Establishment of an in vivo mouse model that can be induced to produce IL-7

Aims/hypothesis: The IL-7 pathway plays an important role in the autoimmune T cell mediated islet beta-cell loss following islet transplantation in T1D, and may be a therapeutic target in cell replacement therapies. An experimental in vivo model to formally demonstrate this and to define the mechanisms involved, as well as strategies to prevent this process, is not available. Methods: Transgenic mice with a tetracycline inducible IL-7 were generated by pronuclear injection and crossed with a mouse line harboring the codon-optimized tetracycline transactivator fused to Glucocorticoid binding domain (irtTA-GBD). Transient induction of IL-7 was performed by i.p. injections of Dexamethasone and Doxycycline for five consecutive days and IL-7 release was measured in the serum using ELISA. Results: In the tet-IL-7-irtTA-GBD mice IL-7 was undetectable in sera before induction and was observed in three founder lines after Dex/Dox injection. For planned islet transplantation studies we showed that IL-7 was released in the supernatant of in vitro cultured tet-IL-7-irtTA-GBD-islets after Dex/Dox exposure and tested functionality of the islets in vivo performing glucose tolerance test. No functional difference could be observed indicating that the islets can be used for transplantation studies. Conclusions: The tet-IL-7-irtTA-GBD-mice provide the possibility to establish an in vivo model of IL-7 promoted autoimmune and alloimmune destruction of islet beta cells. This will help to understand the underlying molecular mechanism and develop strategies to impede IL-7 promoted graft rejection. These models contribute an important pre-clinical tool for studying effects of homeostatic immune cell proliferation during cell replacement therapy and disease.