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Molecular Medicine

, Volume 18, Issue 6, pp 957–970 | Cite as

Expanding the Clinical Indications for α1-Antitrypsin Therapy

  • Eli C Lewis
Review Article

Abstract

α1-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 increase more than fourfold. 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 lifelong 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 (PR-3), but also to exert antiinflammatory and tissue-protective effects independent of protease inhibition. AAT modifies dendritic cell maturation and promotes T regulatory cell differentiation, induces interleukin (IL)-1 receptor antagonist and IL-10 release, protects various cell types from cell death, inhibits caspases-1 and -3 activity and inhibits IL-1 production and activity. Importantly, unlike classic immunosuppressants, AAT allows undeterred isolated T-lymphocyte responses. On the basis of preclinical and clinical studies, AAT therapy for nondeficient 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 human immunodeficiency virus (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.

Notes

Acknowledgments

The author thanks Charles A Dinarello and Sabina Janciauskiene for indispensible insights and advice regarding the biology of AAT. The author also thanks Galit Shahaf, Eyal Ozeri, Mark Mizrahi, Hadas Moser, Keren Bellacen, Noa Kalay, Efrat Ashkenazi, Avishag Abecassis and David Ochayon for exceptional assistance in writing this manuscript.

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Authors and Affiliations

  1. 1.Faculty of Health SciencesBen-Gurion University of the NegevBeer-ShevaIsrael

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