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RNAi-mediated CD40-CD154 interruption promotes tolerance in autoimmune arthritis.

Zheng X, Suzuki M, Zhang X, Ichim TE, Zhu F, Ling H, Shunnar A, Wang MH, Garcia B, Inman RD, Min WP - Arthritis Res. Ther. (2010)

Bottom Line: Therapeutic effects were evaluated by clinical symptoms, histopathology, Ag-specific T cell and B cell immune responses.Disease amelioration was associated with suppression of Th1 cytokines, attenuation of antibody production, and upregulation of T regulatory cells.These studies support the feasibility of transient gene silencing at a systemic level as a mechanism of resetting autoreactive immunity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departments of Surgery, Pathology, Microbiology and Immunology, University of Western Ontario, 1393 Western Road, London, Ontario, N6G 1G9, Canada. xzheng26@uwo.ca

ABSTRACT

Introduction: We have previously demonstrated that ex vivo inhibition of costimulatory molecules on antigen-pulsed dendritic cells (DCs) can be useful for induction of antigen-specific immune deviation and suppression of autoimmune arthritis in the collagen induced arthritis (CIA) model. The current study evaluated a practical method of immune modulation through temporary systemic inhibition of the costimulatory molecule CD40.

Methods: Mice with collagen II (CII)-induced arthritis (CIA) were administered siRNA targeting the CD40 molecule. Therapeutic effects were evaluated by clinical symptoms, histopathology, Ag-specific T cell and B cell immune responses.

Results: Systemic administration of CD40-targeting siRNA can inhibit antigen-specific T cell response to collagen II, as well as prevent pathogenesis of disease in both a pre- and post-immunization manner in the CIA model. Disease amelioration was associated with suppression of Th1 cytokines, attenuation of antibody production, and upregulation of T regulatory cells.

Conclusions: These studies support the feasibility of transient gene silencing at a systemic level as a mechanism of resetting autoreactive immunity.

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Related in: MedlinePlus

Preventing autoimmune arthritis by CD40 siRNA. DBA mice (seven mice per group) were injected with 50 μg of CD40 siRNA or control siRNA using the hydrodynamic injection method. Two days after siRNA treatment, mice were immunized with 200 μg CII antigen, two times on Day 0 and Day 21, respectively. Treatment of CD 40 siRNA was repeated on Day 7 after first CII immunization. Disease severity was scored from the day of last immunization to five weeks a). The swelling of joints of CIA mice was determined by the thickness of each hind paw measured with caliper b). Data are presented as mean ± SEM. Results represent one of three experiments. * = P < 0.05 versus control siRNA.
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Figure 3: Preventing autoimmune arthritis by CD40 siRNA. DBA mice (seven mice per group) were injected with 50 μg of CD40 siRNA or control siRNA using the hydrodynamic injection method. Two days after siRNA treatment, mice were immunized with 200 μg CII antigen, two times on Day 0 and Day 21, respectively. Treatment of CD 40 siRNA was repeated on Day 7 after first CII immunization. Disease severity was scored from the day of last immunization to five weeks a). The swelling of joints of CIA mice was determined by the thickness of each hind paw measured with caliper b). Data are presented as mean ± SEM. Results represent one of three experiments. * = P < 0.05 versus control siRNA.

Mentions: In previous studies we demonstrated that chemical manipulation in DCs through inhibition of IKK, which is responsible for CD40 upregulation in DC, can result in generation of antigen-specific immune regulation and suppression of pathology in the CIA model [15]. Here we tested whether the systemic administration of CD40 siRNA may have a similar effect. DBA mice were treated with a dose of 50 μg CD40 siRNA two days before immunization with CII antigen and subsequently CD40 siRNA was administered on Day 7 after immunization with CII. After a boost immunization on Day 21, onset of CIA was assessed. The disease onset occurred around Day 28 in control siRNA treated group, versus Day 35 in CD40 siRNA treated group, as judged by erythema and swelling of joints. Inhibition of arthritis clinical score was observed in the mice treated with CD40 siRNA, as opposed to control siRNA-treated mice which exhibited no inhibition (Figure 3A). Additionally, the degree of joint swelling was remarkably attenuated (Figure 3B) in the mice treated with CD40-siRNA. These data suggest that systemic administration of CD40 siRNA may prevent autoimmune arthritis.


