title: Alpha-1 antitrypsin protein and gene therapies decrease autoimmunity and delay arthritis development in mouse model.
abstract: BACKGROUND
  Alpha-1 antitrypsin (AAT) is a multi-functional protein that has anti-inflammatory and tissue protective properties. We previously reported that human AAT (hAAT) gene therapy prevented autoimmune diabetes in non-obese diabetic (NOD) mice and suppressed arthritis development in combination with doxycycline in mice. In the present study we investigated the feasibility of hAAT monotherapy for the treatment of chronic arthritis in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA).
  
  
  METHODS
  DBA/1 mice were immunized with bovine type II collagen (bCII) to induce arthritis. These mice were pretreated either with hAAT protein or with recombinant adeno-associated virus vector expressing hAAT (rAAV-hAAT). Control groups received saline injections. Arthritis development was evaluated by prevalence of arthritis and arthritic index. Serum levels of B-cell activating factor of the TNF-α family (BAFF), antibodies against both bovine (bCII) and mouse collagen II (mCII) were tested by ELISA.
  
  
  RESULTS
  Human AAT protein therapy as well as recombinant adeno-associated virus (rAAV8)-mediated hAAT gene therapy significantly delayed onset and ameliorated disease development of arthritis in CIA mouse model. Importantly, hAAT therapies significantly reduced serum levels of BAFF and autoantibodies against bCII and mCII, suggesting that the effects are mediated via B-cells, at least partially.
  
  
  CONCLUSIONS
  These results present a new drug for arthritis therapy. Human AAT protein and gene therapies are able to ameliorate and delay arthritis development and reduce autoimmunity, indicating promising potential of these therapies as a new treatment strategy for RA.
authors.affiliation: Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Grimstein
authors.forename: Young-Kook
authors.initials: YK
authors.lastname: Choi
authors.forename: Clive H
authors.initials: CH
authors.lastname: Wasserfall
authors.forename: Minoru
authors.initials: M
authors.lastname: Satoh
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
authors.forename: Mark L
authors.initials: ML
authors.lastname: Brantly
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.forename: Sihong
authors.initials: S
authors.lastname: Song
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D024043:Collagen Type II / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D013601:T-Lymphocytes / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000235:genetics* / Q000627:therapeutic use*
chemical_list: D001323:Autoantibodies; D053264:B-Cell Activating Factor; D024043:Collagen Type II; D000515:alpha 1-Antitrypsin