Dupilumab blocks the shared receptor component for IL-4 and IL-13, key drivers of type 2 inflammation, including IgE-mediated allergic inflammation in asthma.
The glucocorticoid-insensitive hyperrresponsiveness in isolated human airways induced by IL-13 and IL-4 provides further evidence that the IL-4Rα pathway should be targeted as a new strategy for treatment of airway hyperresponsiveness in asthma.
Asthma is a chronic inflammatory airway disease associated with type 2 cytokines interleukin-4 (IL-4), IL-5, and IL-13, which promote airway eosinophilia, mucus overproduction, bronchial hyperresponsiveness (BHR), and immunogloubulin E (IgE) synthesis.
Additionally, it promoted the occurrence and development of asthma by influencing the expression levels of IL-7 and various relevant inflammatory factors (such as IL-4 and IL-8) and changing the equilibrium between Treg and Th17 cells.
The results indicated that IL-5 may involve in the pathologic process of asthma-like IL-4, and an inflammatory reaction may still exist in the airway during the remission stage of asthma.
We observed differential methylation across multiple genes for all three phenotypes, including genes implicated previously in innate immunity (DICER1), eosinophilic esophagitis and sinusitis (SIGLEC8), the atopic march (AP5B1) and asthma (EPX, IL4, IL5RA, PRG2, SIGLEC8, CLU).
RESULTS The levels of serum IgE and IgG in BLA- or Dex- treated mice were significantly reduced compared to those in the asthma (AS) group (P<0.01), whereas the levels of cytokines IL-4, TNF-α, and MCP-1 were significantly decreased (P<0.01).
The levels of IL-4, IgE, PLA<sub>2</sub>, and TP significantly reduced in groups treated with all concentrations of RA compared to asthma group (P<0.001 for all cases).
The mechanism of MSC therapy in asthma seems to be regulating the balance of Th1 cytokine and Th2 cytokines (IFN-γ: Hedges's g = 4.779 ± 1.408 with 95% CI: 1.099-2.725, P < 0.001; IL-4: Hedges's g = -10.781 ± 1.062 with 95% CI: -12.863 ∼ -8.699, P < 0.001; IL-5: Hedges's g = -10.537 ± 1.269 with 95% CI: -13.025 ∼ -8.050, P < 0.001; IL-13: Hedges's g = -6.773 ± 0.788 with 95% CI: -8.318 ∼ -5.229, P < 0.001).
Dupilumab (a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13) is approved for inadequately controlled moderate-to-severe AD and for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma.
Interleukin-4(IL-4), an anti-inflammatory cytokine, plays significant role in pathogenesis of various diseases such as asthma, tumors, and HIV infections.
Pathway cross-talk analysis highlights that signaling pathways mediated by IL-4/13 and transcription factor HIF-1α and FOXA1 play crucial roles in the pathogenesis of asthma.
Discovered DMRs annotated to genes implicated in allergic asthma, Th2 activation and eosinophilia (EPX, IL4, IL13) and genes previously associated with asthma and IgE in EWAS of blood (ACOT7, SLC25A25).
PM<sub>2.5</sub> exposure and cold stress exacerbates asthma in mice by increasing histone acetylation in IL-4 gene promoter in CD4<sup>+</sup> T cells.
The IL-4-590C/T and Arg130Gln locus gene polymorphisms are associated with the asthma susceptibility and increased serum total IgE in Uygur children in Xinjiang.
These findings coupled with the known insensitivity of CD8<sup>+</sup> T cells to corticosteroids suggests that activation of the IL-4-HIF-1α-IL-13 axis might play a role in the development of steroid-refractory asthma.
The characteristic features of allergic asthma, including airway hyperreactivity, histopathology, cytokine levels (IL-4, -5, -13, -17, and INF-γ), T regulatory (Treg) lymphocytes (Foxp3+CD4+CD25+), and T effector (Teff) lymphocytes (Foxp3-CD25+CD4+) in bronchoalveolar lavage fluid (BALF), and downstream proteins of mTORC1/2 signaling pathway were examined.
In an ovalbumin (OVA)-induced asthmatic model, inhaled MHF showed significant suppression of airway hyperresponsiveness; a decrease in eosinophil and neutrophil counts, IL-4, IL-5 and leukotriene D<sub>4</sub> in bronchoalveolar lavage fluid; a reduction in total IgE and OVA-specific IgE levels in serum; and suppression of eosinophil infiltration in lung tissue after antigen challenge.
IL-38 administration suppressed airway hyperreactivity and asthma-related IL-4 and IL-5 expression in humanized mice, together with significantly decreased CCR3<sup>+</sup> eosinophil numbers in the BALF and lungs, and a reduced percentage of human CD4<sup>+</sup>CRTH2<sup>+</sup> Th2 cells in the lungs and mediastinal lymph nodes.
Development of antagonistic antibody (Ab) against interleukin-4 receptor alpha (IL-4Rα) subunit of IL-4/IL-13 receptors is a promising therapeutic strategy for T helper 2 (T<sub>H</sub>2)-mediated allergic diseases such as asthma and atopic dermatitis.