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Alpha-1 antitrypsin protein and gene therapies decrease autoimmunity and delay arthritis development in mouse model.

Christian Grimstein1, Young-Kook Choi, Clive H Wasserfall

  • 1Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA.

Journal of Translational Medicine
|February 25, 2011
PubMed
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Human alpha-1 antitrypsin (AAT) protein and gene therapies show promise for treating rheumatoid arthritis (RA). These treatments delayed arthritis onset and reduced autoimmune markers in a mouse model, suggesting a new therapeutic avenue for RA.

Area of Science:

  • Immunology
  • Rheumatology
  • Gene Therapy

Background:

  • Alpha-1 antitrypsin (AAT) possesses anti-inflammatory and tissue-protective properties.
  • Previous studies demonstrated efficacy of human AAT (hAAT) gene therapy in preventing autoimmune diabetes and suppressing arthritis.
  • This study explored hAAT monotherapy for chronic arthritis in a collagen-induced arthritis (CIA) mouse model.

Purpose of the Study:

  • To investigate the feasibility of hAAT monotherapy for treating chronic arthritis.
  • To evaluate the therapeutic potential of hAAT protein and gene therapy in a collagen-induced arthritis (CIA) mouse model.

Main Methods:

  • DBA/1 mice were induced with arthritis using bovine type II collagen (bCII).
  • Mice received pretreatment with hAAT protein or recombinant adeno-associated virus vector expressing hAAT (rAAV-hAAT).

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  • Arthritis development, serum BAFF levels, and autoantibodies against collagen II were assessed.

    • Main Results:

    • Both hAAT protein and rAAV8-mediated hAAT gene therapy significantly delayed arthritis onset and reduced disease severity in the CIA model.
    • hAAT therapies markedly decreased serum levels of B-cell activating factor (BAFF) and autoantibodies against bovine and mouse collagen II.
    • These findings suggest that hAAT's therapeutic effects in CIA are, at least partially, mediated through B-cell modulation.

    Conclusions:

    • Human AAT protein and gene therapies represent a novel therapeutic approach for arthritis.
    • These hAAT-based therapies demonstrated the ability to ameliorate arthritis and reduce associated autoimmunity.
    • The results indicate significant potential for hAAT therapies as a new treatment strategy for rheumatoid arthritis (RA).