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

Grimstein C, Choi YK, Wasserfall CH, Satoh M, Atkinson MA, Brantly ML, Campbell-Thompson M, Song S - J Transl Med (2011)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA.

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.

Conclusion: 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.

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Tissue protective effect of hAAT gene therapy in CIA mouse model. DBA/1 mice were intraperitoneally injected with rAAV8-CB-hAAT vector (2 × 1011 particles/mouse, n = 6) or saline (n = 4) two weeks before immunization with CII. Control group received saline. (A) Arthritis development was evaluated based on arthritis score (mean + SD). Open circle represent rAAV8-CB-hAAT vector injected group, open triangle represent control group. Mice were sacrificed on day 28 after CII immunization, hind limbs were harvested and processed for histological assessment. *p < 0.05 by Mann-Whitney U-test. (B) Histopathological evaluation of arthritis development. Mice in gene therapy group (black bars) or control group (empty bars) were evaluated according to histopathological changes by two blinded pathologists. Each hind paw was evaluated based on a scale ranging from 0-3. (mean+SD). *p < 0.05, **p < 0.01 by Mann-Whitney U-test. (INF: Infiltration of Immune Cells, HYP: Hyperplasia, P.F.: Pannus Formation, B.D.: Bone Destruction) (C,D) Representative joint section from mice receiving hAAT gene therapy. (E,F) Representative joint section from mice in control group (saline injection). Magnification: C,E: 100x; D,F: 200x.
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Figure 4: Tissue protective effect of hAAT gene therapy in CIA mouse model. DBA/1 mice were intraperitoneally injected with rAAV8-CB-hAAT vector (2 × 1011 particles/mouse, n = 6) or saline (n = 4) two weeks before immunization with CII. Control group received saline. (A) Arthritis development was evaluated based on arthritis score (mean + SD). Open circle represent rAAV8-CB-hAAT vector injected group, open triangle represent control group. Mice were sacrificed on day 28 after CII immunization, hind limbs were harvested and processed for histological assessment. *p < 0.05 by Mann-Whitney U-test. (B) Histopathological evaluation of arthritis development. Mice in gene therapy group (black bars) or control group (empty bars) were evaluated according to histopathological changes by two blinded pathologists. Each hind paw was evaluated based on a scale ranging from 0-3. (mean+SD). *p < 0.05, **p < 0.01 by Mann-Whitney U-test. (INF: Infiltration of Immune Cells, HYP: Hyperplasia, P.F.: Pannus Formation, B.D.: Bone Destruction) (C,D) Representative joint section from mice receiving hAAT gene therapy. (E,F) Representative joint section from mice in control group (saline injection). Magnification: C,E: 100x; D,F: 200x.

Mentions: In an additional experiment using AAV8 mediated hAAT gene therapy, tissue protective properties of hAAT were evaluated. Similar to the previous experiment, mice in treatment group (n = 6) showed significantly reduced arthritis development at the early disease stage compared to control (n = 4) (Figure 4A, p < 0.05 by Mann-Whitney U-test). As shown in Figure 4B-F, AAV8 mediated hAAT gene therapy resulted in less infiltration of immune cells into the joint cavity accompanied with reduced synovial cell hyperplasia and pannus formation (p < 0.05 Mann-Whitney U-test).


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

Grimstein C, Choi YK, Wasserfall CH, Satoh M, Atkinson MA, Brantly ML, Campbell-Thompson M, Song S - J Transl Med (2011)

Tissue protective effect of hAAT gene therapy in CIA mouse model. DBA/1 mice were intraperitoneally injected with rAAV8-CB-hAAT vector (2 × 1011 particles/mouse, n = 6) or saline (n = 4) two weeks before immunization with CII. Control group received saline. (A) Arthritis development was evaluated based on arthritis score (mean + SD). Open circle represent rAAV8-CB-hAAT vector injected group, open triangle represent control group. Mice were sacrificed on day 28 after CII immunization, hind limbs were harvested and processed for histological assessment. *p < 0.05 by Mann-Whitney U-test. (B) Histopathological evaluation of arthritis development. Mice in gene therapy group (black bars) or control group (empty bars) were evaluated according to histopathological changes by two blinded pathologists. Each hind paw was evaluated based on a scale ranging from 0-3. (mean+SD). *p < 0.05, **p < 0.01 by Mann-Whitney U-test. (INF: Infiltration of Immune Cells, HYP: Hyperplasia, P.F.: Pannus Formation, B.D.: Bone Destruction) (C,D) Representative joint section from mice receiving hAAT gene therapy. (E,F) Representative joint section from mice in control group (saline injection). Magnification: C,E: 100x; D,F: 200x.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3050720&req=5

Figure 4: Tissue protective effect of hAAT gene therapy in CIA mouse model. DBA/1 mice were intraperitoneally injected with rAAV8-CB-hAAT vector (2 × 1011 particles/mouse, n = 6) or saline (n = 4) two weeks before immunization with CII. Control group received saline. (A) Arthritis development was evaluated based on arthritis score (mean + SD). Open circle represent rAAV8-CB-hAAT vector injected group, open triangle represent control group. Mice were sacrificed on day 28 after CII immunization, hind limbs were harvested and processed for histological assessment. *p < 0.05 by Mann-Whitney U-test. (B) Histopathological evaluation of arthritis development. Mice in gene therapy group (black bars) or control group (empty bars) were evaluated according to histopathological changes by two blinded pathologists. Each hind paw was evaluated based on a scale ranging from 0-3. (mean+SD). *p < 0.05, **p < 0.01 by Mann-Whitney U-test. (INF: Infiltration of Immune Cells, HYP: Hyperplasia, P.F.: Pannus Formation, B.D.: Bone Destruction) (C,D) Representative joint section from mice receiving hAAT gene therapy. (E,F) Representative joint section from mice in control group (saline injection). Magnification: C,E: 100x; D,F: 200x.
Mentions: In an additional experiment using AAV8 mediated hAAT gene therapy, tissue protective properties of hAAT were evaluated. Similar to the previous experiment, mice in treatment group (n = 6) showed significantly reduced arthritis development at the early disease stage compared to control (n = 4) (Figure 4A, p < 0.05 by Mann-Whitney U-test). As shown in Figure 4B-F, AAV8 mediated hAAT gene therapy resulted in less infiltration of immune cells into the joint cavity accompanied with reduced synovial cell hyperplasia and pannus formation (p < 0.05 Mann-Whitney U-test).

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA.

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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus