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A letter to the editor is presented that investigates the expansion of CD56bright natural killer (NK) cells in relation to anti-CD25 monoclonal antibodies (mAb).

Indigo naturalis (IN) is a natural product extensively used as a traditional Chinese medicine due to its pharmacological properties. While IN has been proposed to exert its activity, at least partly, via the aryl hydrocarbon receptor (AhR), the pharmacokinetics of its known indole alkaloid AhR ligands and their relative contributions to the net AhR agonistic activity in blood is unknown. We conducted an open-label, placebo-controlled, dose-escalation study (0.25-2.0 g) of orally-administered IN in healthy individuals. Blood samples obtained prior and up to 24 h after ingestion were analysed for net AhR activity and pharmacokinetics of circulating IN-derived AhR ligands determined by HPLC-ESI-MS/MS. Oral administration of IN dose-dependently increased net plasma AhR agonistic activity - initially through the early appearance of tryptanthrin, and later sustained by the more potent AhR agonist indirubin. This first pharmacokinetic study of IN-derived indole alkaloids in humans indicates that the increase in systemic AhR agonistic activity is the result of sequential appearance in blood of highly bioavailable / moderately agonistic (tryptanthrin) and moderately bioavailable / highly agonistic (indirubin and indigo) AhR ligands, challenging the commonly held belief that only highly agonistic indole alkaloids contribute to AhR agonism and therapeutic activity of IN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

The year 2024 was rich in developments in the field of hepatology, gastroenterology, and interventional endoscopy. New molecules have been developed for the treatment of metabolic steatohepatitis, primary biliary cirrhosis, and inflammatory bowel diseases. Technological progress now makes it possible to perform screening measurements for portal hypertension directly under echo-endoscopic guidance and to extend the use of intraluminal stents to surgically modified anatomies. Several new recommendations have also been issued, including some for the nutritional management of inflammatory diseases, the management of polypoid lesions, and intraductal papillary mucinous neoplasms., Competing Interests: Le Dr D. Galasso figure parmi les auteurs de l’article no. 27 de la bibliographie. Les autres auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Infecting humans with controlled doses of small intestinal helminths, such as human hookworm, is proposed as a therapy for the colonic inflammatory disease ulcerative colitis. Strengthening the colonic mucus barrier is a potential mechanism by which small intestinal helminths could treat ulcerative colitis. In this study, we compare C57BL/6 mice infected with the small intestinal helminth Heligmosomoides polygyrus and uninfected controls to investigate changes in colonic mucus. Histology, gene expression, and immunofluorescent analysis demonstrate that this helminth induces goblet cell hyperplasia, and an upregulation of mucin sialylation, and goblet-cell-derived functional proteins resistin-like molecule-beta (RELM-β) and trefoil factors (TFFs), in the colon. Using IL-13 knockout mice, we reveal that these changes are predominantly IL-13-dependent. The assessment of the colonic mucus microbiome demonstrates that H. polygyrus infection increases the abundance of Ruminococcus gnavus , a commensal bacterium capable of utilising sialic acid as an energy source. This study also investigates a human cohort experimentally challenged with human hookworm. It demonstrates that TFF blood levels increase in individuals chronically infected with small intestinal helminths, highlighting a conserved mucus response between humans and mice. Overall, small intestinal helminths modify colonic mucus, highlighting this as a plausible mechanism by which human hookworm therapy could treat ulcerative colitis.

