Rapamycin Prevents and Breaks the Anti-CD3–Induced Tolerance in NOD Mice

  1. Andrea Valle1,2,
  2. Tatiana Jofra1,2,
  3. Angela Stabilini1,2,
  4. Mark Atkinson3,
  5. Maria-Grazia Roncarolo2,4 and
  6. Manuela Battaglia1,2
  1. 1San Raffaele Diabetes Research Institute, Milan, Italy;
  2. 2San Raffaele Telethon Institute for Gene Therapy, Milan, Italy;
  3. 3Department of Pathology, University of Florida, Gainesville, Florida;
  4. 4Università Vita-Salute San Raffaele, Milan Italy.
  1. Corresponding author: Maria-Grazia Roncarolo, m.roncarolo{at}hsr.it, and Manuela Battaglia, manuela.battaglia{at}hsr.it.

Abstract

OBJECTIVE Non–Fc-binding anti-CD3–specific antibodies represent a promising therapy for preserving C-peptide production in subjects with recent-onset type 1 diabetes. However, the mechanisms by which anti-CD3 exerts its beneficial effect are still poorly understood, and it is questionable whether this therapeutic approach will prove durable with regard to its ability to impart metabolic preservation without additional actions designed to maintain immunological tolerance. We used the NOD mouse model to test whether rapamycin, a compound well-known for its immunomodulatory activity in mice and humans, could increase the therapeutic effectiveness of anti-CD3 treatment in type 1 diabetes.

RESEARCH DESIGN AND METHODS Rapamycin was administered to diabetic NOD mice simultaneously with anti-CD3 or to NOD mice cured by anti-CD3 therapy. The ability of this combined therapy to revert type 1 diabetes and maintain a state of long-term tolerance was monitored and compared with that of anti-CD3 therapy alone.

RESULTS Rapamycin inhibited the ability of anti-CD3 to revert disease without affecting the frequency/phenotype of T-cells. Rapamycin also reinstated diabetes in mice whose disease was previously reversed by anti-CD3. Withdrawal of rapamycin in these latter animals promptly restored a normoglycemic state.

CONCLUSIONS Our findings indicate that, when combined with anti-CD3, rapamycin exerts a detrimental effect on the disease outcome in NOD mice for as long as it is administered. These results suggest strong caution with regard to combining these treatments in type 1 diabetic patients.

Footnotes

  • 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.

    • Received October 16, 2008.
    • Accepted January 5, 2009.
  • 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.

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  1. Diabetes vol. 58 no. 4 875-881
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