Immunosuppressive effect of arsenic trioxide on islet xenotransplantation prolongs xenograft survival in mice

Zhao, Bin; Xia, Junjie; Wang, Lu-min; Gao, Chang; Li, Jiali; Liu, Jiayin; Cheng, Qijun; Dai, Chen; Ma, Qin; Qi, Zhongquan; Zhao, Bin

doi:10.1038/s41419-018-0446-8

Cited by 16 publications

(10 citation statements)

References 28 publications

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“…The development of tolerance to grafts is associated with the levels of CD4 + Foxp3 + Tregs 34 and Th1/Th2 balance 35 . In our study, flow cytometric analysis showed no significant change in CD4 + Foxp3 + Tregs in recipient spleen after LEF therapy (data not shown), which was consistent with the reports that LEF cannot induce CD4 + Foxp3 + Treg generation 15 , 16 in xenotransplantation. In addition, the influence of LEF on Th1 (IFN-γ) and Th2 cells (IL-4) was determined in xenografts.…”

Section: Discussionsupporting

confidence: 93%

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Leflunomide Inhibits rat-to-Mouse Cardiac Xenograft Rejection by Suppressing Adaptive Immune Cell Response and NF-κB Signaling Activation

Xie

Guo

et al. 2021

Cell Transplant

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Xenotransplantation is a potential solution for the severe shortage of human donor organs and tissues. The generation of humanized animal models attenuates strong innate immune responses, such as complement-mediated hyperacute rejection. However, acute vascular rejection and cell mediated rejection remain primary barriers to xenotransplantation, which limits its clinical application. In this study, we systematically investigated the immunosuppressive effect of LEF using a rat-to-mouse heart xenotransplantation model. SD rat xenogeneic hearts were transplanted into C57BL/6 mice, and survived 34.5 days after LEF treatment. In contrast, BALB/c allogeneic hearts were transplanted into C57BL/6 mice, and survived 31 days after LEF treatment. Compared to normal saline treatment, LEF treatment decreased xenoreactive T cells and CD19+ B cells in recipient splenocytes. Most importantly, LEF treatment protected myocardial cells by decreasing xenoreactive T and B cell infiltration, inflammatory gene expression, and IgM deposition in grafts. In vivo assays revealed that LEF treatment eliminated xenoreactive and alloreactive T and B lymphocytes by suppressing the activation of the NF-κB signaling pathway. Taken together, these observations complement the evidence supporting the potential use of LEF in xenotransplantation.

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Section: Discussionsupporting

confidence: 93%

“…Thus, LEF has the potential to inhibit both T and B cell functions. However, in vivo experiments have demonstrated the opposite results 15 . In a mouse-to-rat heart transplantation model 16 , LEF monotherapy showed no effect on the production of Th1 cytokines and T cell function.…”

Section: Introductionmentioning

confidence: 99%

Leflunomide Inhibits rat-to-Mouse Cardiac Xenograft Rejection by Suppressing Adaptive Immune Cell Response and NF-κB Signaling Activation

Xie

Guo

et al. 2021

Cell Transplant

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“…Zhao et al reported ATO has the immunosuppressive effect of arsenic trioxide on islet xenotransplantation and they found ATO inhibited proliferation of T lymphocyte and increased the proportion of Foxp3 + regulatory T cells in recipient mice [43]. Based on our results, we suggest ATO induced upregulation of PD-L1, which negatively regulates T cell immunity, is probably one of the underlying molecular mechanisms of the immune suppressive effects of ATO observed in the mouse islet xenotransplantation model.…”

Section: Discussionsupporting

confidence: 72%

Arsenic trioxide (ATO) induced degradation of Cyclin D1 sensitized PD-1/PD-L1 checkpoint inhibitor in oral and esophageal squamous cell carcinoma

