Effects of tacrolimus (FK506) and mycophenolate mofetil (MMF) on regulatory T cells and co-inhibitory receptors in the peripheral blood of human liver allograft patients

Zeng, Qiang; Yuan, Xiaoye; Li, Wei; Liu, Baowang; Zhao, Xinyang; Ren, Guijun; Wang, Yang; Dou, Jianmin; Wang, Guiying

doi:10.1080/08923973.2018.1533026

Cited by 15 publications

(11 citation statements)

References 33 publications

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“…In inflammatory diseases, Tregs are involved in maintaining the immune homeostasis mainly by producing anti-inflammatory cytokines, such as IL-10, IL-35, and TGF- β [ 37 ]. A previous study has demonstrated that long-term use of immunosuppressants increased Tregs in PBMC of patients and mice with organ transplantation [ 38 , 39 ]. Increased Tregs limited immune activation and prevented the development of graft rejection through secreting anti-inflammatory cytokines and inhibiting the activity of effector T cells [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

The Association between Regulatory T Cell Subpopulations and Severe Pneumonia Post Renal Transplantation

Zhuang

Cai

Yang

et al. 2022

Journal of Immunology Research

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Severe pneumonia accounts for the majority of morbidity and mortality in renal allograft recipients due to immunosuppressant maintenance. Regulatory T cells (Tregs), which are involved in tackling infections under immunosuppressive conditions, are rarely uncovered. We aimed to investigate the relationship between various Treg subpopulations and severe pneumonia after kidney transplantation (KTx). KTx recipients with pneumonia were divided into severe pneumonia and mild pneumonia groups. The frequencies and absolute numbers (Ab No.) of total Tregs (CD4+CD25+FoxP3+), six subsets of Tregs (Helios+/-, CD39+/-, and CD45RA+/-), and T cells, B cells, and NK cells were assessed from peripheral blood via flow cytometry using the t or Mann-Whitney test and receiver operating curve analysis. We also determined the median fluorescence intensity (MFI) of human leukocyte antigen- (HLA-) DR on monocytes and CD64 on neutrophils. Logistic regression was used to identify the risk factors of disease progression, and Pearson’s correlation analysis was performed to identify relationships between the measured immune indices and patients’ clinical information. Our research indicated that Treg subpopulations were strongly associated with severe pneumonia progression post KTx. Based on the monitoring of Treg subpopulations, better-individualized prevention and therapy might be achieved for patients with severe pneumonia post KTx.

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Section: Discussionmentioning

confidence: 99%

The Association between Regulatory T Cell Subpopulations and Severe Pneumonia Post Renal Transplantation

Zhuang

Cai

Yang

et al. 2022

Journal of Immunology Research

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“…Several reports have found that FK506 has no effect on Treg cells, 44 others suggest that FK506 may increase the number of Treg cells in organ transplant recipients, [45][46][47] while some others have proved that FK506 can reduce the frequency of Treg cells in MuSK-antibody positive myasthenia gravis and systemic lupus erythematosus patients, 48,49 a finding that is consistent with transplantation studies. 50 Therefore, the effect of FK506 on Treg cells is worthy of in-depth study. In this study, we divided Treg cells into three subgroups and made our findings.…”

Section: Discussionmentioning

confidence: 99%

Plasticity of Treg and imbalance of Treg/Th17 cells in patients with systemic sclerosis modified by FK506

Liu

et al. 2021

Int J Immunopathol Pharmacol

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To determine the effects of Tacrolimus (FK506) on Treg cells and subpopulations in SSc patients and assess the ability of FK506 to modify the immune imbalance of Treg/Th17 cells. We analyzed PBMC from five SSc patients and six healthy control by flow cytometry after cultured with 0, 0.1, 1, or 10 ng/ml FK506 in vitro. The number of Treg cells decreased in SSc patients treated with FK506. The number of FrI cells were decreased in SSc following FK506 treatment. The drug did increase the frequency of FrII/Treg cells, but not FrII cells. However, FK506 significantly decreased FrIII in both SSc patients and controls. FK506 clearly decreased the numbers of Th17 cells and FoxP3+IL-17+ cells. The proliferation capacity of cells was also inhibited by FK506, which had a greater effect on FoxP3− cells than FoxP3+ cells. FK506 did inhibit the proliferation of FrIII cells, but not FrI or FrII cells. Our study provides that FK506 reduced the number of FoxP3low CD45RA− T cells (FrIII) by inhibiting its proliferation. Therefore, FK506 modifies Treg cells and the immune imbalance between Tregs and Th17 cells in SSc patients.

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“…Zeng et al found that FK506 decreases the abundance of CD4 + and CD8 + T cells in the peripheral blood of human liver allograft patients. 26 Recently, FK506 was revealed to enhance Treg function via PD-1. 27 Within the same pathway, we found that without the PD-L1 signal, FK506 could not effectively suppress T cell proliferation in vitro (Figure 5G), which helps to explain the increased amount of splenocytes in vivo (Figure 2A, B).…”

Section: Fkbp51 Is Necessary In Fk506mediated Pd-l1 Regulationmentioning

confidence: 99%

Novel immunosuppressive effect of FK506 by upregulation of PD‐L1 via FKBP51 in heart transplantation

Luo

Du²,

Chen³

et al. 2022

Scand J Immunol

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The calcineurin inhibitor–FK506–is a first‐line immunosuppressant that regulates T cell secretion of IL‐2 and other cytokines. However, the mechanism of its protective effect on target cells and its role on tumour recurrence and interaction with anti‐tumour immune checkpoint inhibitors, such as PD‐L1 blocking, are still unclear. Here, in a murine heart transplantation model, we observed the upregulation of programmed death‐ligand 1 (PD‐L1) expression by FK506 in both dendritic cells (DCs) and allografts. Blocking PD‐L1 during FK506 treatment increased IFN‐γ and TNF‐α expression, enhanced CD4+ and CD8+ T cell proliferation, and suppressed Treg differentiation. Moreover, PD‐L1 decreased T cell infiltration and induced T cell apoptosis in both the spleen and graft. PD‐L1 was not only required in FK506‐mediated immunosuppression but also upregulated by FK506. Treatment with SAFit2, a FKBP51 selective inhibitor, reduced the expression of PD‐L1 on DCs and the grafts and interfered with the immunosuppressive effect of FK506, suggesting that the mechanism depends on FK506‐binding protein (FKBP) 51 expression. Overall, our results add new insights into the role of FK506, not only on T cell cytokine secretion but also on co‐inhibitory molecular regulation and target cell immune privilege.

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Effects of tacrolimus (FK506) and mycophenolate mofetil (MMF) on regulatory T cells and co-inhibitory receptors in the peripheral blood of human liver allograft patients

Cited by 15 publications

References 33 publications

The Association between Regulatory T Cell Subpopulations and Severe Pneumonia Post Renal Transplantation

The Association between Regulatory T Cell Subpopulations and Severe Pneumonia Post Renal Transplantation

Plasticity of Treg and imbalance of Treg/Th17 cells in patients with systemic sclerosis modified by FK506

Novel immunosuppressive effect of FK506 by upregulation of PD‐L1 via FKBP51 in heart transplantation

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