Background: The introduction of complementary foods during the first year of life influences the diversity of the gut microbiome. How this diversity affects immune development and health is unclear., Objective: This study evaluates the effect of consuming kūmara or kūmara with added banana powder (resistant starch) compared to a reference control at 4 months post randomization on the prevalence of respiratory tract infections and the development of the gut microbiome., Methods: This study is a double-blind, randomized controlled trial of mothers and their 6-month-old infants (up to n=300) who have not yet started solids. Infants are randomized into one of 3 groups: control arm (C), standard kūmara intervention (K), and a kūmara intervention with added banana powder product (K+) to be consumed daily for 4 months until the infant is approximately 10 months old. Infants are matched for sex using stratified randomization. Data are collected at baseline (prior to commencing solid food) and at 2 and 4 months after commencing solid food (at around 8 and 10 months of age). Data and samples collected at each timepoint include weight and length, intervention adherence (months 2 and 4), illness and medication history, dietary intake (months 2 and 4), sleep (diary and actigraphy), maternal dietary intake, breast milk, feces (baseline and 4 months), and blood samples (baseline and 4 months)., Results: The trial was approved by the Health and Disability Ethics Committee of the Ministry of Health, New Zealand (reference 20/NTA/9). Recruitment and data collection did not commence until January 2022 due to the COVID-19 pandemic. Data collection and analyses are expected to conclude in January 2024 and early 2025, respectively. Results are to be published in 2024 and 2025., Conclusions: The results of this study will help us understand how the introduction of a specific prebiotic complementary food affects the microbiota and relative abundances of the microbial species, the modulation of immune development, and infant health. It will contribute to the expanding body of research that aims to deepen our understanding of the connections between nutrition, gut microbiota, and early-life postnatal health., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12620000026921; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378654., International Registered Report Identifier (irrid): DERR1-10.2196/56772., (©Clare R Wall, Nicole C Roy, Jane A Mullaney, Warren Charles McNabb, Olivier Gasser, Karl Fraser, Eric Altermann, Wayne Young, Janine Cooney, Robyn Lawrence, Yannan Jiang, Barbara C Galland, Xiaoxi Fu, Jacqueline N Tonkie, Nisha Mahawar, Amy Luisa Lovell. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 02.09.2024.)

Background: Human hookworm has been proposed as a treatment for ulcerative colitis (UC). This pilot study assessed the feasibility of a full-scale randomized control trial examining hookworm to maintain clinical remission in patients with UC., Methods: Twenty patients with UC in disease remission (Simple Clinical Colitis Activity Index [SCCAI] ≤4 and fecal calprotectin (fCal) <100 ug/g) and only on 5-aminosalicylate received 30 hookworm larvae or placebo. Participants stopped 5-aminosalicylate after 12 weeks. Participants were monitored for up to 52 weeks and exited the study if they had a UC flare (SCCAI ≥5 and fCal ≥200 µg/g). The primary outcome was difference in rates of clinical remission at week 52. Differences were assessed for quality of life (QoL) and feasibility aspects including recruitment, safety, effectiveness of blinding, and viability of the hookworm infection., Results: At 52 weeks, 4 of 10 (40%) participants in the hookworm group and 5 of 10 (50%) participants in the placebo group had maintained clinical remission (odds ratio, 0.67; 95% CI, 0.11-3.92). Median time to flare in the hookworm group was 231 days (interquartile range [IQR], 98-365) and 259 days for placebo (IQR, 132-365). Blinding was quite successful in the placebo group (Bang's blinding index 0.22; 95% CI, -0.21 to 1) but less successful in the hookworm group (0.70; 95% CI, 0.37-1.0). Almost all participants in the hookworm group had detectable eggs in their faeces (90%; 95% CI, 0.60-0.98), and all participants in this group developed eosinophilia (peak eosinophilia 4.35 × 10^9/L; IQR, 2.80-6.68). Adverse events experienced were generally mild, and there was no significant difference in QoL., Conclusions: A full-scale randomized control trial examining hookworm therapy as a maintenance treatment in patients with UC appears feasible., (© 2023 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Infecting humans with controlled doses of helminths, such as human hookworm (termed hookworm therapy), is proposed to prevent or treat various intestinal and extraintestinal diseases. However, full-scale clinical trials examining hookworm therapy are limited by the inability to scale-up the production of hookworm larvae to infect sufficient numbers of patients. With the aim of overcoming this challenge, this study infected four healthy individuals with hookworm larvae that had been reanimated from cryopreserved eggs to examine their viability and immunogenicity. We demonstrate that reanimated cryopreserved hookworm larvae establish a viable hookworm infection and elicit a similar immune response to larvae cultured from fresh stool. Furthermore, a refined understanding of the therapeutic mechanisms of hookworm is imperative to determine which diseases to target with hookworm therapy. To investigate potential therapeutic mechanisms, this study assessed changes in the immune cells, microbiome, and plasma metabolome in the four healthy individuals infected with cryopreserved hookworm larvae and another nine individuals infected with larvae cultured from freshly obtained stool. We identified potential immunoregulatory mechanisms by which hookworm may provide a beneficial effect on its host, including increased expression of CTLA-4 on regulatory T cells (Tregs) and upregulation of tryptophan metabolism. Furthermore, we found that a participant's baseline microbiome predicted the severity of symptoms and intestinal inflammation experienced during a controlled hookworm infection. In summary, our findings demonstrate the feasibility of full-scale clinical trials examining hookworm therapy by minimizing the reliance on human donors and optimizing the culturing process, thereby enabling viable hookworm larvae to be mass-produced and enabling on-demand inoculation of patients. Furthermore, this study provides insights into the complex interactions between helminths and their host, which could inform the development of novel therapeutic strategies.

