Receptor Antagonist of <scp>IL</scp>‐13 Exerts a Potential Negative Regulation During Early Infection of Human Schistosomiasis

Al, Figueiredo; Al, Domingues; Wg, Melo; Tashiro, Tetsuo; Vm, de Lorena; Sm, Montenegro; Cn, Morais

doi:10.1111/sji.12472

Cited by 5 publications

(3 citation statements)

References 34 publications

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“…A substantial amount of data indicates that an anti-IL-13 vaccine may be beneficial for the prevention of the amelioration of hepatic fibrosis in Schistosoma infection [68] as well as non-infectious fibrosis, as reported in many studies (see above) [69,70,71]. A preventative effect in this regard could indeed constitute a major independent indication for anti-IL-13 vaccination.…”

Section: Additional Potential Effects Of An Il-13 Vaccinementioning

confidence: 87%

Feasibility Analysis of Interleukin-13 as a Target for a Therapeutic Vaccine

Foerster

Molęda

2019

Vaccines

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Background: The development of therapeutic vaccines requires thorough knowledge of potential hazards associated with long-term inactivation of self-proteins. Among potential targets, interleukin 13 (IL-13) merits consideration, as monoclonal antibodies disrupting IL-13 signaling are proving to be exceedingly effective in common conditions such as atopic dermatitis. Objective: Given the mass publication of scientific data, an appraisal of safety aspects is challenging. Methods: We here provide a three-fold approach to survey clinically relevant information on off-target effects, both adverse and beneficial, that may potentially be encountered in patients undergoing long-term IL-13 inactivation. First, we review non-clinical data in vivo and in vitro. Second, we summarize safety data accumulating from patients dosed with anti-IL-13 drugs. Third, we exploit human mutation data as well as emerging large-scale genetic datasets (global exome data from 60,000 patients) to obtain information on any association of IL-13-inactivating genetic variants with disease states. In addition, we: (1) dissect the precise efficacy signals obtained with various drugs targeting IL-13 and/or IL-4, and (2) summarize unintended, but potentially beneficial effects of prolonged IL-13 inactivation on 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-13Rα1, IL-13Rα2, IL-4, IL-4Rα 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 non-redundant 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 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.

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Section: Additional Potential Effects Of An Il-13 Vaccinementioning

confidence: 87%

Feasibility Analysis of Interleukin-13 as a Target for a Therapeutic Vaccine

Foerster

Molęda

2019

Vaccines

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“…Both parenchymal and immune cells can produce IL-13 in the liver of schistosome-infected mice, and IL-13 signaling induces the expression of type I collagen and other fibrosis-related genes in HSCs ( Liu et al., 2012 ; Zheng et al., 2015 ). The IL-13 signaling receptor complex consists of IL-4Rα, IL-13Rα1, and IL13Rα2 ( Figueiredo et al., 2016 ). IL-13Rα1 combines with IL-4Rα1 to constitute a functional receptor for IL-13 signaling, and IL-13 Rα2 is a bait receptor capable of blocking IL-13 signaling ( Rahaman et al., 2002 ; Zheng et al., 2015 ).…”

Section: Il-13mentioning

confidence: 99%

Pathology and molecular mechanisms of Schistosoma japonicum-associated liver fibrosis

Liu

Zhang

Liang

et al. 2022

Front. Cell. Infect. Microbiol.

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Schistosomiasis has been widely disseminated around the world, and poses a significant threat to human health. Schistosoma eggs and soluble egg antigen (SEA) mediated inflammatory responses promote the formation of egg granulomas and liver fibrosis. With continuous liver injuries and inflammatory stimulation, liver fibrosis can develop into liver cirrhosis and liver cancer. Therefore, anti-fibrotic therapy is crucial to increase the survival rate of patients. However, current research on antifibrotic treatments for schistosomiasis requires further exploration. In the complicated microenvironment of schistosome infections, it is important to understand the mechanism and pathology of schistosomiasis-associated liver fibrosis(SSLF). In this review, we discuss the role of SEA in inhibiting liver fibrosis, describe its mechanism, and comprehensively explore the role of host-derived and schistosome-derived microRNAs (miRNAs) in SSLF. Inflammasomes and cytokines are significant factors in promoting SSLF, and we discuss the mechanisms of some critical inflammatory signals and pro-fibrotic cytokines. Natural killer(NK) cells and Natural killer T(NKT) cells can inhibit SSLF but are rarely described, therefore, we highlight their significance. This summarizes and provides insights into the mechanisms of key molecules involved in SSLF development.

