The advantage of Sirolimus in amplifying regulatory B cells and regulatory T cells in liver transplant patients

Jiang, Song; Du, Gangjun; Chen, Wen; Bao, Pengtao; Li, Binyu; Lü, Qian; Shi, Bingyi

doi:10.1016/j.ejphar.2019.172872

Cited by 16 publications

(14 citation statements)

References 35 publications

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“…In a transgenic model of amyotrophic lateral sclerosis, IL-10 + regulatory B cells adoptive transfer therapy could effectively reduce the number of bone marrow-derived macrophages in the central nervous system (33). Song et al (34). showed that Sirolimus could amplify regulatory B and T cells in liver transplant patients.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19+CD24hiCD27+ Breg Cells

Gao

Zhou

et al. 2020

Front. Immunol.

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CD19+CD24hiCD27+ memory Breg cells exhibit decreased abundance in patients with chronic graft-versus-host disease (cGVHD) after liver transplantation and produce less IL-10 than those from patients without cGVHD and healthy donors. Due to the lack of Breg cells and the difficulty in expanding them in vitro, in mouse models and early human clinical trials, the adoptive transfer of Breg cells to autoimmune diseases is greatly restricted. Glycogen synthase kinase 3β (GSK-3β) is a multifunctional serine/threonine (ser/thr) protein kinase that can participate in B cell growth, metabolic activity, and proliferation. Phosphoprotein array analysis showed that p-GSK-3β-s9 was highly expressed in mBreg cells. Furthermore, here, we demonstrated that GSK-3β expression in mBreg cells is lower than that observed in B cells by flow cytometry. We found that the treatment of B cells with the specific GSK-3β inhibitor SB216763 can significantly increase the proportion and immunosuppressive function of mBreg cells in vitro. Nuclear factor of activated T cells (NFAT) is one of a pivotal regulator of gene expression in adaptive immune system. Here, we observed that inhibition of GSK-3β by SB216763 results in enhanced expression of NFATc1 in B cells, which is essential in regulating the ability of B cells to secrete IL-10. By constructing a xGVHD mouse model, we observed that SB216763-treated mBreg cells effectively prevent xenogeneic GVHD. Here we propose a novel strategy using SB216763 to inhibit GSK-3β and then enhance the proportion and immunosuppressive function of mBreg cells by increasing the expression of NFATc1. This approach may be used as a therapy to ameliorate GVHD and inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19+CD24hiCD27+ Breg Cells

Gao

Zhou

et al. 2020

Front. Immunol.

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“…As discussed earlier, maintenance immunosuppressants such as prednisolone and azathioprine may have an effect on circulating IL‐10 + Breg [16,17]. Sirolimus may also support the in vivo and in vitro expansion of IL‐10 + Bregs as well as FoxP3 + Tregs in liver transplantation [75].…”

Section: Introductionmentioning

confidence: 99%

Regulatory B cells in transplantation: roadmaps to clinic

et al. 2020

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Over the last two decades, an additional and important role for B cells has been established in immune regulation. Preclinical studies demonstrate that regulatory B cells (Breg) can prolong allograft survival in animal models and induce regulatory T cells. Operationally tolerant human kidney transplant recipients demonstrate B-cell-associated gene signatures of immune tolerance, and novel therapeutic agents can induce Bregs in phase I clinical trials in transplantation. Our rapidly expanding appreciation of this novel B-cell subtype has made the road to clinical application a reality. Here, we outline several translational pathways by which Bregs could soon be introduced to the transplant clinic.

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“…Sirolimus, also known as rapamycin, is a macrolide antibiotic immunosuppressant, which has been widely used for liver transplantation (Song et al, 2019;Zhang et al, 2019), kidney transplantation (Ferron et al, 1997;Jiao et al, 2009), kaposiform hemangioendothelioma (Wang et al, 2019a) etc. In addition, it was also been reported that sirolimus has been used for TSC (Franz and Capal, 2017).…”

Section: Discussionmentioning

confidence: 99%

Initial Dosage Recommendation for Sirolimus in Children With Tuberous Sclerosis Complex

Wang

Chen

et al. 2020

Front. Pharmacol.

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Sirolimus is already used in the treatment of tuberous sclerosis complex (TSC), however, with narrow therapeutic range and considerable inter-and intra-individual pharmacokinetic variability, making it hard to develop an appropriate sirolimus initial dosage regimen, especially in children with TSC. The aim of this study was to recommend the optimal sirolimus initial dosing regimen in pediatric patients with TSC. Underlying physiological and genetic factors were collected to explore the effects on clinical sirolimus concentrations by establishing a nonlinear mixed effect (NONMEM) model, and to further simulate the optimal sirolimus initial dosing regimen using Monte Carlo method in pediatric patients with TSC. The once-daily regimen and the twice-daily regimen were recommended, respectively. For once-daily regimen, the dosages of 0.10, 0.07, 0.05, 0.04, 0.03 mg/kg/day were recommended for children with weights of 5-10, 10-20, 20-30, 30-50, and 50-60 kg, respectively. For twice-daily regimen, the dosages of 0.04, 0.03, 0.02 mg/kg/day (the daily dose was divided evenly into two doses) were recommended for children with weights of 5-20, 20-40, 40-60 kg, respectively. The initial dosages of sirolimus in children with TSC were recommended for the first time.

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The advantage of Sirolimus in amplifying regulatory B cells and regulatory T cells in liver transplant patients

Cited by 16 publications

References 35 publications

Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19+CD24hiCD27+ Breg Cells

Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19+CD24hiCD27+ Breg Cells

Regulatory B cells in transplantation: roadmaps to clinic

Initial Dosage Recommendation for Sirolimus in Children With Tuberous Sclerosis Complex

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