Diets high in fruit and vegetables are perceived to be beneficial for intestinal homeostasis, in health as well as in the context of inflammatory bowel diseases (IBDs). Recent breakthroughs in the field of immunology have highlighted the importance of the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) as a critical regulator of mucosal immunity, including the intestinal trafficking of CD4+ helper T cells, an immune cell subset implicated in a wide range of homeostatic and pathogenic processes. Specifically, the AhR has been shown to directly regulate the expression of the chemoattractant receptor G Protein-Coupled Receptor 15 (GPR15) on CD4+ T cells. GPR15 is an important gut homing marker whose expression on CD4+ T cells in the peripheral circulation is elevated in patients suffering from ulcerative colitis, raising the possibility that, in this setting, the beneficial effect of a diet rich in fruits and vegetables may be mediated through the modulation of GPR15 expression. To address this, we screened physiologically-relevant polyphenol and glucosinolate metabolites for their ability to affect both AhR activity and GPR15 expression. Our complementary approach and associated findings suggest that polyphenol and glucosinolate metabolites can regulate GPR15 expression on human CD4+ T cells in an AhR-dependent manner., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: We have previously reported that polyfunctional T cell responses can be induced to the cancer testis antigen NY-ESO-1 in melanoma patients injected with mature autologous monocyte-derived dendritic cells (DCs) loaded with long NY-ESO-1-derived peptides together with α-galactosylceramide (α-GalCer), an agonist for type 1 Natural Killer T (NKT) cells., Objective: To assess whether inclusion of α-GalCer in autologous NY-ESO-1 long peptide-pulsed DC vaccines (DCV + α-GalCer) improves T cell responses when compared to peptide-pulsed DC vaccines without α-GalCer (DCV)., Design, Setting and Participants: Single-centre blinded randomised controlled trial in patients ≥ 18 years old with histologically confirmed, fully resected stage II-IV malignant cutaneous melanoma, conducted between July 2015 and June 2018 at the Wellington Blood and Cancer Centre of the Capital and Coast District Health Board., Interventions: Stage I. Patients were randomised to two cycles of DCV or DCV + α-GalCer (intravenous dose of 10 × 10 6 cells, interval of 28 days). Stage II. Patients assigned to DCV + α-GalCer were randomised to two further cycles of DCV + α-GalCer or observation, while patients initially assigned to DCV crossed over to two cycles of DCV + α-GalCer., Outcome Measures: Primary: Area under the curve (AUC) of mean NY-ESO-1-specific T cell count detected by ex vivo IFN-γ ELISpot in pre- and post-treatment blood samples, compared between treatment arms at Stage I. Secondary: Proportion of responders in each arm at Stage I; NKT cell count in each arm at Stage I; serum cytokine levels at Stage I; adverse events Stage I; T cell count for DCV + α-GalCer versus observation at Stage II, T cell count before versus after cross-over., Results: Thirty-eight patients gave written informed consent; 5 were excluded before randomisation due to progressive disease or incomplete leukapheresis, 17 were assigned to DCV, and 16 to DCV + α-GalCer. The vaccines were well tolerated and associated with increases in mean total T cell count, predominantly CD4 + T cells, but the difference between the treatment arms was not statistically significant (difference - 6.85, 95% confidence interval, - 21.65 to 7.92; P = 0.36). No significant improvements in T cell response were associated with DCV + α-GalCer with increased dosing, or in the cross-over. However, the NKT cell response to α-GalCer-loaded vaccines was limited compared to previous studies, with mean circulating NKT cell levels not significantly increased in the DCV + α-GalCer arm and no significant differences in cytokine response between the treatment arms., Conclusions: A high population coverage of NY-ESO-1-specific T cell responses was achieved with a good safety profile, but we failed to demonstrate that loading with α-GalCer provided an additional advantage to the T cell response with this cellular vaccine design., Clinical Trial Registration: ACTRN12612001101875. Funded by the Health Research Council of New Zealand., (© 2023. The Author(s).)

