Conclusions The clinical use of dupilumab, as well as selective anti-IL-13 drugs, has shown that blocking IL-13 is effective both for the treatment of asthma and atopic dermatitis and may be of use in other atopic conditions (e
Conclusions The clinical use of dupilumab, as well as selective anti-IL-13 drugs, has shown that blocking IL-13 is effective both for the treatment of asthma and atopic dermatitis and may be of use in other atopic conditions (e.g., severe contact allergy). several functional systems. Results: Prolonged repression of IL-13 in several thousand patients so far has not uncovered any non-redundant functions of IL-13 in immune defense. Furthermore, missense mutations in the key genes IL-13, IL-13R1, IL-13R2, IL-4, IL-4R are common, while no case reports have been published on any immune deficiency or increased risk of neoplastic disease associated with such mutations, suggesting that these genes do not harbor nonredundant roles in adult outbred humans. In terms of efficacy, data from clinically used drugs strongly suggest that targeting IL-13 only, as opposed to IL-13 and IL-4, may be effective in eczema while being more selective. Importantly, several lines of evidence suggest that inhibition of IL-13 may in fact harbor potentially beneficial effects Rabbit polyclonal to ANAPC2 on non-targeted systems, including glucose metabolism, hepatic fibrosis, and atherosclerosis, suggesting that respective outcomes should be systematically captured in patients dosed with IL-13 interfering drugs. Collectively, available evidence suggests that IL-13 may fulfill safety requirements required for the target of a therapeutic vaccine. infection. One group of clinically relevant data are studies of associations of human polymorphisms with disease. Thus, Bardoxolone methyl (RTA 402) an promoter variant (?1111T/C) was found to confer slightly increased susceptibly to infection (T/T genotype protective); however, effects of age, gender, and village (the latter likely reflecting variable genetic background) were in fact found to be many orders of magnitude higher [3]. A study on a Brazilian population found a suggestive protective association of the same promoter allele as well as a non-conserved functional allele (rs20541 R130Q) against [4]. A French study found association of the same IL-13 variant (rs1800925) and infection [5]. Another study did not find association of infection and IL-13 Bardoxolone methyl (RTA 402) but only IL-5 polymorphisms [6]. Studies with genetically altered inbred mice indicate that survival in infection is not impaired in IL-13 deficient mice [7] and that granuloma formation Bardoxolone methyl (RTA 402) is only impaired in combined IL-4/IL-13 ablation [8]. In fact, ablation of IL-13 ameliorates lung fibrosis in this setting (see below on this aspect). A recent review of intestinal helminth infection also showed redundancy between IL-4 and IL-13, indicating that IL-13 deficiency can be compensated for by IL-4 in murine models of infection [9]. Taken together, despite the available data suggesting a role for IL-13 in the containment of infections such as intestinal nematodes [10], no evidence has been found by genetic association or patients that deficiency in IL-13 affects susceptibility or disease severity or natural course in humans in infection. Nonetheless, mouse data on inbred strains do suggest that an absence of IL-13 might negatively impact the defense against intestinal parasites [11], suggesting that caution may nevertheless be prudent. 2.2. Leishmaniasis Cutaneous Leishmaniasis (CL) is the most common type of infection causing large ulcers on exposed parts of the body. IL-13 is believed to be responsible for non-healing progressing cutaneous disease, previously demonstrated on wild type, IL-13?/?, IL-4R?/? and IL-4?/? mice that encountered and [12,13,14]. IL-4R?/? mice were fully resistant to infection [14]. A possible explanation for why IL-13?/? mice became resistant to the parasites is that IL-13 is suppressing the functions of interferon-gamma (IFN-) and IL-12, which play key roles in clearance as shown Bardoxolone methyl (RTA 402) in previous investigations, indicating susceptible phenotypes upon their modulation [15,16,17,18]. Thus, an IL-13 vaccine could supress parasite progression to a chronic non-healing state and enhance T helper 1 (Th1) responses, allowing recovery. Certainly, no data exist to suggest that an IL-13 vaccine would exacerbate susceptibility to = 56,560) from Argentina, suggesting that blocking IL-13 in this setting may in fact be beneficial [27]. Despite a targeted search, a study from China found associations between IL-4 but not IL-13 polymorphisms and coal miners pneumoconiosis [35]. commonly cause infections of the respiratory and genital tract. IL-13 increases susceptibility to infection as well as severity by driving increased inflammation and bacterial manifestation [36]. Conversely, respiratory infection in early life was shown to reduce IL-13R2 expression and attenuate IL-13 production with potential secondary benefit later in life on asthma susceptibility [37]. 2.5. Septic Shock A Spanish study on 48 children with sepsis.