Zhu¹,

Li²,

Li³

et al. 2020

J. Cancer

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Arsenic trioxide (ATO) is widely studied for its antitumor efficacy and several recent studies suggested the immune modulatory effects of ATO in animal models. In this study we found ATO treatment induced increased ROS production and DNA damage in esophageal squamous cell carcinoma (ESCC) cells, led to DNA damage mediated degradation of Cyclin D1 and upregulation of PD-L1 in these cancer cells. Mechanistically, we found ATO induced a transient upregulation and nuclear translocation of Cyclin D1 by sumoylation. Followed with increased ubiquitination and degradation of Cyclin D1 through T286 phosphorylation, and at least partly mediated by Stat1 Y701 phosphorylation. We observed inversed correlations between Cyclin D1 and PD-L1 expression levels in human ESCC tissues. With 4NQO induced PD-L1 humanized mouse oral and esophageal squamous carcinoma model, we found combinatory administration of ATO and check point inhibitor resulted in a significant reduction of tumor volumes. Inversed correlation between Cyclin D1 with PD-L1 was also observed in the 4NQO induced mouse ESCC and OSCC model. Together, these data suggested ATO induced degradation of Cyclin D1 and functional suppression of CDK4/6 pathway sensitized OSCC and ESCC to checkpoint inhibitor treatment.

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“…In the treatment of APL, ATO has a specific pro-apoptotic effect on leukaemic cells and decreases the amount and inhibits the function of Treg cells [ 34 ]. However, in a murine islet allotransplantation model, ATO inhibited immune rejection and prolonged islet allograft survival by increasing the proportion of Foxp3+ Treg cells, inhibiting proliferation of T lymphocytes and decreasing B lymphocytes [ 35 ]. ATO, when combined with co-stimulation blockade, prolongs the survival of cardiac allografts in alloantigen-primed mice.…”

Section: Discussionmentioning

confidence: 99%

Safety and efficacy of low-dose intravenous arsenic trioxide in systemic lupus erythematosus: an open-label phase IIa trial (Lupsenic)

et al. 2021

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Background Lupus animal model has shown that arsenic trioxide (ATO), a treatment of acute promyelocytic leukaemia, could be effective in SLE. This is the first clinical study to determine the safety and efficacy of a short course of intravenous ATO in patients with active SLE. Methods This phase IIa, open-label, dose-escalating study enrolled 11 adult SLE patients with a non-organ threatening disease, clinically active despite conventional therapy. Patients received 10 IV infusions of ATO within 24 days. The first group received 0.10 mg/kg per injection, with dose-escalating to 0.15 mg/kg in a second group, and to 0.20 mg/kg in a third group. The primary endpoint was the occurrence of adverse events (AEs) and secondary endpoints were the number of SLE Responder Index 4 (SRI-4) responders at week 24 and reduction of corticosteroid dosage. In an exploratory analysis, we collected long-term data for safety and attainment of lupus low disease activity state (LLDAS). Results Four serious AEs occurred (grade 3 neutropenia, osteitis, neuropathy), 2 of which were attributable to ATO (neutropenia in the 2 patients treated with mycophenolate). Two patients suffered a severe flare during the last 4 weeks of the trial. At W24, five patients among 10 were SRI-4 responders. Overall, mean corticosteroid dosage decreased from 11.25 mg/day at baseline to 6 mg/day at W24 (P < 0.01). In the long term, 6 patients attained LLDAS at W52, which continued at last follow-up (median LLDAS duration 3 years, range 2–4). Conclusions A short course of ATO has an acceptable safety profile in SLE patients and encouraging efficacy. Trial registration ClinicalTrials.gov, NCT01738360 registered 30 November 2012

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Immunosuppressive effect of arsenic trioxide on islet xenotransplantation prolongs xenograft survival in mice

Cited by 16 publications

References 28 publications

Leflunomide Inhibits rat-to-Mouse Cardiac Xenograft Rejection by Suppressing Adaptive Immune Cell Response and NF-κB Signaling Activation

Leflunomide Inhibits rat-to-Mouse Cardiac Xenograft Rejection by Suppressing Adaptive Immune Cell Response and NF-κB Signaling Activation

Arsenic trioxide (ATO) induced degradation of Cyclin D1 sensitized PD-1/PD-L1 checkpoint inhibitor in oral and esophageal squamous cell carcinoma

Safety and efficacy of low-dose intravenous arsenic trioxide in systemic lupus erythematosus: an open-label phase IIa trial (Lupsenic)

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