoE diagnosis have changed over the past 2 decades., Methods: In this retrospective cohort study, adults and children with newly diagnosed EoE were phenotyped as follows: (1) inflammatory vs fibrostenotic vs mixed on endoscopy; (2) atopic vs non-atopic; (3) age at symptom onset; (4) age at diagnosis; (5) presence of autoimmune or connective tissue disease; and (6) responsive to steroids. The prevalence of different phenotypes was categorized by 5-year intervals. Multivariate analysis was performed to assess for changes in patient features over time., Results: Of 1187 EoE patients, age at diagnosis increased over time (from 22.0 years in 2002-2006 to 31.8 years in 2017-2021; p < 0.001) as did the frequency of dysphagia (67% to 92%; p < 0.001). Endoscopic phenotypes were increasingly mixed (26% vs 68%; p < 0.001) and an increasing proportion of patients had later onset of EoE. However, there were no significant trends for concomitant autoimmune/connective tissue disease or steroid responder phenotypes. On multivariate analysis, after accounting for age, dysphagia, and food impaction, the increase in the mixed endoscopic phenotype persisted (aOR 1.51 per each 5-year interval, 95% CI 1.31-1.73)., Conclusion: EoE phenotypes have changed over the past two decades, with increasing age at diagnosis and age at symptom onset. The mixed endoscopic phenotype also increased, even after controlling for age and symptomatology. Whether this reflects changes in provider recognition or disease pathophysiology is yet to be elucidated., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Feeding tubes can provide a temporary or long-term solution for nutritional therapy. Little is known regarding the use of feeding tubes in patients with eosinophilic esophagitis (EoE). We sought to describe the characteristics and outcomes in EoE patients requiring tube feeding., Methods: This was a retrospective cohort study of EoE patients at a large tertiary care health system. Demographics, clinical characteristics, and endoscopic findings were extracted from medical records, and patients who had a feeding tube were identified. Patients with and without a feeding tube were compared. Details about the tube, complications, and treatment were extracted. Growth, global symptomatic, endoscopic, and histopathologic (<15 eos/hpf) responses were compared before and after the initiation of feeding tube therapy., Results: We identified 39 of 1216 EoE patients who had a feeding tube (3%). Feeding tube patients were younger (mean age 6.3 years), reported more vomiting, and had a lower total endoscopic reference score than non-feeding tube patients ( P < 0.01 for all). Tubes were used for therapy for an average of 6.8 years, with most patients (95%) receiving both pharmacologic and formula treatment for EoE. An emergency department visit for a tube complication was required in 26%. Tube feeding improved body mass index z score ( P < 0.01), symptomatic response (42%), endoscopic response (53%), and histologic response (71%)., Conclusions: Among EoE patients, only a small subset required a feeding tube and predominantly were young children with failure to thrive. Feeding tubes significantly improved growth and, when used in combination with other treatments, led to reduced esophageal eosinophilic inflammation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

The gut microbiome is an important modulator of the host immune system. In this study, we found that altering the gut microbiome by oral vancomycin increases liver invariant NKT (iNKT) cell function. Enhanced iNKT cytokine production and activation marker expression were observed in vancomycin-treated mice following both Ag-specific and Ag-independent in vivo iNKT stimulations, with a more prominent effect in the liver than in the spleen. Fecal transplantation studies demonstrated that the iNKT functional regulation is mediated by altering the gut microbiome but uncoupled from the modulation of iNKT cell population size. Interestingly, when stimulated in vitro, iNKT cells from vancomycin-treated mice did not show increased activation, suggesting an indirect regulation. iNKT cells expressed high levels of IL-18 receptor, and vancomycin increased the expression of IL-18 in the liver. Blocking IL-18 by neutralizing Ab or using genetically deficient mice attenuated the enhanced iNKT activation. Liver macrophages were identified as a major source of IL-18. General macrophage depletion by clodronate abolished this iNKT activation. Using anti-CSF-1R depletion or LyzCrexCSF-1RLsL-DTR mice identified CSF-1R+ macrophages as a critical modulator of iNKT function. Vancomycin treatment had no effect on iNKT cell function in vivo in IL-18 knockout macrophage reconstituted mice. Together, our results demonstrate that the gut microbiome controls liver iNKT function via regulating CSF-1R+ macrophages to produce IL-18.

Platelets, the often-overlooked component of the immune system, have been shown to promote tumor growth. Non-alcoholic fatty liver disease (NAFLD) is a common disease in the Western world and rising risk for hepatocellular carcinoma (HCC). Unexpectedly, we observed that platelets can inhibit the growth of established HCC in NAFLD mice. Through pharmacological inhibition and genetic depletion of P2Y12 as well as in vivo transfusion of wild-type (WT) or CD40L -/- platelets, we demonstrate that the anti-tumor function of platelets is mediated through P2Y12-dependent CD40L release, which leads to CD8 + T cell activation by the CD40 receptor. Unlike P2Y12 inhibition, blocking platelets with aspirin does not prevent platelet CD40L release nor accelerate HCC in NAFLD mice. Similar findings were observed in liver metastasis models. All together, our study reveals a complex role of platelets in tumor regulation. Anti-platelet treatment without inhibiting CD40L release could be considered for liver cancer patients with NAFLD., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)