Calcineurin Inhibitors Affect Circulating Regulatory T Cells in Stable Renal Transplant Recipients

Segundo, David San; Ruiz, J.C.; Fernández‐Fresnedo, Gema; Izquierdo, M J; Gómez-Alamillo, C.; Cacho, Eva; Benito, M. Isabel; Rodrigo, Emilio; Palomar, Rosa; López-Hoyos, Marcos; Arias, Manuel

doi:10.1016/j.transproceed.2006.08.081

Cited by 35 publications

(31 citation statements)

References 6 publications

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“…Similarly, C57BL/6 mice receiving rapamycin for 14 days show an enhanced ratio between nTregs and CD4 ϩ T-cells in the spleen and thymus (27). In humans, the frequency of circulating nTregs in renal transplant recipients is preserved under rapamycin treatment, whereas it is significantly decreased during therapy with calcineurin inhibitors (28). Similarly, we observed that rapamycin monotherapy preserves the number of circulating nTregs.…”

Section: Discussionsupporting

confidence: 69%

Rapamycin Monotherapy in Patients With Type 1 Diabetes Modifies CD4+CD25+FOXP3+ Regulatory T-Cells

et al. 2008

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OBJECTIVE-Rapamycin is an immunosuppressive drug currently used to prevent graft rejection in humans, which is considered permissive for tolerance induction. Rapamycin allows expansion of both murine and human naturally occurring CD4 ϩ CD25 ϩ FOXP3 ϩ T regulatory cells (nTregs), which are pivotal for the induction and maintenance of peripheral tolerance. Preclinical murine models have shown that rapamycin enhances nTreg proliferation and regulatory function also in vivo. Objective of this study was to assess whether rapamycin has in vivo effects on human nTregs.RESEARCH DESIGN AND METHODS-nTreg numbers and function were examined in a unique set of patients with type 1 diabetes who underwent rapamycin monotherapy before islet transplantation.RESULTS-We found that rapamycin monotherapy did not alter the frequency and functional features, namely proliferation and cytokine production, of circulating nTregs. However, nTregs isolated from type 1 diabetic patients under rapamycin treatment had an increased capability to suppress proliferation of CD4 ϩ CD25Ϫ effector T-cells compared with that before treatment.CONCLUSIONS-These findings demonstrate that rapamycin directly affects human nTreg function in vivo, which consists of refitting their suppressive activity, whereas it does not directly change effector T-cell function.

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Section: Discussionsupporting

confidence: 69%

Rapamycin Monotherapy in Patients With Type 1 Diabetes Modifies CD4+CD25+FOXP3+ Regulatory T-Cells

et al. 2008

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“…Why RAPA-treated patients were not protected from chronic allograft rejection, despite the enhanced expression of Tregs and their strong antiproliferative effect on alloreactive T cells [20] remained a matter of speculation. When looking at the control groups, both healthy subject and end-stage renal disease subjects showed a percentage of CD4 + CD25 + /CD25 high T cells equivalent to the RAPA group patients [21,23,24]. The author [21] proposed that one possibility was that the number of circulating Tregs, although increased in the RAPA group as compared to pretransplant values, did not reach the threshold level to properly suppress the complex pathways of T effector cells, and thus to limit chronic graft injury.…”

Section: Renal Transplantationmentioning

confidence: 97%

Can Proliferation Signal Inhibitor-Induced Tregs Really Reflect Transplantation Tolerance in Clinical Solid Organ Transplantation?

Kuang

Huang

2009

International Reviews of Immunology

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Exploring new immunosuppressive strategies inducing donor-specific hyporesponsiveness is a great challenge in transplantation. For this purpose, monitoring the alloimmune response is a critical step to carrying out protolerogenic immunosuppressive protocols. Regulatory T cells (Tregs), known as controlling various immune responses, were found to play an important part in allograft transplant tolerance. It is said that Rapamycin (RAPA), one of the proliferation signal inhibitors (PSIs), could achieve true tolerance through the induction of Tregs in clinical trials. Can PSI-induced Tregs in peripheral blood mononuclear cells (PBMC) really reflect transplantation tolerance in clinical solid organ transplantation?

