Rapamycin Promotes Expansion of Functional CD4+CD25+FOXP3+ Regulatory T Cells of Both Healthy Subjects and Type 1 Diabetic Patients

San Raffaele Telethon Institute for Gene Therapy, Via Olgettina 58, 20132 Milan, Italy.
The Journal of Immunology (Impact Factor: 4.92). 01/2007; 177(12):8338-47. DOI: 10.4049/jimmunol.177.12.8338
Source: PubMed

ABSTRACT CD4+CD25+FOXP3+ T regulatory cells (Tregs) are pivotal for the induction and maintenance of peripheral tolerance in both mice and humans. Rapamycin has been shown to promote tolerance in experimental models and to favor CD4+CD25+ Treg-dependent suppression. We recently reported that rapamycin allows in vitro expansion of murine CD4+CD25+FoxP3+ Tregs, which preserve their suppressive function. In the current study, we show that activation of human CD4+ T cells from healthy subjects in the presence of rapamycin leads to growth of CD4+CD25+FOXP3+ Tregs and to selective depletion of CD4+CD25- T effector cells, which are highly sensitive to the antiproliferative effect of the compound. The rapamycin-expanded Tregs suppress proliferation of both syngeneic and allogeneic CD4+ and CD8+ T cells. Interestingly, rapamycin promotes expansion of functional CD4+CD25+FOXP3+ Tregs also in type 1 diabetic patients, in whom a defect in freshly isolated CD4+CD25+ Tregs has been reported. The capacity of rapamycin to allow growth of functional CD4+CD25+FOXP3+ Tregs, but also to deplete T effector cells, can be exploited for the design of novel and safe in vitro protocols for cellular immunotherapy in T cell-mediated diseases.

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    • "Therefore, certain cytokines and chemicals need to be determined to enable the expansion of functional Treg cells, which will not secrete pro-inflammatory cytokines. Rapamycin (also known as Sirolimus/Rapamune) likely be useful as a component as it substantially increases the purity of Treg cells by eliminating non-Treg cells (71). "
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    ABSTRACT: Regulatory T (Treg) cells are essential for normal immune surveillance systems, and their dysfunction leads to development of diseases, such as autoimmune disorders. CD4(+)CD25(+) Treg cells are well-known suppressive cells, which express the transcription factor Foxp3, are indispensable for the maintenance of immune self-tolerance and homeostasis by suppressing aberrant or excessive immune response. Other Foxp3(-) Treg cells include Tr1, Th3, CD8(+)CD28(-/-), and Qa1-restricted T cells; however, the contribution of these Treg cells to self-tolerance, immune homeostasis as well as preventing autoimmunity is not well defined. Here, we discuss the phenotypes and function of Foxp3(+) Treg cells and the potential use of such Treg cells against rheumatoid arthritis (RA). Of note, even though most expanded populations of Foxp3(+) Treg cells exhibit suppressive activity, tissue-associated or antigen-specific Treg cells appear superior in suppressing local autoimmune disorders such as RA. In addition, utilizing tissue-associated Foxp3(+) Treg cells from stem cells may stable Foxp3 expression and avoid induction of a potentially detrimental systemic immunosuppression.
    Frontiers in Oncology 08/2014; 4:209. DOI:10.3389/fonc.2014.00209
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    • "Rapamycin is an inhibitor of mTOR pathway, which is able to favor the proliferation of Treg cells [31]. Here we conclude that iTreg induced from naïve T cells would acquire an enhanced CD25 and FoxP3 expression in the presence of rapamycin. "
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    ABSTRACT: It has been shown that rapamycin is able to significantly increase the expression of FoxP3 and suppress activity in induced Treg (iTreg) cells in vivo and in vitro. CD39 is a newly determined Treg marker that relates to cell suppression. Runx1, a regulator of FoxP3, controls the expression of adenosine deaminase (ADA) gene, which is found recently in the downstream of CD39 pathway in trophoblast cells. Whether rapamycin would influence CD39 pathway and regulate the expression of Runx1 remains to be determined. The addition of rapamycin to human CD4+ naïve cells in the presence of IL-2, TGF-β promotes the expression of FoxP3. In this paper, we found that CD39 positively correlated with the FoxP3 expression in iTreg cells. Rapamycin induced iTreg cells showed a stronger CD39/Runx1 expression with the enhanced suppressive function. These data suggested that CD39 expression was involved in iTreg generation and the enhanced suppressive ability of rapamycin induced Treg was partly due to Runx1 pathway. We conclude that rapamycin favors CD39/Runx1 expression in human iTreg and provides a novel insight into the mechanisms of iTreg generation enhanced by rapamycin.
    Journal of Immunology Research 03/2014; 2014:989434. DOI:10.1155/2014/989434 · 2.93 Impact Factor
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    • "We have here tested for the first time the impact of ex vivo expanded human Tregs on the innate immune responses to human islet allograft in the humanized mice. Several groups have developed an optimal protocol for expanding Tregs for therapeutic use [47]–[49]. Tregs used in current study were expanded in the presence of CD3/CD28 beads and rapamycin as we previously published [14]. Rapamycin prevents outgrowth of contaminating non-regulatory cells, enhances Treg survival and expands the most stable subpopulation of Tregs [49]. "
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    ABSTRACT: Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by immune-mediated destruction of insulin-secreting β cells of the pancreas. Near complete dependence on exogenous insulin makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even death. Allograft transplantation of pancreatic islets restores normoglycemia with a low risk of surgical complications. However, although successful immediately after transplantation, islets are progressively lost, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent requirement for the development of new strategies to prevent islet rejection. In this study, we explored the importance of human regulatory T cells in the control of islets allograft rejection. We developed a pre-clinical model of human islet transplantation by reconstituting NOD-scid IL2rγnull mice with cord blood-derived human CD34+ stem cells and demonstrated that although the engrafted human immune system mediated the rejection of human islets, their survival was significantly prolonged following adoptive transfer of ex vivo expanded human Tregs. Mechanistically, Tregs inhibited the infiltration of innate immune cells and CD4+ T cells into the graft by down-regulating the islet graft-derived monocyte chemoattractant protein-1. Our findings might contribute to the development of clinical strategies for Treg therapy to control human islet rejection. We also show for the first time that CD34+ cells-reconstituted NOD-scid IL2rγnull mouse model could be beneficial for investigating human innate immunity in vivo.
    PLoS ONE 03/2014; 9(3):e90387. DOI:10.1371/journal.pone.0090387 · 3.23 Impact Factor
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