Endometrial cancer is rising in prevalence. The standard treatment modality of hysterectomy is becoming increasingly inadequate due primarily to the direct link between endometrial cancer and high BMI which increases surgical risks. This is an immunogenic cancer, with unique molecular subtypes associated with differential immune infiltration. Despite the immunogenicity of endometrial cancer, there is limited pre-clinical and clinical evidence of the function of immune cells in both the normal and cancerous endometrium. Immune checkpoint inhibitors for endometrial cancer are the most well studied type of immune therapy but these are not currently used as standard-of-care and importantly, they represent only one method of immune manipulation. There is limited evidence regarding the use of other immunotherapies as surgical adjuvants or alternatives. Levonorgestrel-loaded intra-uterine systems can also be effective for early-stage disease, but with varying success. There is currently no known reason as to what predisposes some patients to respond while others do not. As hormones can directly influence immune cell function, it is worth investigating the immune compartment in this context. This review assesses the immunological components of the endometrium and describes how the immune microenvironment changes with hormones, obesity, and in progression to malignancy. It also describes the importance of investigating novel pathways for immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 van der Woude, Hally, Currie, Gasser and Henry.)

The fortification of flour with folic acid for the prevention of neural tube defects (NTD) is currently mandated in over eighty countries worldwide, hence compelling its consumption by the greater part of the world's population. Notwithstanding its beneficial impact on rates of NTD, pervasive folic acid supplementation has invariably led to additive daily intakes reaching well beyond their original target, resulting in the circulation of unmetabolized folic acid. Associated idiopathic side-effects ranging from allergies to cancer have been suggested, albeit inconclusively. Herein, we hypothesize that their inconsistent detection and elusive etiology are linked to the in vivo generation of the immunosuppressive folic acid metabolite 6-formylpterin, which interferes with the still emerging and varied functions of Major Histocompatibility Complex-related molecule 1 (MR1)-restricted T cells. Accordingly, we predict that fortification-related adverse health outcomes can be eliminated by substituting folic acid with the bioequivalent folate vitamer 5-methyltetrahydrofolate, which does not break down into 6-formylpterin., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tang, Cait, White, Arabshahi, O’Sullivan and Gasser.)

During an event, the organizer is responsible for ensuring compliance with all standards, including in the medical and health field. It is therefore up to them to set up a display capable of handling potential patients. The planning of this display requires a preliminary risk assessment, including an estimate of the probability of occurrence and the potential severity in the event of occurrence. There are few decision-making tools available to plan such a device; the impact of major events, particularly on the surrounding care structures, or the sizing of such devices remains a poorly studied field. This article provides an update on recommendations and trends in this area, illustrated by the experience of the 2019 Fête des Vignerons., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article. Les résultats présentés dans cet article sont tirés du travail de Master en médecine de Mme O. Gasser ;18 travail qui a fait l’objet d’une autorisation de la Commission d’éthique de la recherche du Canton de Vaud (CER-VD) et de l’État-major cantonal de conduite (EMCC).

Background: The introduction of complementary foods and changes in milk feeding result in modifications to gastrointestinal function. The interplay between indigestible carbohydrates, host physiology, and microbiome, and immune system development are areas of intense research relevant to early and later-life health., Methods: This 6-month prospective non-randomised feasibility study was conducted in Auckland, New Zealand (NZ), in January 2018. Forty parents/caregivers and their infants were enrolled, with 30 infants allocated to receive a prebiotic NZ kūmara (flesh and skin; a type of sweet potato) prepared as a freeze-dried powder, and ten infants allocated to receive a commercially available probiotic control known to show relevant immune benefits (10 9 CFU Bifidobacterium lactis BB-12®). The primary outcome was the study feasibility measures which are reported here., Results: Recruitment, participant retention, and data collection met feasibility targets. Some limitations to biological sample collection were encountered, with difficulties in obtaining sufficient plasma sample volumes for the proposed immune parameter analyses. Acceptability of the kūmara powder was met with no reported adverse events., Conclusion: This study indicates that recruiting infants before introducing complementary foods is feasible, with acceptable adherence to the food-based intervention. These results will inform the protocol of a full-scale randomised controlled trial (RCT) with adjustments to the collection of biological samples to examine the effect of a prebiotic food on the prevalence of respiratory tract infections during infancy. Trial registration Australia New Zealand Clinical Trials Registry ACTRN12618000157279 . Prospectively registered on 02/01/2018., (© 2022. The Author(s).)

