Islet Allograft Protection by Low Levels of Circulating Transgenic Lung-Specific Human Alpha-1-Antitrypsin (141.49)

Abstract

Abstract Alpha-1-antitrypsin (AAT) exerts anti-inflammatory activities during islet allograft transplantation in several diabetes mouse models. We sought to examine inflammatory pathways in the previously described lung-specific human AAT (hAAT) transgenic mice, and establish whether transgenic circulating hAAT is sufficient to protect islet allografts from acute rejection. Homozygote mice exhibited circulating hAAT levels that were unaffected by age and by inflammatory stimuli (50-200 ng/ml). Transgene expression was limited to lung epithelia and was absent from macrophages and islets. Homozygote mice exhibited marked anti-inflammatory serum and lung tissue cytokine profiles (high IL-1 receptor antagonist and low IL-6 levels). In vivo, 48 hours after streptozotocin challenge (STZ, 225 mg/kg), blood glucose levels were 50% lower then those elicited in wild-type mice (n = 3). In islet allograft transplantation model, grafts were accepted in homozygote mice and rejected in wild-type mice (n = 4). We conclude that as low as 50-200 ng/ml transgenic circulating hAAT is sufficient to generate an anti-inflammatory cytokine milieu, improve islet viability and induce islet allograft immune protection. These low levels of the transgenic product are below its physiological anti-protease inhibitory threshold, suggesting that AAT may contain anti-inflammatory activities independent of protease inhibition.