Comparative Study of Immunomodulatory Agents to Induce Human T Regulatory (Treg) Cells: Preferential Treg-Stimulatory Effect of Prednisolone and Rapamycin

Janyst, Michał; Kaleta, Beata; Janyst, Karolina; Zagożdżon, Radosław; Kozłowska, Ewa; Lasek, Witold

doi:10.1007/s00005-020-00582-6

Cited by 13 publications

(7 citation statements)

References 49 publications

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“…Rapamycin-treated PBMCs didn't exhibited differences on the frequency and functions of regulatory T cells (Tregs), which may probably due to the insufficient time and lack of added Treg inducers (TGFB, IL2, etc.) (21,22) (Supplemental Figure 4).…”

Section: Rapamycin Decreased the Frequency Of Cd4+ Ctls In Pbmcs Of G...mentioning

confidence: 99%

Rapamycin improves Graves’ orbitopathy by suppressing CD4+ cytotoxic T lymphocytes

et al. 2023

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CD4+ cytotoxic T lymphocytes (CTLs) were recently implicated in immune-mediated inflammation and fibrosis progression of Graves' orbitopathy (GO). However, little is known about therapeutic targeting CD4+ CTLs. Herein, we studied the effect of rapamycin, an approved mammalian target of rapamycin complex 1(mTORC1) inhibitor, in GO mouse model, in vitro and in refractory GO patients. In the adenovirus-induced model, rapamycin significantly decreased the incidence of GO. This was accompanied by reduction of both CD4+ CTLs, as well as reduction of orbital inflammation, adipogenesis and fibrosis. CD4+CTLs from active GO patients showed upregulation of mTOR pathway, while rapamycin decreased their proportions and cytotoxic function. Low-dose rapamycin treatment substantially improved diplopia and clinical activity score in steroid-refractory GO patients. Single-cell RNA sequencing revealed that eye motility improvement was closely related to suppression of inflammation and chemotaxis in CD4+ CTLs. In conclusion, rapamycin is a promising treatment for CD4+ CTL-mediated inflammation and fibrosis in GO.

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Section: Rapamycin Decreased the Frequency Of Cd4+ Ctls In Pbmcs Of G...mentioning

confidence: 99%

Rapamycin improves Graves’ orbitopathy by suppressing CD4+ cytotoxic T lymphocytes

et al. 2023

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“…Treatment of ENL with prednisolone is associated with an increased proportion of Tregs which leads to the inhibition of inflammation [ 49 ]. It is suggested that prednisolone controls inflammation via TGFβ and TGFβ suppresses the functions of Th1 effector cells and promotes the generation of Tregs [ 50 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

Regulatory T cells in erythema nodosum leprosum maintain anti-inflammatory function

