The effects of leflunomide on CD4+CD25+Foxp3+ T regulatory cells in mice receiving allogeneic bone marrow transplantation

Jin, Dong-Yan; Duan, Kaizhong; Zhang, Lianjun; Peng, Jiao; Zhao, Yong

doi:10.1007/s00011-011-0388-4

Cited by 6 publications

(4 citation statements)

References 48 publications

(44 reference statements)

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“…Our study found that low-dose sirolimus (0.5 mg per other day with the serum concentration of 1.8 ± 0.4 ng/ml) had an immunoregulatory property besides immunosuppression by the rebalancing of Th17 and Tregs. Conventional immunosuppressant medications can alleviate disease activity by inhibiting lymphocytes nonspecifically [28, 29]. Our results showed that conventional immunosuppressive strategy not only decreased the proinflammatory Th17 cells but also reduced anti-inflammatory Tregs, which may aggravate the disturbance of the immune balance.…”

Section: Discussionmentioning

confidence: 75%

Low-Dose Sirolimus Immunoregulation Therapy in Patients with Active Rheumatoid Arthritis: A 24-Week Follow-Up of the Randomized, Open-Label, Parallel-Controlled Trial

Wen

Wang

Zhang

et al. 2019

Journal of Immunology Research

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Background We have reported previously the insufficient absolute number or functional defects of regulatory T cells (Tregs) in patients with rheumatoid arthritis (RA), challenging conventional unspecific immunosuppressive therapy. Sirolimus, a mTOR inhibitor, is reported to allow growth of functional Tregs; here, we investigated the efficacy of low-dose sirolimus combined with conventional immunosuppressants (sirolimus immunoregulation therapy) for RA treatment with lower side effects and better tolerance. Methods In this nonblinded and parallel-group trial, we randomly assigned 62 patients to receive conventional glucocorticoids and immunosuppressants with or without sirolimus at a dosage of 0.5 mg on alternate days for 24 weeks in a 2 : 1 ratio. The demographic features, clinical manifestations, and laboratory indicators including peripheral blood lymphocyte subgroups and CD4+T subsets were compared before and after the treatment. Results Finally, 37 patients in the sirolimus group and 18 in the conventional treated group completed the 6-month study. By 24 weeks, the patients with sirolimus experienced significant reduction in disease activity indicators including DAS28, ESR, and the number of tender joints and swollen joints (p < 0.001). Notably, they had a higher level of Tregs as compared with those with conventional therapy alone (p < 0.05), indicating that sirolimus could partly restore the reduced Tregs. Concomitantly, their usage of immunosuppressants for controlling disease activity was decreased as compared with the conventional group with no difference in blood routine, and liver and renal functions both before and after the treatment of sirolimus and between the two groups (p > 0.05). Conclusions Low-dose sirolimus immunoregulatory therapy selectively upregulated Tregs and partly replaced the usage of immunosuppressants to control disease activity without overtreatment and evaluable side effect. Further study is required using a large sample of RA patients treated with sirolimus for a longer period. This trial is registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/showproj.aspx?proj=17245).

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Section: Discussionmentioning

confidence: 75%

Low-Dose Sirolimus Immunoregulation Therapy in Patients with Active Rheumatoid Arthritis: A 24-Week Follow-Up of the Randomized, Open-Label, Parallel-Controlled Trial

Wen

Wang

Zhang

et al. 2019

Journal of Immunology Research

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“…In contrast to the results for Th17, we observed no significant alternation in the proportions of CD4 + CD25 + Foxp3+ Tregs in LEF treated CIA mice comparing to CIA groups. In Di Jin research [ 20 ], differential changes of CD4 + CD25 + Foxp3+ Treg cells in different peripheral immune tissues or organs were observed after LEF treatment in mice with and without body mass index (BMI). The ratios of Treg cells were enhanced in the thymus, but significantly decreased in the spleens but not in PBLs and LNs.…”

Section: Discussionmentioning

confidence: 99%

Experimental immunology Modulating effects of leflunomide on the balance of Th17/Treg cells in collagen-induced arthritis DBA/1 mice