Influenza vaccination is an effective public health measure to reduce the risk of influenza illness, particularly when the vaccine is well matched to circulating strains. Notwithstanding, the efficacy of influenza vaccination varies greatly among vaccinees due to largely unknown immunological determinants, thereby dampening population-wide protection. Here, we report that dietary fibre may play a significant role in humoral vaccine responses. We found dietary fibre intake and the abundance of fibre-fermenting intestinal bacteria to be positively correlated with humoral influenza vaccine-specific immune responses in human vaccinees, albeit without reaching statistical significance. Importantly, this correlation was largely driven by first-time vaccinees; prior influenza vaccination negatively correlated with vaccine immunogenicity. In support of these observations, dietary fibre consumption significantly enhanced humoral influenza vaccine responses in mice, where the effect was mechanistically linked to short-chain fatty acids, the bacterial fermentation product of dietary fibre. Overall, these findings may bear significant importance for emerging infectious agents, such as COVID-19, and associated de novo vaccinations., Competing Interests: SE and GW were employed by Food Savvy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2021 Cait, Mooney, Poyntz, Shortt, Jones, Gestin, Gell, Grooby, O’Sullivan, Tang, Young, Thayabaran, Sparks, Ostapowicz, Tay, Poppitt, Elliott, Wakefield, Parry-Strong, Ralston, Beasley, Weatherall, Braithwaite, Forbes-Blom and Gasser.)

Background: Mucosal-associated invariant T (MAIT) cells are unconventional T cells which recognize microbial metabolites presented by the major histocompatibility complex class I-related molecule MR1. Although MAIT cells have been shown to reside in human and murine skin, their contribution to atopic dermatitis (AD), an inflammatory skin disease associated with barrier dysfunction and microbial translocation, has not yet been determined., Methods: Genetic deletion of MR1 and topical treatment with inhibitory MR1 ligands, which result in the absence and functional inhibition of MAIT cells, respectively, were used to investigate the role of MR1-dependent immune surveillance in a MC903-driven murine model of AD., Results: The absence or inhibition of MR1 arrested AD disease progression through the blockade of both eosinophil activation and recruitment of IL-4- and IL-13-producing cells. In addition, the therapeutic efficacy of phototherapy against MC903-driven AD could be increased with prior application of folate, which photodegrades into the inhibitory MR1 ligand 6-formylpterin., Conclusion: We identified MAIT cells as sentinels and mediators of cutaneous type 2 immunity. Their pathogenic activity can be inhibited by topical application or endogenous generation, via phototherapy, of inhibitory MR1 ligands., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: The type 2 cytokines IL-4 and IL-13 promote not only atopic dermatitis (AD) but also the resolution of inflammation. How type 2 cytokines participate in the resolution of AD is poorly known., Objective: Our aim was to determine the mechanisms and cell types governing skin inflammation, barrier dysfunction, and resolution of inflammation in a model of AD., Methods: Mice that exhibit expression of IL-4, IL-13, and MCPT8 or that could be depleted of basophils or eosinophils, be deficient in IL-4 or MHC class II molecules, or have basophils lacking macrophage colony-stimulating factor (M-CSF) were treated with calcipotriol (MC903) as an acute model of AD. Kinetics of the disease; keratinocyte differentiation; and leukocyte accumulation, phenotype, function, and cytokine production were measured by transepidermal water loss, histopathology, molecular biology, or unbiased analysis of spectral flow cytometry., Results: In this model of AD, basophils were activated systemically and were the initial and main source of IL-4 in the skin. Basophils and IL-4 promoted epidermal hyperplasia and skin barrier dysfunction by acting on keratinocyte differentiation during inflammation. Basophils, IL-4, and basophil-derived M-CSF inhibited the accumulation of proinflammatory cells in the skin while promoting the expansion and function of proresolution M2-like macrophages and the expression of probarrier genes. Basophils kept their proresolution properties during AD resolution., Conclusion: Basophils can display both beneficial and detrimental type 2 functions simultaneously during atopic inflammation., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. All rights reserved.)