Attenuation of antigenic immunogenicity by kynurenine, a novel suppressive adjuvant

Duan, Zhiqing; Yun-qing, Duan; Huan-gui, Lei; Hu, Ningzhu; Shi, Jiandong; Dong, Shen; Wang, Xi; Hu, Yunzhang

doi:10.4161/hv.28099

Cited by 11 publications

(5 citation statements)

References 56 publications

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“… 52 , 81 In this pathway, IFN-γ strongly induces the conversion of tryptophan into kynurenine, mediated by the IDO-1 enzyme. 53 , 72 , 82 The kynurenine may then induce an immunomodulatory impact by binding to AhR. 52 , 83 , 84 , 85 Once activated upon the binding of kynurenine, AhR is translocated from the cytoplasm into the nucleus and initiates the transcription of the anti-inflammatory TGF-β and in turn causes the reduced expression of IFN-γ.…”

Section: Discussionmentioning

confidence: 99%

Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response

Oljuskin,

Azodi,

Volpedo

et al. 2023

iScience

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Section: Discussionmentioning

confidence: 99%

Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response

Oljuskin,

Azodi,

Volpedo

et al. 2023

iScience

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“…Kynurenine has been the subject of much interest due to its immunomodulatory role through an interaction with the Aryl Hydrocarbon Receptor (AhR) (Mezrich et al, 2010; Nguyen et al, 2010). In this pathway, IFN-γ strongly induces the conversion of tryptophan into kynurenine, mediated by the IDO-1 enzyme (Duan et al, 2014; Fiore and Murray, 2021; Proietti et al, 2020). The kynurenine may then induce an immunomodulatory impact by binding to AhR (Clement et al, 2021; Grohmann and Puccetti, 2015; Head and Lawrence, 2009; Mezrich et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Leishmania major centrinknock-out parasites alter the kynurenine- aryl hydrocarbon receptor signaling to produce a pro-inflammatory response

Oljuskin

Azodi²,

Volpedo

et al. 2022

Preprint

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Leishmaniasis is a parasitic disease that is prevalent in approximately 88 countries, and yet no licensed human vaccine exists against it. Towards control of leishmaniasis, we have developed Leishmania major Centrin gene deletion mutant strains (LmCen-/-) as a live attenuated vaccine, which induces a strong Th1 response to provide IFN-γ-mediated protection to the host. However, the immune mechanisms of such protection remain to be understood. Metabolomic reprogramming of the host cells following Leishmania-infection has been shown to play a critical role in pathogenicity and shaping the immune response following infection. Here, we applied untargeted mass spectrometric analysis to study the metabolic changes induced by infection with LmCen-/- and compared with virulent L. major parasite infection to identify the immune mechanism of protection. Our data shows that immunization with LmCen-/- parasites, in contrast to virulent L. major infection, alters tryptophan metabolism to down-regulate Kynurenine-AhR signaling and promote a pro-inflammatory response.

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“…Consequently, it is necessary to add inhibitory adjuvants in the process of vaccine use. Our previous studies have shown that Kyn may be used as a suppressive adjuvant to reduce the immunogenicity of HAV, a TD antigen, in vivo, and LPS, a TI antigen, in vitro (48). As an endogenous ligand of AHR, Kyn can activate the AHR signaling pathway and may control immunity and autoimmunity while providing us with a new opportunity for autoimmune disease therapeutic.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Immunosuppressive Adjuvant Kynurenine on Type 1 Diabetes Vaccine

Sun

Shi

et al. 2021

Front. Immunol.

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Inducing antigen-specific tolerance is a promising treatment for preventing or reversing Type 1 diabetes (T1D). In contrast to a vaccine that induces immune responses against pathogens, a tolerogenic vaccine can suppress immunity against antigens causing diseases by administrating a mixture of self-antigens with an adjuvant that decreases the strength of antigen-specific response. Kynurenine (Kyn) is an endogenous substance that can inhibit the natural killer cell and T cell proliferation and promote the differentiation of naïve T cells into regulatory T cells (Tregs). In this study, we evaluated the efficacy of Kyn as a novel suppressive adjuvant. Kyn was co-immunized with GAD65 phage vaccine to induce Treg cells and tolerogenic responses for the prevention of T1D in NOD mouse model. Mice were subcutaneously immunized two times with 1011 Pfu (100μL,1012 Pfu/ml) GAD65 phage vaccine doses mixed with 200 μg of Kyn. Serum antibodies and cytokines were detected by ELISA and electrochemiluminescence, respectively. Flow cytometry assay was used to analyze DC and Treg. MTS was used for the analysis of spleen lymphocyte proliferation. RNA sequencing was used to investigate mRNA and miRNA expression profiles in spleen lymphocytes. Compared to GAD65 phage vaccine alone, co-immunization of Kyn and GAD65 phage vaccine resulted in the prevention of hyperglycemia in 60% of mice for at least one month. Further, Kyn enhances GAD65-specific Th2-mediated immune responses; regulates the Th1/Th2 imbalance and increases the secretion of Th2 cytokines and the number of CD4+CD25+Foxp3+T cells; suppresses DC maturation and GAD65-specific T lymphocyte proliferation. Moreover, we integrated Kyn related miRNA and mRNA expression profiles obtained from the spleen lymphocyte RNA-sequencing which was stimulated by Kyn in vitro. These data provide an important basis for understanding the mechanisms underlying Kyn as an immunosuppressive adjuvant which regulated the immune response. These findings suggest that Kyn can serve as an effective suppressive adjuvant candidate for Type 1 diabetes vaccines.

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Attenuation of antigenic immunogenicity by kynurenine, a novel suppressive adjuvant

Cited by 11 publications

References 56 publications

Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response

Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response

Leishmania major centrinknock-out parasites alter the kynurenine- aryl hydrocarbon receptor signaling to produce a pro-inflammatory response

The Effect of Immunosuppressive Adjuvant Kynurenine on Type 1 Diabetes Vaccine

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