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“… 11 , 12 Evidence both from patient and from mouse model indicates that IL-13 is a strong accelerator for the progress of liver fibrosis after Schistosoma infection. 13 , 14 IL-4, IL-10 and IL-13 can also stimulate macrophage transformation into alternatively activated macrophages, which are a major source found in inflammatory zone protein 1/resistin-like molecule-α, favoring the conversion of HSCs into fibroblasts. 15 At 12 weeks after infection, the Th2 immune response is downregulated, which may be attributed to IL-10 and TGF-β inducing regulatory T cells to regulate the balance of the Th1/Th2 response.…”

Section: Introductionmentioning

confidence: 99%

MULT1-Encoding DNA Alleviates Schistosomiasis-Associated Hepatic Fibrosis via Modulating Cellular Immune Response

Yang¹,

Sun²,

Cao³

et al. 2022

JIR

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Purpose In schistosomiasis-associated hepatic fibrosis, the role of murine UL16-binding protein-like transcript 1 (MULT1), the strongest ligand of natural killer group 2-member D receptor (NKG2D), remains unclear. Here, Schistosoma japonicum -infected mice administered with MULT1-encoding DNA were used to test MULT1 as a potential therapy for schistosomiasis-associated hepatic fibrosis and explore relevant mechanisms. Materials and Methods A recombinant plasmid encoding MULT1 (p-rMULT1) was constructed and administered to Schistosoma japonicum -infected BALB/c mice via hydrodynamic tail vein injection. Egg granulomas in liver, hepatic fibrosis biomarkers and levels of cytokines were investigated. Comparisons of CD4+ T, CD8+ T, NK and NKT proportions as well as their phenotype were performed not only between Schistosoma infected, p-rMULT1 treated group and Schistosoma infected, backbone plasmid pEGFP-N1 treated group but also between infected, nontreated group and health control group. Results Reduced area of granuloma formation and fibrosis around single eggs, downregulated expression of collagen I, α-smooth muscle actin, TGF-β and IL-10, and upregulated expression of IFN-γ, were observed in the livers of p-rMULT1 treated mice. p-rMULT1 treatment improved Schistosoma infection impacted immune microenvironment by modulating proportion of CD4 + T CD8 + T, natural killer (NK) and NKT cells, enhancing expression of NKG2D, in lymphocytes, and augmenting IFN-γ secretion by CD4 + T, CD8 + T, NK and NKT cells, as well as partially reversing some other phenotype changes of lymphocytes. Conclusion To the best of our knowledge, we provided the first in vivo evidence that MULT1 is a favorable anti-fibrosis factor in the context of schistosomiasis. The inhibitory effect of MULT1 overexpression on schistosomiasis associated with hepatic fibrosis may result from augmenting the proportion and function of NKG2D-expressing immune cells, and from enhancing NK- and T-cell activation, as well as regulating the helper T (Th)1/Th2 balance.

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Receptor Antagonist of IL‐13 Exerts a Potential Negative Regulation During Early Infection of Human Schistosomiasis

Cited by 5 publications

References 34 publications

Feasibility Analysis of Interleukin-13 as a Target for a Therapeutic Vaccine

Feasibility Analysis of Interleukin-13 as a Target for a Therapeutic Vaccine

Pathology and molecular mechanisms of Schistosoma japonicum-associated liver fibrosis

MULT1-Encoding DNA Alleviates Schistosomiasis-Associated Hepatic Fibrosis via Modulating Cellular Immune Response

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