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“…Foxp3 + Tregs can be expanded with rapamycin without losing their suppressive activity [42]. San Segundo et al [43] performed a clinical cohort study to evaluate renal transplant recipients with stable function under maintenance treatment with CNIs or rapamycin. Twelve months after transplantation, the number of Foxp3 + Tregs was significantly lower in the patients treated with CNIs than in the rapamycin-treated patients, as measured by flow cytometry.…”

Section: Effects Of Maintenance Immunosuppressive Therapies On Foxp3 mentioning

confidence: 99%

“…Twelve months after transplantation, the number of Foxp3 + Tregs was significantly lower in the patients treated with CNIs than in the rapamycin-treated patients, as measured by flow cytometry. However, the expression level of Foxp3 on individual Tregs was not affected [43]. In another study, Baan et al [44] examined heart transplant recipients and found that rapamycin inhibited IL-2 production, but preserved TGF-β 1 , which is essential to the induction of the regulatory phenotype of CD4 + CD25 -T cells.…”

Section: Effects Of Maintenance Immunosuppressive Therapies On Foxp3 mentioning

confidence: 99%

Targeting Regulatory T Cells for Transplant Tolerance: New Insights and Future Perspectives

et al. 2018

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Background: Organ transplantation is considered the ultimate therapy for end-stage organ disease. While pharmacologic immunosuppression is the mainstay of therapeutic strategies to prolong the survival of the graft, long-term use of immunosuppressive medications carries the risk of organ toxicity, malignancies, serious opportunistic infections, and diabetes. Therapies that promote recipient tolerance in solid organ transplantation are able to improve patient outcomes by eliminating the need for long-term immunosuppression. Summary: Establishing tolerance to an allograft has become an area of intense study and would be the ideal therapy in clinical practice. The discovery of a subset of T cells naturally committed to perform immunoregulation has led to further investigation into their role in the immunopathogenesis of transplantation. Evidence suggests that regulatory T cells (Tregs) are fundamentally involved in promoting allograft tolerance. Efforts to characterize specific markers for Tregs, while challenging, have identified Foxp3 gene expression as a crucial step in promoting the tolerance-inducing features of Tregs. A number of approaches, including those based on targeting the glycogen synthase kinase 3β signaling pathway or activating the melanocortinergic pathway, have been tested as a way to promote Treg lineage commitment and maintenance as well as to facilitate immune tolerance. In order to be effective in clinical practice, Tregs must be allospecific and possess a specific phenotype to avoid suppression of other aspects of the immune system or increasing the risk of malignancy or infections. Multiple experimental and clinical studies have demonstrated the impact of currently used immunosuppressants on the immunoregulatory activities of Tregs and their Foxp3 expression status. Pharmacological induction of tolerogenic Tregs for inducing transplant tolerance, including epigenetic therapies, is in the ascendant. Key Messages: Therapies that promote Treg function and survival may represent a novel strategy for achieving immune tolerance in transplant patients.

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Calcineurin Inhibitors Affect Circulating Regulatory T Cells in Stable Renal Transplant Recipients

Cited by 35 publications

References 6 publications

Rapamycin Monotherapy in Patients With Type 1 Diabetes Modifies CD4+CD25+FOXP3+ Regulatory T-Cells

Rapamycin Monotherapy in Patients With Type 1 Diabetes Modifies CD4+CD25+FOXP3+ Regulatory T-Cells

Can Proliferation Signal Inhibitor-Induced Tregs Really Reflect Transplantation Tolerance in Clinical Solid Organ Transplantation?

Targeting Regulatory T Cells for Transplant Tolerance: New Insights and Future Perspectives

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