Rapamycin/IL-2 Combination Therapy in Patients with Type 1 Diabetes Augments Tregs yet Transiently Impairs β-Cell Function
- S. Alice Long1,
- Mary Rieck1,
- Srinath Sanda2,
- Jennifer B. Bollyky2,
- Peter L. Samuels1,
- Robin Goland3,
- Andrew Ahmann4,
- Alex Rabinovitch5,
- Sudeepta Aggarwal6,
- Deborah Phippard6,
- Laurence A. Turka6,7,
- Mario R. Ehlers8,
- Peter J. Bianchine9,
- Karen D. Boyle10,
- Steven A. Adah9,
- Jeffrey A. Bluestone11,
- Jane H. Buckner1⇓,
- Carla J. Greenbaum2⇓ and
- for Diabetes TrialNet and the Immune Tolerance Network
- 1Translational Immunology Program, Benaroya Research Institute, Seattle, Washington
- 2Diabetes Program, Benaroya Research Institute, Seattle, Washington
- 3Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, New York
- 4Harold Schnitzer Diabetes Health Center, Oregon Health and Science University, Portland, Oregon
- 5Sanford Research, University of South Dakota, Sioux Falls, South Dakota
- 6Tolerance Assays and Data Analysis Group, Immune Tolerance Network, Bethesda, Maryland
- 7Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
- 8Clinical Trials Group, Immune Tolerance Network, San Francisco, California
- 9Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
- 10Rho Federal Systems Division, Inc., Chapel Hill, North Carolina
- 11Diabetes Center and Department of Medicine, University of California San Francisco, San Francisco, California
- Corresponding authors: Carla J. Greenbaum, , and Jane H. Buckner, .
Rapamycin/interleukin-2 (IL-2) combination treatment of NOD mice effectively treats autoimmune diabetes. We performed a phase 1 clinical trial to test the safety and immunologic effects of rapamycin/IL-2 combination therapy in type 1 diabetic (T1D) patients. Nine T1D subjects were treated with 2–4 mg/day rapamycin orally for 3 months and 4.5 × 106 IU IL-2 s.c. three times per week for 1 month. β-Cell function was monitored by measuring C-peptide. Immunologic changes were monitored using flow cytometry and serum analyses. Regulatory T cells (Tregs) increased within the first month of therapy, yet clinical and metabolic data demonstrated a transient worsening in all subjects. The increase in Tregs was transient, paralleling IL-2 treatment, whereas the response of Tregs to IL-2, as measured by STAT5 phosphorylation, increased and persisted after treatment. No differences were observed in effector T-cell subset frequencies, but an increase in natural killer cells and eosinophils occurred with IL-2 therapy. Rapamycin/IL-2 therapy, as given in this phase 1 study, resulted in transient β-cell dysfunction despite an increase in Tregs. Such results highlight the difficulties in translating therapies to the clinic and emphasize the importance of broadly interrogating the immune system to evaluate the effects of therapy.
- Received January 13, 2012.
- Accepted April 10, 2012.
- © 2012 by the American Diabetes Association.
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.