RNAi-mediated CD40-CD154 interruption promotes tolerance in autoimmune arthritis.

Zheng X, Suzuki M, Zhang X, Ichim TE, Zhu F, Ling H, Shunnar A, Wang MH, Garcia B, Inman RD, Min WP - Arthritis Res. Ther. (2010)

Preventing autoimmune arthritis by CD40 siRNA. DBA mice (seven mice per group) were injected with 50 μg of CD40 siRNA or control siRNA using the hydrodynamic injection method. Two days after siRNA treatment, mice were immunized with 200 μg CII antigen, two times on Day 0 and Day 21, respectively. Treatment of CD 40 siRNA was repeated on Day 7 after first CII immunization. Disease severity was scored from the day of last immunization to five weeks a). The swelling of joints of CIA mice was determined by the thickness of each hind paw measured with caliper b). Data are presented as mean ± SEM. Results represent one of three experiments. * = P < 0.05 versus control siRNA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2875641&req=5

Figure 3: Preventing autoimmune arthritis by CD40 siRNA. DBA mice (seven mice per group) were injected with 50 μg of CD40 siRNA or control siRNA using the hydrodynamic injection method. Two days after siRNA treatment, mice were immunized with 200 μg CII antigen, two times on Day 0 and Day 21, respectively. Treatment of CD 40 siRNA was repeated on Day 7 after first CII immunization. Disease severity was scored from the day of last immunization to five weeks a). The swelling of joints of CIA mice was determined by the thickness of each hind paw measured with caliper b). Data are presented as mean ± SEM. Results represent one of three experiments. * = P < 0.05 versus control siRNA.
Mentions: In previous studies we demonstrated that chemical manipulation in DCs through inhibition of IKK, which is responsible for CD40 upregulation in DC, can result in generation of antigen-specific immune regulation and suppression of pathology in the CIA model [15]. Here we tested whether the systemic administration of CD40 siRNA may have a similar effect. DBA mice were treated with a dose of 50 μg CD40 siRNA two days before immunization with CII antigen and subsequently CD40 siRNA was administered on Day 7 after immunization with CII. After a boost immunization on Day 21, onset of CIA was assessed. The disease onset occurred around Day 28 in control siRNA treated group, versus Day 35 in CD40 siRNA treated group, as judged by erythema and swelling of joints. Inhibition of arthritis clinical score was observed in the mice treated with CD40 siRNA, as opposed to control siRNA-treated mice which exhibited no inhibition (Figure 3A). Additionally, the degree of joint swelling was remarkably attenuated (Figure 3B) in the mice treated with CD40-siRNA. These data suggest that systemic administration of CD40 siRNA may prevent autoimmune arthritis.

Bottom Line: Therapeutic effects were evaluated by clinical symptoms, histopathology, Ag-specific T cell and B cell immune responses.Disease amelioration was associated with suppression of Th1 cytokines, attenuation of antibody production, and upregulation of T regulatory cells.These studies support the feasibility of transient gene silencing at a systemic level as a mechanism of resetting autoreactive immunity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departments of Surgery, Pathology, Microbiology and Immunology, University of Western Ontario, 1393 Western Road, London, Ontario, N6G 1G9, Canada. xzheng26@uwo.ca

ABSTRACT

Introduction: We have previously demonstrated that ex vivo inhibition of costimulatory molecules on antigen-pulsed dendritic cells (DCs) can be useful for induction of antigen-specific immune deviation and suppression of autoimmune arthritis in the collagen induced arthritis (CIA) model. The current study evaluated a practical method of immune modulation through temporary systemic inhibition of the costimulatory molecule CD40.

Methods: Mice with collagen II (CII)-induced arthritis (CIA) were administered siRNA targeting the CD40 molecule. Therapeutic effects were evaluated by clinical symptoms, histopathology, Ag-specific T cell and B cell immune responses.

Results: Systemic administration of CD40-targeting siRNA can inhibit antigen-specific T cell response to collagen II, as well as prevent pathogenesis of disease in both a pre- and post-immunization manner in the CIA model. Disease amelioration was associated with suppression of Th1 cytokines, attenuation of antibody production, and upregulation of T regulatory cells.

Conclusions: These studies support the feasibility of transient gene silencing at a systemic level as a mechanism of resetting autoreactive immunity.

Show MeSH
Related in: MedlinePlus