Plasma levels of chemokines decrease during elexacaftor/tezacaftor/ivacaftor therapy in adults with cystic fibrosis.

Background: Cystic fibrosis (CF) is associated with dysregulated immune responses, exaggerated inflammation and chronic infection. CF transmembrane conductance regulator (CFTR) modulator therapies directly target the underlying protein defects and resulted in significant clinical benefits for people with CF (pwCF). This study analysed the effects of triple CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) on CF-associated inflammation, especially systemic chemokines. Methods: A bead-based immunoassay was used to quantify proinflammatory chemokines (IL-8, IP-10, Eotaxin, TARC, RANTES, MIP-1α, MIP-1ß, MIP-3α, MIG, ENA-78, GROα, I-TAC) in plasma samples from pwCF collected before, at three, and at six months after starting ETI therapy. Results: Fifty-one pwCF (47 % female; mean age 32 ± 10.4 years) were included. At baseline, 67 % were already receiving CFTR modulator therapy with tezacaftor/ivacaftor or lumacaftor/ivacaftor. After initiation of ETI therapy there was a significant improvement in percent predicted forced expiratory volume in 1 s (+12.7 points, p < 0.001) and a significant decrease in sweat chloride levels (-53.6 %, p < 0.001). After 6 months' treatment with ETI therapy there were significant decreases in plasma levels of MIP-3α (-68.2 %, p = 0.018), GROα (-17.7 %, p = 0.013), ENA-78 (-16.3 %, p = 0.034) and I-TAC (-3.4 %, p = 0.032). IL-8 exhibited a reduction that did not reach statistical significance (-17.8 %, p = 0.057); levels of other assessed cytokines did not change significantly from baseline. Conclusions: ETI appears to affect a distinct group of chemokines that are predominately associated with neutrophilic inflammation, demonstrating the anti-inflammatory properties of ETI therapy.

Microbes little helpers and suppliers for therapeutic asthma approaches.

Bronchial asthma is a prevalent and increasingly chronic inflammatory lung disease affecting over 300 million people globally. Initially considered an allergic disorder driven by mast cells and eosinophils, asthma is now recognized as a complex syndrome with various clinical phenotypes and immunological endotypes. These encompass type 2 inflammatory endotypes characterized by interleukin (IL)-4, IL-5, and IL-13 dominance, alongside others featuring mixed or non-eosinophilic inflammation. Therapeutic success varies significantly based on asthma phenotypes, with inhaled corticosteroids and beta-2 agonists effective for milder forms, but limited in severe cases. Novel antibody-based therapies have shown promise, primarily for severe allergic and type 2-high asthma. To address this gap, novel treatment strategies are essential for better control of asthma pathology, prevention, and exacerbation reduction. One promising approach involves stimulating endogenous anti-inflammatory responses through regulatory T cells (Tregs). Tregs play a vital role in maintaining immune homeostasis, preventing autoimmunity, and mitigating excessive inflammation after pathogenic encounters. Tregs have demonstrated their ability to control both type 2-high and type 2-low inflammation in murine models and dampen human cell-dependent allergic airway inflammation. Furthermore, microbes, typically associated with disease development, have shown immune-dampening properties that could be harnessed for therapeutic benefits. Both commensal microbiota and pathogenic microbes have demonstrated potential in bacterial-host interactions for therapeutic purposes. This review explores microbe-associated approaches as potential treatments for inflammatory diseases, shedding light on current and future therapeutics.

Therapeutic properties of Helicobacter pylori-derived vacuolating cytotoxin A in an animal model of chronic allergic airway disease.

BACKGROUND: It has previously been shown that the Helicobacter pylori (H. pylori)-derived molecule vacuolating cytotoxin A (VacA) could be suitable for the treatment of allergic airway disease. The therapeutic activity of the protein, which acts through modulation of dendritic cells (DC) and regulatory T cells (Tregs), was demonstrated in murine short-term acute models. The aim of this study is to further evaluate the therapeutic potential of VacA by determining the effectiveness of different application routes and the suitability of the protein for treating the chronic phase of allergic airway disease. METHODS: VacA was administered by the intraperitoneal (i.p.), oral (p.o.) or intratracheal (i.t.) routes, and long-term therapeutic effectiveness, allergic airway disease hallmarks, and immune phenotype were analyzed in murine models of acute and chronic allergic airway disease. RESULTS: Administration of VacA via the i.p., p.o or i.t. routes was associated with a reduction in airway inflammation. The i.p. route showed the most consistent effect in reducing airway inflammation and i.p. treatment with VacA was the only treatment that significantly reduced mucus cell hyperplasia. In a murine model of chronic allergic airway disease, both short- and long-term treatment with VacA showed a therapeutic effect, with a reduction in a variety of asthma hallmarks, including bronchoalveolar lavage eosinophilia, lung inflammation and goblet cell metaplasia. Short-term treatment was associated with induction of Tregs, while repetitive long-term administration of VacA influenced immunological memory in the lung. CONCLUSIONS: In addition to showing therapeutic efficacy in short-term models, treatment with VacA also appeared to be effective in suppressing inflammation in a chronic airway disease model. The observation that treatment was effective after administration via several different routes highlights the potential of VacA as a therapeutic agent with different routes of administration in humans.

