Foxp3
            <sup>+</sup>
            T Regulatory Cells as a Potential Target for Immunotherapy against Primary Infection with Echinococcus multilocularis Eggs

Wang, Junhua; Cardoso, Rita; Marreros, Nelson; Müller, Norbert; Lundström‐Stadelmann, Britta; Siffert, Myriam; Vuitton, Dominique A.; Boué, Franck; Lin, Renyong; Wen, Hao; Gottstein, Bruno

doi:10.1128/iai.00542-18

Cited by 36 publications

(45 citation statements)

References 36 publications

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“…infection, SAE) not only when Foxp3 + Tregs were depleted preventively before E. multilocularis infection, but also when they were depleted therapeutically when the infection was already established (oral infection, PAE) . The significantly smaller average lesion size in the liver due to Foxp3 + Tregs depletion in PAE was associated with a higher Th1 immune response, a lower IL‐10 production and upregulation of APC activation . The late infection of both SAE and PAE was characterized by a strong Foxp3 expression and weak expression of most mediators, suggesting that their production is suppressed by Tregs .…”

Section: Discussionmentioning

confidence: 98%

“…With inducible depletion of Foxp3 + Tregs, the metacestode growth yielded a significantly lower parasite load (i.p. infection, SAE) not only when Foxp3 + Tregs were depleted preventively before E. multilocularis infection, but also when they were depleted therapeutically when the infection was already established (oral infection, PAE) . The significantly smaller average lesion size in the liver due to Foxp3 + Tregs depletion in PAE was associated with a higher Th1 immune response, a lower IL‐10 production and upregulation of APC activation .…”

Section: Discussionmentioning

confidence: 99%

“…The significantly smaller average lesion size in the liver due to Foxp3 + Tregs depletion in PAE was associated with a higher Th1 immune response, a lower IL‐10 production and upregulation of APC activation . The late infection of both SAE and PAE was characterized by a strong Foxp3 expression and weak expression of most mediators, suggesting that their production is suppressed by Tregs . Understanding how Tregs regulates the immune process in AE could thus help finding new immunotherapeutical targets, that is, PD‐1/PD‐L1 ligation.…”

Section: Discussionmentioning

confidence: 99%

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Immunotherapy of alveolar echinococcosis via PD‐1/PD‐L1 immune checkpoint blockade in mice

Wang

Jebbawi

Bellanger

et al. 2018

Parasite Immunology

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Summary The growth potential of the tumour‐like Echinococcus multilocularis metacestode (causing alveolar echinococcosis, AE ) is directly dependent upon the nature/function of the periparasitic adaptive host immune‐mediated processes. PD ‐1/ PD ‐L1 pathway (programmed cell death 1), which inhibits lymphocytic proliferation in tumour development, is over‐expressed at the chronic stage of AE . We tested the impact of a PD ‐1/ PD ‐L1 pathway blockade on the outcome of both chronic AE (intraperitoneal metacestode inoculation, secondary AE and SAE ) and acute AE (peroral egg infection, primary AE and PAE ). To assess the parasite proliferation potential, we measured parasite mass weight for SAE and liver lesion number for PAE . In both models, the parasite load was significantly decreased in response to anti‐ PD ‐L1 antibody treatment. In SAE , anti‐ PDL 1 administration was associated with increased Th1 response parameters and decreased Treg responses, while in PAE anti‐ PDL 1 administration was associated with fewer lesions in the liver and decreased Treg/Th2 responses. Our findings highly suggested that a PD ‐1/ PD ‐L1 pathway blockade triggered the host immune responses in favour of an immune‐mediated control of E. multilocularis proliferation. Based on this, future studies that combine PD ‐1/ PD ‐L1 blockade with a parasitostatic albendazole medication may yield in a putatively curative therapeutic approach to control alveolar echinococcosis.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Immunotherapy of alveolar echinococcosis via PD‐1/PD‐L1 immune checkpoint blockade in mice

Wang

Jebbawi

Bellanger

et al. 2018

Parasite Immunology

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“…During echinococcosis, the impaired host immune response is paralleled by an increased expression of TGF-β signaling components in periparasitic host cells and tissues [10,11,16,24–27] with the expansion of tolerogenic CD4 + CD25 + Foxp3 + Treg cells [6,15,28–30]. Echinococcus antigens can stimulate the expression of CD25 by CD4 + T helper cells from AE infected patients, contributing to the differentiation into Treg [31].…”

Section: Introductionmentioning

confidence: 99%

“…This group also found Foxp3 gene expression to be elevated in these cells and a higher frequency of CD4 + CD25 + Foxp3 + Treg cells in the peritoneum and the spleen of E. multilocularis -infected mice [15,28]. Subsequent studies then convincingly revealed Foxp3+ Treg as key players in the immunoregulatory processes that facilitate the establishment and persistence of E. multilocularis metacestode in their mammalian hosts [28–30]. Consistent with such observations, our previous report of the ability of E. multilocularis metacestode E/S products to expand host Treg in vitro [6], ultimately suggested that Treg expansion during AE, as increasingly reported in the literature, could go beyond a simple homeostatic balancing mechanism.…”

