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Therapeutic effects of antibodies to tumor necrosis factor-alpha, interleukin-6 and cytotoxic T-lymphocyte antigen 4 immunoglobulin in mice with glucose-6-phosphate isomerase induced arthritis.

Matsumoto I, Zhang H, Yasukochi T, Iwanami K, Tanaka Y, Inoue A, Goto D, Ito S, Tsutsumi A, Sumida T - Arthritis Res. Ther. (2008)

Bottom Line: Anti-TNF-alpha mAbs and CTLA-4Ig suppressed TNF-alpha production, whereas anti-IFN-gamma mAbs, anti-IL-12 mAbs, and CTLA-4 Ig inhibited IFN-gamma production.Therapeutic efficacy tended to correlate with reduction in anti-GPI antibodies.Because the therapeutic effects of the tested molecules used in this study are similar to those in patients with rheumatoid arthritis, GPI-induced arthritis appears to be a suitable tool with which to examine the effect of various therapies on rheumatoid arthritis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Clinical Immunology, Major of Advanced Biomedical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennodai, Tsukuba 305-8575, Japan. ismatsu@md.tsukuba.ac.jp

ABSTRACT

Introduction: Immunization with glucose-6-phosphate isomerase (GPI) induces severe arthritis in DBA/1 mice. The present study was designed to identify the cytokines and co-stimulatory molecules involved in the development of GPI-induced arthritis.

Methods: Arthritis was induced in DBA/1 mice with 300 microg human recombinant GPI. CD4+ T cells and antigen-presenting cells from splenocytes of arthritic mice were cultured in the presence of GPI. Tumor necrosis factor (TNF)-alpha, IFN-gamma, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-12 levels were assessed using cytometric bead array. Monoclonal antibodies to TNF-alpha, IFN-gamma, IL-12, CD40L, inducible co-stimulator (ICOS), and cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA-4Ig) were used to block TNF-alpha and IFN-gamma production, examine clinical index in mice with GPI-induced arthritis, and determine anti-GPI antibody production.

Results: Large amounts of TNF-alpha and IFN-gamma and small amounts of IL-2 and IL-6 were produced by splenocytes from mice with GPI-induced arthritis. Anti-TNF-alpha mAbs and CTLA-4Ig suppressed TNF-alpha production, whereas anti-IFN-gamma mAbs, anti-IL-12 mAbs, and CTLA-4 Ig inhibited IFN-gamma production. A single injection of anti-TNF-alpha and anti-IL-6 mAbs and two injections of CTLA-4Ig reduced the severity of arthritis in mice, whereas injections of anti-IFN-gamma and anti-IL-12 mAbs tended to exacerbate arthritis. Therapeutic efficacy tended to correlate with reduction in anti-GPI antibodies.

Conclusion: TNF-alpha and IL-6 play an important role in GPI-induced arthritis, whereas IFN-gamma appears to function as a regulator of arthritis. Because the therapeutic effects of the tested molecules used in this study are similar to those in patients with rheumatoid arthritis, GPI-induced arthritis appears to be a suitable tool with which to examine the effect of various therapies on rheumatoid arthritis.

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Effective treatments tend to alter anti-GPI antibody production. Glucose-6-phosphate isomerase (GPI)-induced arthritic mice were treated with 100 μg anti-tumor necrosis factor (TNF)-α mAb, anti-IL-6 mAb, cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA-4Ig), and anti-IL-12 mAb on day 8, and CTLA-4 Ig on day 12. Serum samples were collected on day 14. The titers of anti-GPI antibodies were analyzed by enzyme-linked immunosorbent assay. Each symbol represents a single animal. Data are expressed as mean ± standard deviation of optical density.
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Figure 5: Effective treatments tend to alter anti-GPI antibody production. Glucose-6-phosphate isomerase (GPI)-induced arthritic mice were treated with 100 μg anti-tumor necrosis factor (TNF)-α mAb, anti-IL-6 mAb, cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA-4Ig), and anti-IL-12 mAb on day 8, and CTLA-4 Ig on day 12. Serum samples were collected on day 14. The titers of anti-GPI antibodies were analyzed by enzyme-linked immunosorbent assay. Each symbol represents a single animal. Data are expressed as mean ± standard deviation of optical density.

Mentions: Anti-GPI antibodies have potent arthritogenic capacity in K/B × N mice. However, anti-GPI antibodies from mice with GPI-induced arthritis do not solely cause arthritis (Schubert and coworkers [11] and our preliminary observations). In GPI-induced arthritis, IgG and C3 are co-localized on the articular surface of arthritic joints (Tanaka and coworkers, unpublished data). Accordingly, we compared the effects of anti-cytokine mAbs, immunomodulatory molecule CTLA-4Ig, and control immunoglobulin on the production of anti-GPI antibodies in mice with GPI-induced arthritis. The antigen was injected on day 8, and then sera were collected on day 14. As shown in Figure 5, anti-TNF-α, anti-IL-6, and CTLA-4Ig tended to suppress the production of anti-GPI antibodies, whereas IL-12 mAb slightly enhanced the production of the antibodies. These findings suggest that effective treatments might also alter autoantibody production during this phase of GPI-induced arthritis.


