Lechman E R, Keravala A, Nash J, Kim S-H, Mi Z, Robbins P D
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Gene Ther. 2003 Nov;10(24):2029-35. doi: 10.1038/sj.gt.3302109.
We have demonstrated previously that local, adenoviral-mediated gene transfer of vIL-10 to a single joint of rabbits and mice with experimental arthritis can suppress disease in both the treated and untreated contralateral joints. These therapeutic effects observed in distant untreated joints following local intra-articular gene delivery have been termed the 'contralateral effect'. To begin to understand the underlying immunologic mechanism that confers this effect, a dual-antigen model of antigen-induced arthritis (AIA) in rabbit knee joints was utilized. Rabbits were immunized against two antigens, ovalbumin and keyhole limpet hemocyanin, and AIA generated by intra-articular injection of each antigen into contralateral knees. Intra-articular adenovirus-mediated gene transfer of vIL-10 significantly reduced intra-articular leukocytosis and cartilage matrix degradation, while preserving near normal levels of cartilage matrix synthesis within treated joints. However, no antiarthritic effect was conferred in the contralateral control joints that received only a marker gene, in contrast to the results seen in a single-antigen AIA model. These results suggest that the distant antiarthritic effects associated with local gene delivery to joints are antigen-specific, and not due to vIL-10-induced generalized immunosuppression of the animal.
我们之前已经证明，通过腺病毒介导将vIL-10基因局部导入患有实验性关节炎的兔和小鼠的单个关节，可抑制治疗关节和未治疗的对侧关节中的疾病。在局部关节内基因递送后，在远处未治疗的关节中观察到的这些治疗效果被称为“对侧效应”。为了开始了解赋予这种效应的潜在免疫机制，我们利用了兔膝关节抗原诱导性关节炎（AIA）的双抗原模型。用两种抗原（卵清蛋白和钥孔戚血蓝蛋白）对兔子进行免疫，然后通过向对侧膝关节内注射每种抗原诱导产生AIA。腺病毒介导的vIL-10基因关节内转移显著降低了关节内白细胞增多和软骨基质降解，同时在治疗关节内保持了接近正常水平的软骨基质合成。然而，与单抗原AIA模型的结果相反，仅接受标记基因的对侧对照关节未产生抗关节炎作用。这些结果表明，与局部基因递送关节相关的远处抗关节炎作用是抗原特异性的，而不是由于vIL-10诱导的动物全身性免疫抑制。
