Abstract
Rheumatoid arthritis is one major chronic inflammatory systemic autoimmune disease. The CD154-CD40 interactions play a critical role in the regulation of immune responses and the maintenance of autoimmunity. Therefore, we aimed to determine whether anti-CD154 antibody treatment show positive effects on immunomodulation and clinical improvement of sustained severe rheumatoid arthritis in cynomolgus monkeys. Arthritis was induced using chicken type II collagen (CII) and arthritic monkey were divided into control and anti-CD154 treatment groups based on their concentrations of anti-CII antibodies on week 7 post-immunization. Blood and tissue samples were collected on week 16 post-immunization. Anti-CD154 antibody treatment improved arthritis and movement, and significantly decreased the numbers of proliferating B cells and the serum levels of anti-type II collagen antibody and sCD154 compared with non-treatment group. Further anti-CD154 antibody treatment significantly decreased the percentage of CD4+ cells and the ratio of CD4+ to CD8+ T cells and significantly increased the percentage of CD8+ cells and effector memory CD8+ cells in peripheral blood. We have shown for the first time in a nonhuman primate model of RA that CD154 blockade has beneficial effects. This study might be valuable as preclinical data of CD154 blockade in nonhuman primate models of severe rheumatoid arthritis.
Highlights
Rheumatoid arthritis (RA) is one of the major chronic inflammatory systemic autoimmune diseases[1,2]
After treatment with anti-CD154 antibody, the sum of soft tissue swelling scores decreased in the anti-CD154 group (RA1 and RA7) but not in the control group (RA2, RA3, and RA8) (Fig. 1A); since soft tissue swelling was not observed in all monkeys, statistical significance was not obtained
The expression of CD154 on activated T cells and serum levels of sCD154 are increased in autoimmune diseases, and increased signaling via CD40
Summary
Rheumatoid arthritis (RA) is one of the major chronic inflammatory systemic autoimmune diseases[1,2]. Monoclonal antibodies to certain proteins are shared by humans and monkeys and treatment using these antibodies can be carried out in monkey models with greater predictive value of efficacy, side effects, and the pathological roles of the proteins in humans than using rodent models[6]. It was reported that patients with systemic lupus erythematosus (SLE), RA, and Sjögren's disease showed increased levels of soluble CD154. Some preclinical and clinical studies evaluating the use of anti-CD154 antibody for autoimmune diseases have been conducted. Anti-CD154 antibody treatment prior to disease onset prolonged survival, prevented proteinuria, decreased levels of anti-dsDNA antibodies, and ameliorated glomerulonephritis in murine systemic lupus erythematosus models such as (NZB × NZW) F1 and (SWR × NZB) F1 mice[19,20]. Anti-CD154 antibody treatment after disease onset delayed disease progression and reversed proteinuria in spite of ongoing immune complex glomerulonephritis[19,20]
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