Authors:
K Ozer MD, V Yechoor MD, E Buras, V Liu, and L Chan MD
Summary:
A definitive therapy for stable reversal of autoimmune type 1 diabetes (T1D) must tackle all aspects of its pathogenesis, including autoimmunity and near complete β-cell deficiency. Thus, it is necessary to combine β-cell mass restoration with protection of the restored cells from autoimmune attack. We have previously shown that hepatic gene transfer of the islet transcription factor Neurogenin-3 (Ngn3) and the islet growth factor Betacellulin (Btc) induces islet neogenesis in the liver and reverses streptozotocin-induced diabetes in mice. This treatment failed to reverse diabetes in overtly diabetic NOD (non-obese diabetic) mice due to the autoimmune destruction of the newly formed hepatic β-cells. We investigated whether the addition of Interleukin-10 (IL-10) to the regimen would suppress the cell-mediated
autoimmunity and protect the neo-β cells from immune destruction. IL-10 had been shown previously to prevent diabetes development in NOD mice, but was found to be ineffective in reversing diabetes once it has developed. Here, we present data on the effect of helper-dependent adenovirus-mediated hepatic delivery of a combined Ngn3/Btc and IL-10 regimen in overtly diabetic NOD mice. Our data show a long-term (>20 month follow-up) and complete reversal of
diabetes in 50% of treated mice, consisting of a return to euglycemia, with the restoration of normal glucose tolerance as documented by a normal glucose and insulin response during a glucose tolerance test as well as normalization of fasting and postprandial glucose and insulin levels. Treated animals regained their body weight and developed insulin-positive islet-like cell clusters in the peri-portal region of the liver and insulin expression at the RNA and protein
levels in the liver. The newly formed β-cells were able to appropriately turn off insulin production as efficiently as nondiabetic wild-type mice during a 72-hour fast. Characterization of the nature of the immune protection is under way: Experiments thus far demonstrate that splenocytes from treated mice which showed reversal of diabetes did not lose their diabetogenicity in an adoptive transfer experiment, suggesting a locally protective role for the combination regimen. In addition to gaining new mechanistic insights into islet neogenesis and immunopathogenesis of autoimmune diabetes, we are hopeful that our investigation will pave the way for an optimized gene therapy regimen for the treatment of patients with T1D in the future.
Source:
The Endocrine Society's 92nd Annual Meeting; P2-114; Endocrine Reviews; Supplement 1, 31(3), S984 (06/10)