Regulatory T cell enhancement in adults with cystic fibrosis receiving Elexacaftor/Tezacaftor/Ivacaftor therapy.

Introduction: Cystic fibrosis (CF), especially CF lung disease, is characterized by chronic infection, immune dysfunction including impairment of regulatory T cells (Tregs) and an exaggerated inflammatory response. CF transmembrane conductance regulator (CFTR) modulators have shown to improve clinical outcomes in people with CF (PwCF) with a wide range of CFTR mutations. However, it remains unclear whether CFTR modulator therapy also affects CF-associated inflammation. We aimed to examine the effect of elexacaftor/tezacaftor/ivacaftor therapy on lymphocyte subsets and systemic cytokines in PwCF. Methods: Peripheral blood mononuclear cells and plasma were collected before and at three and six months after the initiation of elexacaftor/tezacaftor/ivacaftor therapy; lymphocyte subsets and systemic cytokines were determined using flow cytometry. Results: Elexacaftor/tezacaftor/ivacaftor treatment was initiated in 77 PwCF and improved percent predicted FEV1 by 12.5 points (p<0.001) at 3 months. During elexacaftor/tezacaftor/ivacaftor therapy, percentages of Tregs were enhanced (+18.7%, p<0.001), with an increased proportion of Tregs expressing CD39 as a marker of stability (+14.4%, p<0.001). Treg enhancement was more pronounced in PwCF clearing Pseudomonas aeruginosa infection. Only minor, non-significant shifts were observed among Th1-, Th2- and Th17-expressing effector T helper cells. These results were stable at 3- and 6-month follow-up. Cytokine measurements showed a significant decrease in interleukin-6 levels during treatment with elexacaftor/tezacaftor/ivacaftor (-50.2%, p<0.001). Conclusion: Treatment with elexacaftor/tezacaftor/ivacaftor was associated with an increased percentage of Tregs, especially in PwCF clearing Pseudomonas aeruginosa infection. Targeting Treg homeostasis is a therapeutic option for PwCF with persistent Treg impairment.

Treatment with Helicobacter pylori-derived VacA attenuates allergic airway disease.

Background: Asthma is an incurable heterogeneous disease with variations in clinical and underlying immunological phenotype. New approaches could help to support existing therapy concepts. Neonatal infection of mice with Helicobacter pylori or administration of H. pylori-derived extracts or molecules after birth have been shown to prevent the development of allergic airway disease later in life. This study evaluated the potential therapeutic efficacy of H. pylori vacuolating cytotoxin A (VacA) in allergic airway inflammation and investigated the underlying immunological mechanisms for its actions. Methods: Murine models of allergic airway diseases, and murine and human in vitro models were used. Results: In both an acute model and a therapeutic house dust mite model of allergic airway disease, treatment with H. pylori-derived VacA reduced several asthma hallmarks, including airway hyperresponsiveness, inflammation and goblet cell metaplasia. Flow cytometry and ELISA analyses revealed induction of tolerogenic dendritic cells (DC) and FoxP3 positive regulatory T cells (Tregs), and a shift in the composition of allergen-specific immunoglobulins. Depletion of Tregs during treatment with VacA reversed treatment-mediated suppression of allergic airway disease. Human monocyte derived DCs (moDC) that were exposed to VacA induced Tregs in co-cultured naïve autologous T cells, replicating key observations made in vivo. Conclusion: H. pylori-derived VacA suppressed allergic airway inflammation via induction of Tregs in both allergic airway disease models. These data suggest that the immunomodulatory activity of VacA could potentially be exploited for the prevention and treatment of allergic airway disease.