Increased frequency of regulatory T Cells and selection of highly potent CD62L+ cells during treatment of human lung transplant recipients with rapamycin

Abstract

Summary The currently available immunosuppressive agents applied in human transplantation medicine are highly potent in the protection from acute allograft rejection. However, long‐term allograft survival is still poor as these drugs fail to sufficiently prevent chronic allograft rejection. Naturally occurring regulatory T cells have been postulated as the key players to establish long‐lasting transplantation tolerance. Thus, the development of immunosuppressive regimens which shift the pathological balance of cytopathic versus regulatory T cells of human allograft recipients towards a protective T‐cell composition is a promising approach to overcome limitations of current transplantation medicine. Thirty‐three patients that received rapamycin (RPM) or calcineurin inhibitor treatment following lung transplantation were included and their T‐cell compartments analysed. Twelve healthy volunteers without history of lung disease served as controls. In this article, we show that treatment of human lung transplant recipients with RPM is associated with an increased frequency of regulatory T cells, as compared with treatment with calcineurin inhibitors or to healthy controls. Moreover, regulatory T cells during treatment with RPM were CD62Lhigh, a phenotype that displayed an enhanced immunosuppressive capacity ex vivo. Our data support the use of RPM in human lung transplant recipients and undertaking of further prospective studies evaluating its impact on allograft and patient survival.

Effect of rapamycin on immunity induced by vector-mediated dystrophin expression in mdx skeletal muscle

“…This down-regulation of immunity to vector-mediated dystrophin expression may be mediated by Treg cells, as the ratios of Treg cells to both CD4 + and CD8 + effector T cell populations increased in RAPA-treated, vector-injected TA muscles compared to the mice that received either only the vector, or blank beads and vector. The effect of RAPA on selective survival of Treg cells, which can then lead to the increase of their ratio over effector CD4 and CD8 T cells shown in our study, is in agreement with previous findings where RAPA induced preferential expansion of Treg cells in other studied tissues21223132. Furthermore, this study demonstrates RAPA bead-mediated suppression of humoral immunity specific to recombinant murine dystrophin expression, although variability between mice and small sample size limit the strength of conclusions that can be drawn from this observation.…”

“…The immunosuppressive drug, RAPA, has demonstrated suppression of immunity in multiple clinical applications2021. Mechanisms of action of RAPA for immune suppression include Treg expansion, inhibition of effector T cell activation and proliferation, and prevention of inflammatory cytokine production222324.…”

Rapamycin Ameliorates Dystrophic Phenotype in mdx Mouse Skeletal Muscle

“…Furthermore, RAPA has been used widely in various studies to expand or select for Foxp3 + Tregs (15,16,(31)(32)(33). In contrast to the inhibitory effect of RAPA on proliferation of effector T cells, Tregs proliferate and function in the presence of RAPA (15,16,26,33 We demonstrated that RAPA administration ameliorated the dystrophic phenotype of mdx muscle. There was a significant reduction of muscle fiber necrosis in both TA and Dia muscles of the mdx mouse.…”

“…The activation of mTOR by phosphorylation in the presence of energy, nutrients or growth factors is known to be important for muscle fiber growth (26), and RAPA can block this activation. Therefore, we examined the level of mTOR activation in TA and Dia muscles of 6-wk-old (during active necrosis) and 12-wk-old (after the peak of active necrosis) age-matched untreated mdx and wild-type B10 mice.…”

Ex Vivo–Expanded but Not In Vitro–Induced Human Regulatory T Cells Are Candidates for Cell Therapy in Autoimmune Diseases Thanks to Stable Demethylation of the FOXP3 Regulatory T Cell–Specific Demethylated Region

“…Rapa is routinely used in the clinics to prevent allograft rejection(51), and is currently being tested as a therapy for autoimmunity(52, 53). In most reports, the clinical formulation of rapa (Sirolimus) boosts both number and function of Tregs (53-55).…”