Alpha-1-antitrypsin (AAT) is a 52-kDa circulating serine protease inhibitor. Production of AAT by the liver maintains 0.9-1.75 mg/ml circulating levels. During acute phase responses, circulating AAT levels incraese >4-fold. In individuals with one of several inherited mutations in AAT, low circulating levels increase the risk for lung, liver and pancreatic destructive diseases, particularly emphysema.

These individuals are treated with life-long weekly infusions of human plasma-derived AAT. An increasing amount of evidence appears to suggest that AAT possesses not only the ability to inhibit serine proteases, such as elastase and proteinase-3, but also to exert anti-inflammatory and tissue protective effects independent of protease inhibition. AAT modifies dendritic cell maturation and promotes T regulatory cell differentiation, induces interleukin-1 receptor antagonist and interleukin-10 release, protects various cell types from cell death, inhibits caspases-1 and -3 activity and inhibits interleukin-1 production and activity. Importantly, unlike classic immunosuppressants, AAT allows undetered isolated T-lymphocyte responses.

Based on preclinical and clinical studies, AAT therapy for non-deficient individuals may interfere with disease progression in Type-1 and Type-2 diabetes, acute myocardial infarction, rheumatoid arthritis, inflammatory bowel disease, cystic fibrosis, transplant rejection, graft-versus-host-disease and multiple sclerosis. AAT also appears to be antibacterial and an inhibitor of viral infections, such as influenza and HIV, and is currently evaluated in clinical trials for Type-1 diabetes, cystic fibrosis and graft-versus-host-disease.

Thus, AAT therapy appears to have advanced from replacement therapy, to a safe and potential treatment for a broad spectrum of inflammatory and immune-mediated diseases.