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

• Published in: Diabetes (New York, N.Y.) Vol. 57; no. 9; pp. 2341 - 2347
• Main Authors: MONTI, Paolo, SCIRPOLI, Miriam, MAFFI, Paola, PIEMONTI, Lorenzo, SECCHI, Antonio, BONIFACIO, Ezio, RONCAROLO, Maria-Grazia, BATTAGLIA, Manuela
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.09.2008
• Subjects: Adult; Biological and medical sciences; CD4 Antigens - metabolism; CD4 Lymphocyte Count; Combined Modality Therapy; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - surgery; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Flow Cytometry; Forkhead Transcription Factors - metabolism; Graft Rejection - drug therapy; Graft Rejection - immunology; Graft Rejection - prevention & control; Humans; Immunology and Transplantation; Immunosuppressive Agents - administration & dosage; Interleukin-2 Receptor alpha Subunit - metabolism; Islets of Langerhans Transplantation; Male; Medical sciences; Middle Aged; Preoperative Care; Sirolimus - administration & dosage; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Endocrinopathy; Human; Immunopathology; Autoimmune disease; Type 1 diabetes; T-Lymphocyte
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db08-0138

Rapamycin Monotherapy in Patients With Type 1 Diabetes Modifies CD4 + CD25 + FOXP3 + Regulatory T-Cells Paolo Monti 1 , Miriam Scirpoli 1 , Paola Maffi 2 , Lorenzo Piemonti 1 , Antonio Secchi 2 , Ezio Bonifacio 1 , Maria-Grazia Roncarolo 3 4 and Manuela Battaglia 3 5 1 Telethon-Juvenile Diabetes Research Foundation Center for Beta Cell Replacement, San Raffaele Scientific Institute, Milan, Italy 2 Department of Medicine, Transplant Unit, San Raffaele Scientific Institute, Milan, Italy 3 San Raffaele Telethon Institute for Gene Therapy, Milan, Italy 4 Università Vita-Salute San Raffaele, Milan, Italy 5 San Raffaele Scientific Institute, Immunology of Diabetes Unit, Milan, Italy Corresponding author: Manuela Battaglia, manuela.battaglia{at}hsr.it 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 + 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. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 16 June 2008. E.B. is currently affiliated with the Center for Regenerative Therapies-Dresden, Dresden University of Technology, Dresden, Germany. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 21, 2008. Received January 31, 2008. DIABETES