Arsenic Trioxide Induces T Cell Apoptosis and Prolongs Islet Allograft Survival in Mice

Gao, Chang; Jiang, Jie; Ma, Ping; Cheng, Panpan; Lian, Yunsong; Zhao, Bin; Li, Chenglin; Peng, Yuanzheng; Wang, Feiyu; Lin, Yingying; Jin, Ning; Li, Jiali; Li, Qing; Leng, Yun; Xia, Junjie; Qi, Zhongquan

doi:10.1097/tp.0000000000000735

Cited by 15 publications

(21 citation statements)

References 66 publications

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“…Traditional Chinese medicines are attracting attention because of their many medicinal herb resources. Among them, Tripterygium wilfordii , 11 arsenic trioxide (As 2 O 3 ) 12 and Radix Isatidis 13 possess anti‐inflammatory and immunosuppressive properties. In this study, we focused on DCAAA, a new compound derived from Radix Isatidis .…”

Section: Discussionmentioning

confidence: 99%

Combination of N, N′‐dicyclohexyl‐N‐arachidonic acylurea and tacrolimus prolongs cardiac allograft survival in mice

Qin

et al. 2020

Immunol Cell Biol

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Current immunosuppressive agents for organ transplantation are not ideal because of their strong toxicity and adverse effects. Hence, there is an urgent need to develop novel immunosuppressive agents. The compound N, N 0dicyclohexyl-N-arachidonic acylurea (DCAAA) is a novel highly unsaturated fatty acid from the traditional Chinese medicinal plant Radix Isatidis. In this study, we systematically investigated the toxicity, immunosuppressive effect and mechanisms underlying the activity of DCAAA. The toxicity tests showed that DCAAA treatment did not lead to red blood cell hemolysis and did not affect the liver and kidney functions in mice. The lymphocyte transformation test showed that DCAAA treatment inhibited lymphocyte proliferation in a dosedependent manner. An in vivo cardiac allotransplantation experiment showed that DCAAA treatment could suppress the immune rejection and significantly prolong the survival of cardiac allografts in recipient mice by reducing the proportion of CD4 + T cells in the spleen and grafts, concentration of interferon-c in the supernatant and serum and infiltration of inflammatory cells into the grafts. Moreover, a combination treatment with DCAAA and tacrolimus had a synergistic effect in preventing acute rejection of heart transplants. In vitro molecular biology experiments showed that DCAAA treatment inhibited activation of the T-cell receptor-mediated phosphoinostide 3-kinase-protein kinase B pathway, thereby arresting cell cycle transition from the G 1 to the S phase, and inhibiting lymphocyte proliferation. Overall, our study reveals a novel, low-toxicity immunosuppressive agent that has the potential to reduce the toxic side effects of existing immunosuppressive agents when used in combination with them.

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Section: Discussionmentioning

confidence: 99%

Combination of N, N′‐dicyclohexyl‐N‐arachidonic acylurea and tacrolimus prolongs cardiac allograft survival in mice

Qin

et al. 2020

Immunol Cell Biol

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“…Moreover, As 2 O 3 and leflunomide showed non‐toxicity under the dose used in this study. Gao et al also proved in a mouse islet allotransplant model that As 2 O 3 is non‐toxic . These results indicated that As 2 O 3 may be the best option for combination with leflunomide.…”

Section: Discussionmentioning

confidence: 92%

“…As 2 O 3 has been used in clinical therapy of leukemia patients, and the mechanisms involved have been unveiled, but current studies indicated that As 2 O 3 could suppress alloimmune rejection . However, the efficacy of As 2 O 3 in xenotransplantation remains unknown.…”

Section: Discussionmentioning

confidence: 99%

As₂O₃ combined with leflunomide prolongs heart xenograft survival via suppressing the response of Th1, Th2, and B cells in a rat model

Jiao

Leng

Xia

et al. 2016

Xenotransplantation

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Xenotransplantation remits the severe shortage of human organs and tissues for transplantation, which is a problem that severely limits the application of transplantation to the treatment of human disease. However, severe immune rejection significantly limits the efficacy of xenotransplantation. In this study, we systematically investigated the immunosuppressive effect and mechanism of action of As2 O3 and leflunomide using a hamster-to-rat heart xenotransplantation model. We initially examined heart xenograft survival following As2 O3 and leflunomide treatment alone or combined treatment. We found that treatment with As2 O3 combined with leflunomide can significantly prolong the survival of heart xenograft by inhibiting Th1 and Th2 differentiation and reducing the production of IgG and IgM. Interestingly, As2 O3 and leflunomide showed low toxicity to the organs of the recipient. Taken together, these observations indicate that treatment with As2 O3 combined with leflunomide may be a promising immunosuppressive schedule for xenotransplantation.

