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

  1. Paolo Monti1,
  2. Miriam Scirpoli1,
  3. Paola Maffi2,
  4. Lorenzo Piemonti1,
  5. Antonio Secchi2,
  6. Ezio Bonifacio1,
  7. Maria-Grazia Roncarolo34 and
  8. Manuela Battaglia35
  1. 1Telethon-Juvenile Diabetes Research Foundation Center for Beta Cell Replacement, San Raffaele Scientific Institute, Milan, Italy
  2. 2Department of Medicine, Transplant Unit, San Raffaele Scientific Institute, Milan, Italy
  3. 3San Raffaele Telethon Institute for Gene Therapy, Milan, Italy
  4. 4Università Vita-Salute San Raffaele, Milan, Italy
  5. 5San Raffaele Scientific Institute, Immunology of Diabetes Unit, Milan, Italy
  1. Corresponding author: Manuela Battaglia, manuela.battaglia{at}


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 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.


  • Published ahead of print at on 16 June 2008.

    E.B. is currently affiliated with the Center for Regenerative Therapies-Dresden, Dresden University of Technology, Dresden, Germany.

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    • Accepted May 21, 2008.
    • Received January 31, 2008.
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  1. Diabetes vol. 57 no. 9 2341-2347
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