Rapamycin monotherapy in patients with type 1 diabetes modifies CD4(+)CD25(+)FOXP3(+) regulatory T-Cells

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
CD4CD25FOXP3 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
CD25 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. Diabetes 57:2341–2347, 2008