Acute-phase protein α1-anti-trypsin: Diverting injurious innate and adaptive immune responses from non-authentic threats

O. Guttman, B. M. Baranovski, R. Schuster, Z. Kaner, G. S. Freixo-Lima, N. Bahar, N. Kalay, M. I. Mizrahi, I. Brami, D. E. Ochayon, E. C. Lewis

Research output: Contribution to journalReview articlepeer-review


One would assume that the anti-inflammatory activity of α1-anti-trypsin (AAT) is the result of inhibiting neutrophil enzymes. However, AAT exhibits tolerogenic activities that are difficult to explain by serine-protease inhibition or by reduced inflammatory parameters. Targets outside the serine-protease family have been identified, supporting the notion that elastase inhibition, the only functional factory release criteria for clinical-grade AAT, is over-emphasized. Non-obvious developments in the understanding of AAT biology disqualify it from being a straightforward anti-inflammatory agent: AAT does not block dendritic cell activities, nor does it promote viral and tumour susceptibilities, stunt B lymphocyte responses or render treated patients susceptible to infections; accordingly, outcomes of elevated AAT do not overlap those attained by immunosuppression. Aside from the acute-phase response, AAT rises during the third trimester of pregnancy and also in advanced age. At the molecular level, AAT docks onto cholesterol-rich lipid-rafts and circulating lipid particles, directly binds interleukin (IL)-8, ADAM metallopeptidase domain 17 (ADAM17) and danger-associated molecular pattern (DAMP) molecules, and its activity is lost to smoke, high glucose levels and bacterial proteases, introducing a novel entity - 'relative AAT deficiency'. Unlike immunosuppression, AAT appears to help the immune system to distinguish between desired responses against authentic threats, and unwanted responses fuelled by a positive feedback loop perpetuated by, and at the expense of, inflamed injured innocent bystander cells. With a remarkable clinical safety record, AAT treatment is currently tested in clinical trials for its potential benefit in a variety of categorically distinct pathologies that share at least one common driving force: cell injury.

Original languageEnglish
Pages (from-to)161-172
Number of pages12
JournalClinical and Experimental Immunology
Issue number2
StatePublished - 1 Feb 2015


  • Acute-phase proteins
  • Diabetes
  • Transplantation

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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