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

Abstract

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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“…Similar to the effect of EPA and DHA, rapamycin also blocked the Th1 differentiation induced by AA. Such results are also reminiscent of the anti-diabetes and autoimmunity prevention effects of rapamycin in NOD mice that were reported by several groups (55)(56)(57)(58)(59).…”

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“…Reactive changes in CD25, CD62L and FOXP3 as phenotypic markers of putative Treg have been previously observed with immunomodulatory agents such as Cy, anti-IL-2, anti-CD25 and anti-CD3, and have been generally associated with positive outcome of immunomodulation in NOD mice [4,5,16,28]. A similar reactive increase in FOXP3 expression has recently been associated with beneficial effects of Treg activation achieved by several immunomodulatory modalities, including IL-2/IL-2 antibody complexes, anti-thymocyte globulin, complete Freund's adjuvant, vasoactive intestinal peptide and rapamycin [18,[40][41][42][43][44]. Considering the very different mechanisms of action of these agents, it can be proposed that dominance of CD25 − FOXP3 + T cells is mediated by superior survival and faster expansion.…”

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“…This phenomenon of selective destruction of beta cells was also observed in recipients of cadaveric pancreatic grafts [36] and in recipients of islet allografts [37] without evidence of alloimmune rejection [34][35][36]. Further studies strongly suggested that recurrence of T1D autoimmunity was due to autoreactive, antigenspecific memory CD8 + and CD4 + T cells after islet and pancreas transplantation [37][38][39][40]. In a multicenter, randomized, double-blind, placebo-controlled clinical trial of recent onset T1D patients, treatment with alefacept, preserved their C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at one year, even after one year of termination of therapy.…”