Arsenic trioxide inhibits accelerated allograft rejection mediated by alloreactive CD8+ memory T cells and prolongs allograft survival time

Li, Chun; Guan, Tianjun; Gao, Chang; Lin, Yingying; Yan, Guoliang; Zhu, Maoshu; Lv, Chong-Shan; Xia, Junjie; Qi, Zhongquan

doi:10.1016/j.trim.2015.05.004

Cited by 9 publications

(10 citation statements)

References 44 publications

(45 reference statements)

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“…The results indicated that neutralization of CXCL10 prolonged re-allograft mean survival time, reduced the proportion of CD8 + Tm cells and mitigated inflammatory cell infiltration. In addition, Tm cells also produce effector cytokines in situ to recruit additional immune cells that mediate early graft tissue damage (34,35); for instance, IL-2 secreted by tissue-residing Tm cells and IFN-γ secreted by effector Tm cells. In the present study, the serum and tissue expression levels of rejection-associated cytokines were assessed.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of C‑X‑C motif chemokine 10 reduces graft loss mediated by memory CD8+ T cells in a rat cardiac re‑transplant model

Deng

et al. 2017

Exp Ther Med

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Abstract. The interaction of chemokine (C-X-C motif) ligand 10 (CXCL10) with its receptor (CXCR3) is a critical process in recruiting donor reactive T cells to a graft and alloantigen-specific memory T (Tm) cells exert a principal function in promoting graft dysfunction during accelerated cardiac rejection. However, whether CXCL10 chemokine exerts any effects on acute accelerated rejection mediated by CD8 + Tm cells in a re-transplant model has remained elusive. The present study established a cardiac transplant model by advanced microsurgery technology and improved organ storage. A novel rat model of cardiac re-transplantation was established at 40 days following primary heart transplant. The experiment included two parts, and when models were established, the rats were divided into two groups: Primary cardiac transplant (HTx) and re-transplantation without treatment (HRTx). In part 1, recipients from part 2, including re-transplantation without treatment (HRTx+NS) and re-transplantation treated with anti-CXCL10 antibodies (500 µg every other day by intraperitoneal injection; HRTx+CXCL10 Abs group). The graft survival time was observed and graft infiltration by inflammatory cells was assessed via histology of cardiac graft sections; in addition, the gene expression and the serum concentration of CXCL10 in each group was assessed. Indexes such as rejection-associated cytokines were assayed by reverse-transcription quantitative PCR and ELISA kits, and flow cytometry of splenocytes was used to detect Tm cells in the re-transplantation groups. The results demonstrated that level of CXCL10 was significantly increased and the graft mean survival time was shortened accompanied with aggravated lymphocyte cell infiltration in the HRTx group when compared that in the HTx group; in addition, the serum levels and mRNA expression of interleukin (IL)-2 and interferon (IFN)-γ were increased, while transforming growth factor (TGF)-β was decreased in the HRTx group. Furthermore, neutralization of CXCL10 prolonged the graft mean survival time and delayed accelerated rejection. Compared with that in the HRTx+NS group, serum levels and graft tissue mRNA expression of IFN-γ and IL-2 were decreased in the HRTx+CXCL10 Abs group, while TGF-β mRNA was significantly increased but the serum concentration was not significantly affected. In addition, there was no difference in IL-10 between the two groups, while delayed accelerated rejection paralleled with inflammatory cell infiltration decreased and the proliferation and differentiation of CD8 + Tm cells in secondary lymphoid organs were reduced in the HRTx+CXCL10 Abs group vs. those in the HRTx+NS group. The present study demonstrated that CXCL10 had a crucial role in cardiac transplantation and re-transplantation, and that treatment with CXCL10 antibodies delays accelerated acute rejection mediated by Tm cells in a rat model of cardiac re-transplantation. IntroductionA multidisciplinary program has been initiated to better establish transplantation for prolonging survival time of cardi...

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Section: Discussionmentioning

confidence: 99%

Inhibition of C‑X‑C motif chemokine 10 reduces graft loss mediated by memory CD8+ T cells in a rat cardiac re‑transplant model

Deng

et al. 2017

Exp Ther Med

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

Section: Introductionmentioning

confidence: 97%

Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice by inducing CD4+ T cell apoptosis

Xue

Zhong

et al. 2020

J Neuroinflammation

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Background: Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system characterized by severe white matter demyelination. Because of its complex pathogenesis, there is no definite cure for MS. 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 with 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 yet been clearly elucidated. In this study, we attempted to assess whether ATO could be used 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 the 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 an apoptosis assay, JC-1 staining, imaging under a 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 levels 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 cell apoptosis via the mitochondrial pathway both in vitro and in vivo. Additionally, the administration of ATO had no adverse effect on the heart, liver, or kidney function, nor did it 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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“…The metalloid inhibits the alloreactive process by selectively killing activated DCs and CD4-positive T cells. In addition, ATO prolongs cardiac and islet allograft survival in acute rejection murine models through the repression of alloreactive CD4+ and CD8+ memory T cells [61][62][63]. Finally, the fact that arsenic blocks inflammasome activity and the subsequent IL-1 production in human macrophages suggests that arsenic may limit chronic inflammation in severe inflammasomemediated disease [47].…”

Section: Potential Beneficial Effects Of Arsenic-induced Immunosupprementioning

confidence: 99%

Arsenic and the immune system

Bellamri

Morzadec

Fardel

et al. 2018

Current Opinion in Toxicology

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Arsenic is a metalloid to which millions of individuals are exposed worldwide, primarily through the consumption of contaminated drinking water or food items. Chronic arsenic exposure is associated with an increased incidence of several diseases, including lung infections and skin cancers. Epidemiological and experimental evidence demonstrates that the metalloid impairs the activity of both the innate and adaptive immune systems. Arsenic alters the differentiation, activation and/or proliferation of human macrophages, dendritic cells and T lymphocytes. Arsenic immunotoxicity results from intracellular oxidative lesions modulating basal gene expression or leading to DNA damage. Arsenic also induces epigenetic effects by modulating DNA methylation and post-translational histone modifications. In addition, the metalloid has recently been found to inhibit in vitro and in vivo inflammasome activities. Arsenic immunotoxicity likely contributes to the systemic effects associated with arsenic exposure by limiting immune surveillance and/or promoting inflammation. Experimental studies also suggest that the immunosuppressive effects of arsenic efficiently prevent or treat severe immune-related diseases. The purpose of this review is to summarize the current knowledge of the impact of arsenic on the immune system.

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Arsenic trioxide inhibits accelerated allograft rejection mediated by alloreactive CD8+ memory T cells and prolongs allograft survival time

Cited by 9 publications

References 44 publications

Inhibition of C‑X‑C motif chemokine 10 reduces graft loss mediated by memory CD8+ T cells in a rat cardiac re‑transplant model

Inhibition of C‑X‑C motif chemokine 10 reduces graft loss mediated by memory CD8+ T cells in a rat cardiac re‑transplant model

Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice by inducing CD4+ T cell apoptosis

Arsenic and the immune system

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