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 subsequent induction of autoantibodies directed against glucose-6-phosphate isomerase (G6PI). This study sought to analyze the potential of anti-CD40 ligand (anti-CD40L) and anti-tumor necrosis factor alpha (anti-TNFalpha) antibodies in preventing and treating arthritis in this murine model.


METHODS
Groups of K/BxN mice were injected with anti-CD40L and anti-TNFalpha 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 the arthritis development in K/BxN mice when given a week before the onset of clinically apparent disease. However, no effect on disease was seen when the antibodies were administered after clinical onset. Surprisingly, neutralizing anti-TNFalpha antibodies were unable to prevent arthritis in K/BxN mice. The success of antibody treatment in preventing disease correlated with low levels of anti-G6PI antibodies in the serum.


CONCLUSIONS
These results suggest that anti-CD40L treatment can prevent arthritis development in a model of immunoglobulin-mediated arthritis, but anti-TNFalpha treatment cannot. The unsuccessful treatment of established disease was possibly due to the continued presence of autoreactive antibodies in the arthritic mice.
Kyburz
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D
University of California, San Diego, La Jolla 92093-0663, USA.
Carson
D A
DA
Corr
M
M
D000818:Animals; D000906:Antibodies / Q000097:blood / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000473:pathology* / Q000503:physiopathology* / Q000517:prevention & control; D023201:CD40 Ligand / Q000276:immunology / Q000502:physiology*; D004195:Disease Models, Animal; D005956:Glucose-6-Phosphate Isomerase / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000906:Antibodies; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D005956:Glucose-6-Phosphate Isomerase