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“…In MRL/lpr mice, treatment with 5 mg/kg/day of ATO for 2 months inhibited autoreactive lymphocytes and blocked the progression of autoimmune diseases [19]. In mice allogeneic islet transplantation model, treatment with 1 mg/kg/day of ATO twice per day significantly prolonged the survival of islet allograft [22]. A recent study suggested that ATO (1 mg/kg/day) suppressed acute graft-versus-host disease in mice [20].…”

Section: Discussionmentioning

confidence: 99%

“…A recent study suggested that ATO suppressed acute graft-versus-host disease in mice [20]. Our previous work demonstrated that ATO attenuated acute rejection and prolonged graft survival in heart [21] and islet [22] transplantation models. These findings indicate that ATO elicits anti-inflammatory and immunosuppressive effects.…”

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confidence: 96%

Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice through inducing apoptosis of CD4+ T cells

Xue

Zhong

et al. 2020

Preprint

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Background: Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system characterized by severe demyelination of white matter. There is no definite cure for MS owing to its complex pathogenesis. Experimental autoimmune encephalomyelitis (EAE) is an ideal animal model for the study of MS. Arsenic trioxide (ATO) is an ancient Chinese medicine used for its therapeutic properties for several autoimmune diseases. It is also used to inhibit acute immune rejection due to its anti-inflammatory and immunosuppressive properties. However, it is unclear whether ATO has a therapeutic effect on EAE, and the underlying mechanisms have not been clearly elucidated. In this study, we attempted to explore the possibility of using ATO to ameliorate EAE in mice.Methods: ATO (0.5 mg/kg/day) was administered intraperitoneally to EAE mice 10 days post-immunization for 8 days. On day 22 post-immunization, the spinal cord, spleen, and blood were collected to analyze demyelination, inflammation, microglia activation, and proportion of CD4+ T cells. In vitro, for mechanistic studies, CD4+ T cells were sorted from the spleen of naïve C57BL/6 mice and treated with ATO and then used for apoptosis assay, JC-1 staining, transmission electron microscope, and western blotting.Results: ATO delayed the onset of EAE and alleviated the severity of EAE in mice. Treatment with ATO also attenuated demyelination, alleviated inflammation, reduced microglia activation and decreased the expression of IL-2, IFN-γ, IL-1β, IL-6, and TNF-α in EAE mice. Moreover, the number and proportion of CD4+ T cells in the spinal cord, spleen, and peripheral blood were reduced in ATO-treated EAE mice. Finally, ATO induced CD4+ T cells apoptosis through the mitochondrial pathway both in vitro and in vivo. Additionally, the administration of ATO had no adverse effect on the heart, liver, and kidney function and did not induce apoptosis in the spinal cord.Conclusions: Overall, our findings indicated that ATO plays a protective role in the initiation and progression of EAE and has the potential to be a novel drug in the treatment of MS.

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Arsenic Trioxide Induces T Cell Apoptosis and Prolongs Islet Allograft Survival in Mice

Abstract: Arsenic trioxide may prevent allograft rejection by inhibiting T-cell proliferation and inducing T-cell apoptosis.

Cited by 15 publications

References 66 publications

Combination of N, N′‐dicyclohexyl‐N‐arachidonic acylurea and tacrolimus prolongs cardiac allograft survival in mice

Combination of N, N′‐dicyclohexyl‐N‐arachidonic acylurea and tacrolimus prolongs cardiac allograft survival in mice

As₂O₃ combined with leflunomide prolongs heart xenograft survival via suppressing the response of Th1, Th2, and B cells in a rat model

Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice through inducing apoptosis of CD4+ T cells

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Arsenic Trioxide Induces T Cell Apoptosis and Prolongs Islet Allograft Survival in Mice

Abstract: Arsenic trioxide may prevent allograft rejection by inhibiting T-cell proliferation and inducing T-cell apoptosis.

Cited by 15 publications

References 66 publications

Combination of N, N′‐dicyclohexyl‐N‐arachidonic acylurea and tacrolimus prolongs cardiac allograft survival in mice

Combination of N, N′‐dicyclohexyl‐N‐arachidonic acylurea and tacrolimus prolongs cardiac allograft survival in mice

As2O3 combined with leflunomide prolongs heart xenograft survival via suppressing the response of Th1, Th2, and B cells in a rat model

Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice through inducing apoptosis of CD4+ T cells

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As₂O₃ combined with leflunomide prolongs heart xenograft survival via suppressing the response of Th1, Th2, and B cells in a rat model