Inhibition of cardiac allograft rejection in mice using interleukin‐35‐modified mesenchymal stem cells

Wang, Wei; Zhao, Ning; Li, Baozhu; Gao, Haopeng; Yan, Yaohua; Guo, Hao

doi:10.1111/sji.12750

Cited by 15 publications

(16 citation statements)

References 45 publications

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“…In previous studies, we cloned the IL‐35‐expressing genes into mesenchymal stem cells (MSCs) and proved that exogenous IL‐35 expression effectively inhibited the proliferation of CD4 + T cells in vitro [21]. In addition, IL‐35 gene‐modified MSCs prolong graft survival by alleviating acute transplant rejection [22], ameliorate ulcerative colitis by inhibiting inflammatory cytokine secretion [23] and protect mice from concanavalin A‐induced liver injury by decreasing IFN‐γ expression [24].…”

Section: Discussionmentioning

confidence: 99%

Interleukin-35 has a tumor-promoting role in hepatocellular carcinoma

Liu

Ren

Guo

et al. 2020

Clinical and Experimental Immunology

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Summary Hepatic inflammatory response is a risk factor for liver cancer initiation and progression. Interleukin (IL)-35 is the newest member of the IL-12 cytokine family, and has been reported to play an essential role in the immunosuppressive liver microenvironment. Herein we focus on the expression profiles of IL-35 in hepatocellular carcinoma (HCC) and effects on local immune status. HCC transcriptome array data were downloaded from Gene Expression Omnibus (GEO). Analysis was performed by BRB-Array Tools and Ingenuity Pathway Analysis (IPA) software. Serum IL-35 level was detected by AimPlet bead-based immunoassay. In-situ IL-35 detection was performed by immunohistochemical staining and Western blot. The n-vitro effect of IL-35 on CD4+ or CD8+ T cell function was detected by flow cytometry. Our results showed that there were large amounts of IL-35 expressed in HCC serum and tumor tissues. IL-35 expression affects the transcript of thousands of genes, most differentially expressed genes (DEGs), in tumor tissues correlated with T cell immunity. The IL-35 high-expression group exhibited enhancement of regulatory T cells (Tregs) and impairment of cytolytic T cells. In-vitro experiments proved that exogenous IL-35 stimulated the expression of programmed cell death 1 (PD-1) and lymphocyte activation gene-3 (LAG3) in CD4+ and CD8+ T cells. In addition, the stimulating effect was time-dependent. Furthermore, IL-35 inhibited interferon (IFN)-γ secretion by CD4+ and CD8+ T cells. Elevated IL-35 had an immune suppressive role in HCC tumor microenvironments through affecting inhibitor receptor expression and cytokine secretion of CD4+ and CD8+ T cells. Dissection of the precise targets and underlying molecular mechanisms would mean alternative treatments for HCC patients.

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Section: Discussionmentioning

confidence: 99%

Interleukin-35 has a tumor-promoting role in hepatocellular carcinoma

Liu

Ren

Guo

et al. 2020

Clinical and Experimental Immunology

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“…IL-35-MSCs show a strong immunosuppressive ability compared to MSCs by reducing the percentage of Th17 cells, increasing the proportion of CD4+, Foxp3+ T cells, and regulating Th1/Th2 balance in heart transplant mice. These findings showing that IL-35-MSCs have more advantages than MSCs in inhibiting graft rejection suggest that IL-35 could be key factor for allograft tolerance [32,33].…”

Section: Introductionmentioning

confidence: 93%

At Embryo Implantation Site IL-35 Secreted by Trophoblast, Polarizing T Cells towards IL-35+ IL-10+ IL-4+ Th2-Type Cells, Could Favour Fetal Allograft Tolerance and Pregnancy Success

Lombardelli

Logiodice

Kullolli

et al. 2022

IJMS

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We investigated the role of rhIL-35, at low concentrations compatible with those produced by human trophoblast cells (less than 1 ng/mL), on human T helper (Th) cell functions and the presence of decidual IL-35-producing Th cells in human pregnancy. We found that human trophoblast cells produced IL-35 but not IL-4 or IL-10. RhIL-35, at concentrations produced by human trophoblasts, polarized T cells towards IL-35+, IL-10+, IL-4+ Th2-type cells and to Foxp3+ EBI3+ p35+ T reg cells producing IL-35 but not IL-10 and IL-4. Moreover, rhIL-35 at low concentrations did not suppress the proliferation of Th cells but stimulated IL-4 and IL-10 production by established Th clones. In particular, Th1-type clones acquired the capacity to produce IL-4. In addition, purified human trophoblast cell supernatants containing IL-35 upregulated IL-4 and IL-10 production by Th clones. Finally, IL-35+, IL-10+, IL-4+ Th2-type cells, which were found to be induced by low concentrations of IL-35 compatible with those produced by human trophoblasts, are exclusively present in the decidua of a successful pregnancy and at the embryo implantation site, suggesting their stringent dependence on trophoblast cells. Thus, the proximity of Th cells to IL-35-producing trophoblasts could be the determining factor for the differentiation of IL-35+, IL-10+, IL-4+ Th2-type cells that are crucial for human pregnancy success.

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“…Infusion of IL-35-AD-MSCs in cardiac transplantation recipients significantly prolonged allograft survival, in addition to suppressing the production of Th17 within the grafted heart and spleen. Lower Th1/Th2 ratio and increased production of CD4 + FoxP3 + Treg were also noted in the spleen [ 66 ].…”

Section: Improving Msc Efficacy By Preconditioningmentioning

confidence: 99%

Preconditioned Mesenchymal Stromal Cells to Improve Allotransplantation Outcome

Cheng

Anggelia

Lin

et al. 2021

Cells

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Mesenchymal stromal cells (MSCs) are tissue-derived progenitor cells with immunomodulatory as well as multilineage differentiation capacities, and have been widely applied as cellular therapeutics in different disease systems in both preclinical models and clinical studies. Although many studies have applied MSCs in different types of allotransplantation, the efficacy varies. It has been demonstrated that preconditioning MSCs prior to in vivo administration may enhance their efficacy. In the field of organ/tissue allotransplantation, many recent studies have shown that preconditioning of MSCs with (1) pretreatment with bioactive factors or reagents such as cytokines, or (2) specific gene transfection, could prolong allotransplant survival and improve allotransplant function. Herein, we review these preconditioning strategies and discuss potential directions for further improvement.

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Inhibition of cardiac allograft rejection in mice using interleukin‐35‐modified mesenchymal stem cells

Cited by 15 publications

References 45 publications

Interleukin-35 has a tumor-promoting role in hepatocellular carcinoma

Interleukin-35 has a tumor-promoting role in hepatocellular carcinoma

At Embryo Implantation Site IL-35 Secreted by Trophoblast, Polarizing T Cells towards IL-35+ IL-10+ IL-4+ Th2-Type Cells, Could Favour Fetal Allograft Tolerance and Pregnancy Success

Preconditioned Mesenchymal Stromal Cells to Improve Allotransplantation Outcome

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