Kyburz D, Carson D A, Corr M
University of California, San Diego, La Jolla 92093-0663, USA.
Arthritis Rheum. 2000 Nov;43(11):2571-7. doi: 10.1002/1529-0131(200011)43:11<2571::AID-ANR26>3.0.CO;2-4.
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.
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.
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.
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.
KRN转基因小鼠（K/BxN）模型中的自发性关节炎是由于转基因T细胞受体的自身反应性以及随后诱导产生针对葡萄糖-6-磷酸异构酶（G6PI）的自身抗体所致。本研究旨在分析抗CD40配体（抗CD40L）和抗肿瘤坏死因子α（抗TNFα）抗体在预防和治疗该小鼠模型关节炎中的潜力。
在关节炎的不同阶段，给多组K/BxN小鼠注射抗CD40L和抗TNFα抗体。通过临床评分、爪肿胀测量和组织学评估疾病情况。结果与通过酶联免疫吸附测定评估的血清中自身抗体水平相关。
在临床明显疾病发作前一周给予抗CD40L抗体治疗，能够显著减轻K/BxN小鼠的关节炎发展。然而，在临床发作后给予抗体时，未观察到对疾病的影响。令人惊讶的是，中和抗TNFα抗体无法预防K/BxN小鼠的关节炎。抗体治疗预防疾病的成功与血清中低水平的抗G6PI抗体相关联。
这些结果表明，抗CD40L治疗可以在免疫球蛋白介导的关节炎模型中预防关节炎发展，但抗TNFα治疗则不能。对已确诊疾病治疗失败可能是由于关节炎小鼠中持续存在自身反应性抗体。