Section: Introductionmentioning

confidence: 99%

A secreted Echinococcus multilocularis activin A homologue promotes regulatory T cell expansion

Nono

Lutz

Brehm

2019

Preprint

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21Background: Alveolar echinococcosis (AE), caused by the metacestode larval stage of 22 the fox-tapeworm Echinococcus multilocularis, is a chronic zoonosis associated with 23 significant modulation of the host immune response. A role of regulatory T-cells (Treg) in 24 generating an immunosuppressive environment around the metacestode during chronic 25 disease has been reported, but the molecular mechanisms of Treg induction by E. 26 multilocularis remain elusive so far. 27Methodology/Principal findings: We herein demonstrate that excretory/secretory (E/S) 28 products of the E. multilocularis metacestode promote the formation of Foxp3 + Treg from 29 CD4 + T-cells in vitro in a TGF--dependent manner. We also show that host T-cells 30 secrete elevated levels of the immunosuppressive cytokine IL-10 in response to 31 metacestode E/S products. Within the E/S fraction of the metacestode we identified an E. 32 multilocularis activin A homolog (EmACT) that displays significant similarities to 33 mammalian Transforming Growth Factor- (TGF-/activin subfamily members. EmACT 34 obtained from heterologous expression promoted host TGF--driven CD4 + Foxp3 + Treg 35 conversion in vitro. Furthermore, like in the case of metacestode E/S products, EmACT-36 treated CD4 + T-cells secreted higher levels of IL-10. These observations suggest a 37 contribution of EmACT in the in vitro expansion of Foxp3 + Treg by the E. multilocularis 38 metacestode. Using infection experiments we show that intraperitoneally injected 39 metacestode tissue expands host Foxp3 + Treg, confirming the expansion of this cell type 40 in vivo during parasite establishment. 3 41Conclusions/Significance: In conclusion, we herein show that E. multilocularis larvae 42 secrete a factor with clear structural and functional homologies to mammalian activin A. 43 Like its mammalian homolog, this protein induces the secretion of IL-10 by T-cells and 44 contributes to the expansion of TGF-β-driven Foxp3 + Treg, a cell type that has been 45 reported crucial for generating a tolerogenic environment to support parasite 46 establishment and proliferation. 47 48 AUTHOR SUMMARY 49The metacestode larval stage of the tapeworm E. multilocularis grows infiltratively, like a 50 malignant tumor, within the organs of its human host, thus causing the lethal disease 51 alveolar echinococcosis (AE). Immunosuppression plays an important role in both survival 52 and proliferation of the metacestode, which mainly depends on factors that are released 53 by the parasite. These parasite-derived molecules are potential targets for developing new 54 anti-echinococcosis drugs and/or improving the effectiveness of current therapies. 55Additionally, an optimized use of such factors could help minimize pathologies resulting 56 from over-reactive immune responses, like allergies and autoimmune diseases. The 57 authors herein demonstrate that the E. multilocularis metacestode releases a protein, 58EmACT, with significant homology to activin A, a cytokine that might support host TGF-...

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Novel Chemotherapeutical Approaches Against Echinococcosis: A Swiss Perspective

Lundström-Stadelmann,

Preza,

Kaethner

et al. 2024

Parasitology Research Monographs

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Foxp3 ⁺ T Regulatory Cells as a Potential Target for Immunotherapy against Primary Infection with Echinococcus multilocularis Eggs

Cited by 36 publications

References 36 publications

Immunotherapy of alveolar echinococcosis via PD‐1/PD‐L1 immune checkpoint blockade in mice

Immunotherapy of alveolar echinococcosis via PD‐1/PD‐L1 immune checkpoint blockade in mice

A secreted Echinococcus multilocularis activin A homologue promotes regulatory T cell expansion

Novel Chemotherapeutical Approaches Against Echinococcosis: A Swiss Perspective

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Foxp3 + T Regulatory Cells as a Potential Target for Immunotherapy against Primary Infection with Echinococcus multilocularis Eggs

Cited by 36 publications

References 36 publications

Immunotherapy of alveolar echinococcosis via PD‐1/PD‐L1 immune checkpoint blockade in mice

Immunotherapy of alveolar echinococcosis via PD‐1/PD‐L1 immune checkpoint blockade in mice

A secreted Echinococcus multilocularis activin A homologue promotes regulatory T cell expansion

Novel Chemotherapeutical Approaches Against Echinococcosis: A Swiss Perspective

Contact Info

Product

Resources

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Foxp3 ⁺ T Regulatory Cells as a Potential Target for Immunotherapy against Primary Infection with Echinococcus multilocularis Eggs