The role of CD40 ligand and tumor necrosis factor alpha signaling in the transgenic K/BxN mouse model of rheumatoid arthritis

Objective. Spontaneous arthritis in the KRN transgenic mouse (K/BxN) model is due to the autoreactivity of the transgenic T cell receptor and subseque nt induction of autoantibodies directed against glucose-6-phosphate isomera se (G6PI), This study sought to analyze the potential of anti-CD40 ligand ( anti-CD40L) and anti-tumor necrosis factor alpha (anti-TNF alpha) antibodie s in preventing and treating arthritis in this murine model. Methods. Groups of K/BxN mice were injected with anti-CD40L and anti-TNF al pha antibodies during various stages of arthritis. Disease was assessed by clinical scoring, measurements of paw swelling, and histology, The results were correlated with the levels of autoantibodies in the serum, as assessed by enzyme-linked immunosorbent assay. Results. Anti-CD40L antibody treatment was able to diminish significantly t he arthritis development in K/BxN mice when given a week before the onset o f clinically apparent disease. However, no effect on disease was seen when the antibodies were administered after clinical onset, Surprisingly, neutra lizing anti-TNF alpha antibodies were unable to prevent arthritis in K/BxN mice. The success of antibody treatment in preventing disease correlated wi th low levels of anti-G6PI antibodies in the serum, Conclusion. These results suggest that anti-CD40L treatment can prevent art hritis development in a model of immunoglobulin-mediated arthritis, but ant i-TNF alpha treatment cannot. The unsuccessful treatment of established dis ease was possibly due to the continued presence of autoreactive antibodies in the arthritic mice.