Negera

Bobosha²,

Aseffa³

et al. 2022

PLoS Negl Trop Dis

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Background The numbers of circulating regulatory T cells (Tregs) are increased in lepromatous leprosy (LL) but reduced in erythema nodosum leprosum (ENL), the inflammatory complication of LL. It is unclear whether the suppressive function of Tregs is intact in both these conditions. Methods A longitudinal study recruited participants at ALERT Hospital, Ethiopia. Peripheral blood samples were obtained before and after 24 weeks of prednisolone treatment for ENL and multidrug therapy (MDT) for participants with LL. We evaluated the suppressive function of Tregs in the peripheral blood mononuclear cells (PBMCs) of participants with LL and ENL by analysis of TNFα, IFNγ and IL-10 responses to Mycobacterium leprae (M. leprae) stimulation before and after depletion of CD25+ cells. Results 30 LL participants with ENL and 30 LL participants without ENL were recruited. The depletion of CD25+ cells from PBMCs was associated with enhanced TNFα and IFNγ responses to M. leprae stimulation before and after 24 weeks treatment of LL with MDT and of ENL with prednisolone. The addition of autologous CD25+ cells to CD25+ depleted PBMCs abolished these responses. In both non-reactional LL and ENL groups mitogen (PHA)-induced TNFα and IFNγ responses were not affected by depletion of CD25+ cells either before or after treatment. Depleting CD25+ cells did not affect the IL-10 response to M. leprae before and after 24 weeks of MDT in participants with LL. However, depletion of CD25+ cells was associated with an enhanced IL-10 response on stimulation with M. leprae in untreated participants with ENL and reduced IL-10 responses in treated individuals with ENL. The enhanced IL-10 in untreated ENL and the reduced IL-10 response in prednisolone treated individuals with ENL was abolished by addition of autologous CD25+ cells. Conclusion The findings support the hypothesis that the impaired cell-mediated immune response in individuals with LL is M. leprae antigen specific and the unresponsiveness can be reversed by depleting CD25+ cells. Our results suggest that the suppressive function of Tregs in ENL is intact despite ENL being associated with reduced numbers of Tregs. The lack of difference in IL-10 response in control PBMCs and CD25+ depleted PBMCs in individuals with LL and the increased IL-10 response following the depletion of CD25+ cells in individuals with untreated ENL suggest that the mechanism of immune regulation by Tregs in leprosy appears independent of IL-10 or that other cells may be responsible for IL-10 production in leprosy. The present findings highlight mechanisms of T cell regulation in LL and ENL and provide insights into the control of peripheral immune tolerance, identifying Tregs as a potential therapeutic target.

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“…Some studies indicate that mTOR inhibition can expand the number of Tregs regardless of antigen levels. [46][47][48][49] In a transforming growth factor-β (TGF-β)-dependent manner, an mTOR-I enhanced the expression of Foxp3. 50 Tregs that are expanded by an mTOR-I suppress the proliferation of both syngeneic and allogeneic CD4 + and CD8 + T cells in vitro and prevent allograft rejection in vivo.…”

Section: Induction Of T Regulatory Cells (Tregs) and Tolerancementioning

confidence: 99%

The case for the therapeutic use of mechanistic/mammalian target of rapamycin (mTOR) inhibitors in xenotransplantation

Maenaka

Kinoshita

Hara

et al. 2023

Xenotransplantation

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The mechanistic/mammalian target of rapamycin (mTOR) is one of the systems that are necessary to maintain cell homeostasis, such as survival, proliferation, and differentiation. mTOR inhibitors (mTOR‐Is) are utilized as immunosuppressants and anti‐cancer drugs. In organ allotransplantation, current regimens infrequently include an mTOR‐I, which are positioned more commonly as alternative immunosuppressants. In clinical allotransplantation, long‐term efficacy has been established, but there is a significant incidence of adverse events, for example, inhibition of wound healing, buccal ulceration, anemia, hyperglycemia, dyslipidemia, and thrombocytopenia, some of which are dose‐dependent. mTOR‐Is have properties that may be especially beneficial in xenotransplantation. These include suppression of T cell proliferation, increases in the number of T regulatory cells, inhibition of pig graft growth, and anti‐inflammatory, anti‐viral, and anti‐cancer effects. We here review the potential benefits and risks of mTOR‐Is in xenotransplantation and suggest that the benefits exceed the adverse effects.

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Comparative Study of Immunomodulatory Agents to Induce Human T Regulatory (Treg) Cells: Preferential Treg-Stimulatory Effect of Prednisolone and Rapamycin

Cited by 13 publications

References 49 publications

Rapamycin improves Graves’ orbitopathy by suppressing CD4+ cytotoxic T lymphocytes

Rapamycin improves Graves’ orbitopathy by suppressing CD4+ cytotoxic T lymphocytes

Regulatory T cells in erythema nodosum leprosum maintain anti-inflammatory function

The case for the therapeutic use of mechanistic/mammalian target of rapamycin (mTOR) inhibitors in xenotransplantation

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