Zhu¹,

Xu²,

Li³

et al. 2014

cejoi

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To evaluated the effect and mechanism of leflunomide (LEF) in murine model of collage-induced arthritis (CIA) on modulating the balance of Th17/Treg cells. DBA mice were divided into: control, CIA, CIA + LEF and CIA + Ibuprofen group. After 14 days immunization with bovine type II collagen (CII), except control group, mice were orally administered saline (CIA group), LEF or ibuprofen daily for 14 days. The severity of arthritis joint was assessed by using arthritis score. The numbers of CD3 + CD4 + interleukin 17 (IL-17) + Th17 cells and CD4 + CD25 + Foxp3+ Tregs were determined by flow cytometry, the expression of ROR-γt, Foxp3 and IL-21 mRNA in spleen were quantified by RT-PCR and IL-17, IL-21 and transforming growth factor β (TGF-β) level in serum was measured by ELISA.In comparison with CIA group, CIA + LEF and CIA + Ibuprofen group reduced the disease severity obviously (p < 0.05). Leflunomide reduced Th17 cells, the expression of ROR-γt and IL-21 mRNA (p < 0.05) and the levels of IL-17 and IL-21 in serum. In addition, Ibuprofen but not LEF has effect on Treg cells number, Foxp3 mRNA expression and TGF-β secretion.These results indicate that LEF effect on the balance od Th17/Treg through suppressing Th17 cells, but not stimulating Treg cells. Leflunomide may act as a potential immunomodulator for the treatment of rheumatoid arthritis (RA).

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“…CD4 + CD25 + Treg cells were subsequently added to each well in different ratios to CD4 + CD25 - T cells. Cells were cultured with 3μg/ml Con A at 37°C and 5% CO 2 condition for 4 days [ 12 ]. 0.5 μCi [ 3 H]thymidine (185GBq/mmol; Atomic Energy Research Establishment, China) was given for the last 16 hours.…”

Section: Methodsmentioning

confidence: 99%

Indirubin Increases CD4+CD25+Foxp3+ Regulatory T Cells to Prevent Immune Thrombocytopenia in Mice

et al. 2015

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Indirubin, a traditional Chinese medicine, is used to treat autoimmune diseases in clinics. However, the effects of indirubin on the immunosuppressive CD4+CD25+Foxp3+ regulatory T cells (Treg) have not been addressed. Thus, we aimed to investigate the effects of indirubin on CD4+CD25+Treg cells in immune thrombocytopenia (ITP) CBA mice, which were established by immunization with Wistar rat platelets. 50 mg/kg indirubin treatment daily for 4 weeks significantly decreased anti-platelet antibody production and prevented the decrease of platelets caused by immunization in ITP mice. Consistently, indirubin significantly enhanced the percentage and cell number of CD4+CD25+Foxp3+Treg cells in the peripheral blood, spleen and lymph nodes. We also observed a significant increase of the frequency and cell number of CD4+CD25+Foxp3+Treg cells in the thymus upon indirubin treatment. Furthermore, CD4+CD25+Treg cells from indirubin-treated mice showed similar immunosuppression on T effector cells as compared to those from control mice. Altogether, indirubin ameliorates ITP by enhancing CD4+CD25+Foxp3+Treg cell level with preserving immunosuppressive function.

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The effects of leflunomide on CD4+CD25+Foxp3+ T regulatory cells in mice receiving allogeneic bone marrow transplantation

Abstract: LEF decreases peripheral CD4(+)CD25(+) Treg cells in un-immunizing and immunizing recipients, indicating that LEF might not be an ideal candidate for the treatment of autoimmune diseases or graft rejection with respect to induction of immune tolerance.

Cited by 6 publications

References 48 publications

Low-Dose Sirolimus Immunoregulation Therapy in Patients with Active Rheumatoid Arthritis: A 24-Week Follow-Up of the Randomized, Open-Label, Parallel-Controlled Trial

Low-Dose Sirolimus Immunoregulation Therapy in Patients with Active Rheumatoid Arthritis: A 24-Week Follow-Up of the Randomized, Open-Label, Parallel-Controlled Trial

Experimental immunology Modulating effects of leflunomide on the balance of Th17/Treg cells in collagen-induced arthritis DBA/1 mice

Indirubin Increases CD4+CD25+Foxp3+ Regulatory T Cells to Prevent Immune Thrombocytopenia in Mice

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