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Rapamycin monotherapy in patients with type 1 diabetes modifies CD4⁺CD25⁺FOXP3⁺ regulatory T cells

¹Telethon-JDRF Center for Beta Cell Replacement, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, ITALY.
²Department of Medicine, Transplant Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, ITALY.
³Current address: Center for Regenerative Therapies-Dresden, Dresden University of Technology, Dresden, GERMANY.
⁴San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) Via Olgettina 58, 20132 Milano, ITALY.
⁵Università Vita-Salute San Raffaele, Via Olgettina 60, 20132 Milano (ITALY).
⁶San Raffaele Scientific Institute, Immunology of Diabetes Unit, Via Olgettina 60, 20132 Milano, ITALY

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⁺CD25⁺FOXP3⁺ 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 (T1D) who underwent rapamycin monotherapy prior to 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 T1D patients under rapamycin treatment had an increased capability to suppress proliferation of CD4⁺CD25^- effector T cells, as compared to that before treatment.

Conclusions:: These findings demonstrate that rapamycin directly affects human nTreg function in vivo, which consists in re-fitting their suppressive activity, while it does not directly change effector T cell function.

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