Virtual Optimization of Nasal Insulin Therapy Predicts Immunization Frequency to Be Crucial for Diabetes Protection
- Georgia Fousteri1,
- Jason R. Chan2,
- Yanan Zheng2,
- Chan Whiting2,
- Amy Dave1,
- Damien Bresson1,
- Michael Croft1 and
- Matthias von Herrath1
- 1Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, California;
- 2Entelos, Foster City, California.
- Corresponding authors: Jason R. Chan, , and Matthias von Herrath, .
G.F. and J.R.C. contributed equally to this work.
OBJECTIVE Development of antigen-specific strategies to treat or prevent type 1 diabetes has been slow and difficult because of the lack of experimental tools and defined biomarkers that account for the underlying therapeutic mechanisms.
RESEARCH DESIGN AND METHODS The type 1 diabetes PhysioLab platform, a large-scale mathematical model of disease pathogenesis in the nonobese diabetic (NOD) mouse, was used to investigate the possible mechanisms underlying the efficacy of nasal insulin B:9-23 peptide therapy. The experimental aim was to evaluate the impact of dose, frequency of administration, and age at treatment on Treg induction and optimal therapeutic outcome.
RESULTS In virtual NOD mice, treatment efficacy was predicted to depend primarily on the immunization frequency and stage of the disease and to a lesser extent on the dose. Whereas low-frequency immunization protected from diabetes atrributed to Treg and interleukin (IL)-10 induction in the pancreas 1–2 weeks after treatment, high-frequency immunization failed. These predictions were confirmed with wet-lab approaches, where only low-frequency immunization started at an early disease stage in the NOD mouse resulted in significant protection from diabetes by inducing IL-10 and Treg.
CONCLUSIONS Here, the advantage of applying computer modeling in optimizing the therapeutic efficacy of nasal insulin immunotherapy was confirmed. In silico modeling was able to streamline the experimental design and to identify the particular time frame at which biomarkers associated with protection in live NODs were induced. These results support the development and application of humanized platforms for the design of clinical trials (i.e., for the ongoing nasal insulin prevention studies).
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- Received May 21, 2010.
- Accepted September 13, 2010.
- © 2010 by the American Diabetes Association.
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