Therapeutic effects of antibodies to tumor necrosis factor-alpha, interleukin-6 and cytotoxic T-lymphocyte antigen 4 immunoglobulin in mice with glucose-6-phosphate isomerase induced arthritis.

Matsumoto I, Zhang H, Yasukochi T, Iwanami K, Tanaka Y, Inoue A, Goto D, Ito S, Tsutsumi A, Sumida T - Arthritis Res. Ther. (2008)

Effective treatments tend to alter anti-GPI antibody production. Glucose-6-phosphate isomerase (GPI)-induced arthritic mice were treated with 100 μg anti-tumor necrosis factor (TNF)-α mAb, anti-IL-6 mAb, cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA-4Ig), and anti-IL-12 mAb on day 8, and CTLA-4 Ig on day 12. Serum samples were collected on day 14. The titers of anti-GPI antibodies were analyzed by enzyme-linked immunosorbent assay. Each symbol represents a single animal. Data are expressed as mean ± standard deviation of optical density.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2483457&req=5

Figure 5: Effective treatments tend to alter anti-GPI antibody production. Glucose-6-phosphate isomerase (GPI)-induced arthritic mice were treated with 100 μg anti-tumor necrosis factor (TNF)-α mAb, anti-IL-6 mAb, cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA-4Ig), and anti-IL-12 mAb on day 8, and CTLA-4 Ig on day 12. Serum samples were collected on day 14. The titers of anti-GPI antibodies were analyzed by enzyme-linked immunosorbent assay. Each symbol represents a single animal. Data are expressed as mean ± standard deviation of optical density.
Mentions: Anti-GPI antibodies have potent arthritogenic capacity in K/B × N mice. However, anti-GPI antibodies from mice with GPI-induced arthritis do not solely cause arthritis (Schubert and coworkers [11] and our preliminary observations). In GPI-induced arthritis, IgG and C3 are co-localized on the articular surface of arthritic joints (Tanaka and coworkers, unpublished data). Accordingly, we compared the effects of anti-cytokine mAbs, immunomodulatory molecule CTLA-4Ig, and control immunoglobulin on the production of anti-GPI antibodies in mice with GPI-induced arthritis. The antigen was injected on day 8, and then sera were collected on day 14. As shown in Figure 5, anti-TNF-α, anti-IL-6, and CTLA-4Ig tended to suppress the production of anti-GPI antibodies, whereas IL-12 mAb slightly enhanced the production of the antibodies. These findings suggest that effective treatments might also alter autoantibody production during this phase of GPI-induced arthritis.

Bottom Line: Anti-TNF-alpha mAbs and CTLA-4Ig suppressed TNF-alpha production, whereas anti-IFN-gamma mAbs, anti-IL-12 mAbs, and CTLA-4 Ig inhibited IFN-gamma production.Therapeutic efficacy tended to correlate with reduction in anti-GPI antibodies.Because the therapeutic effects of the tested molecules used in this study are similar to those in patients with rheumatoid arthritis, GPI-induced arthritis appears to be a suitable tool with which to examine the effect of various therapies on rheumatoid arthritis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Clinical Immunology, Major of Advanced Biomedical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennodai, Tsukuba 305-8575, Japan. ismatsu@md.tsukuba.ac.jp

ABSTRACT

Introduction: Immunization with glucose-6-phosphate isomerase (GPI) induces severe arthritis in DBA/1 mice. The present study was designed to identify the cytokines and co-stimulatory molecules involved in the development of GPI-induced arthritis.

Methods: Arthritis was induced in DBA/1 mice with 300 microg human recombinant GPI. CD4+ T cells and antigen-presenting cells from splenocytes of arthritic mice were cultured in the presence of GPI. Tumor necrosis factor (TNF)-alpha, IFN-gamma, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-12 levels were assessed using cytometric bead array. Monoclonal antibodies to TNF-alpha, IFN-gamma, IL-12, CD40L, inducible co-stimulator (ICOS), and cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA-4Ig) were used to block TNF-alpha and IFN-gamma production, examine clinical index in mice with GPI-induced arthritis, and determine anti-GPI antibody production.

Results: Large amounts of TNF-alpha and IFN-gamma and small amounts of IL-2 and IL-6 were produced by splenocytes from mice with GPI-induced arthritis. Anti-TNF-alpha mAbs and CTLA-4Ig suppressed TNF-alpha production, whereas anti-IFN-gamma mAbs, anti-IL-12 mAbs, and CTLA-4 Ig inhibited IFN-gamma production. A single injection of anti-TNF-alpha and anti-IL-6 mAbs and two injections of CTLA-4Ig reduced the severity of arthritis in mice, whereas injections of anti-IFN-gamma and anti-IL-12 mAbs tended to exacerbate arthritis. Therapeutic efficacy tended to correlate with reduction in anti-GPI antibodies.

Conclusion: TNF-alpha and IL-6 play an important role in GPI-induced arthritis, whereas IFN-gamma appears to function as a regulator of arthritis. Because the therapeutic effects of the tested molecules used in this study are similar to those in patients with rheumatoid arthritis, GPI-induced arthritis appears to be a suitable tool with which to examine the effect of various therapies on rheumatoid arthritis.

Show MeSH
Related in: MedlinePlus