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目的通过人ＨＬＡＤＲ４转基因小鼠的胶原性关节炎动物模型研究易感基因对类风湿关节炎及药物治疗的影响。方法将人ＨＬＡＤＲα＋４β基因转入Ｃ５７ＢＬ／６×ＤＢＡ／１Ｆ１代小鼠复制出转基因动物，并予胶原和佐剂免疫建立胶原性关节炎模型。以分子生物学技术检测外源基因的整合和表达，以发病时间、病理评分及血清Ⅱ型胶原抗体水平研究ＨＬＡＤＲ４基因对关节炎易感性及甲氨蝶呤治疗的影响。在体外通过淋巴细胞增殖及阻断实验研究Ⅱ型胶原及抗ＨＬＡＤＲ、Ｌｙｔ２和Ｌ３Ｔ４单抗对淋巴细胞增殖的影响。结果①人ＨＬＡＤＲ４基因稳定整合于Ｃ５７ＢＬ／６×ＤＢＡ／１Ｆ１代小鼠，主要在脾、肾中表达。②ＨＬＡＤＲ４转基因小鼠对照组发病时间较非转基因小鼠组提早（Ｐ＜００５）。③ＨＬＡＤＲ４转基因小鼠的对照组总病理评分和软骨破坏评分较相应的甲氨蝶呤治疗组高（Ｐ＜００５），非转基因小鼠的对照组的总病理评分、软骨破坏评分和骨质侵蚀评分较相应的甲氨蝶呤治疗组高（Ｐ＜００５，Ｐ＜００１）。④ＨＬＡＤＲ４转基因小鼠对照组和甲氨蝶呤治疗组的Ⅱ型胶原抗体水平较相应的非转基因小鼠组高（Ｐ＜００５，Ｐ＜０００１），且均高于二组正常血清对照组（Ｐ＜?
Objective To study the effects of susceptibility genes on rheumatoid arthritis and drug therapy by using collagen type arthritis animal model of human HLADR4 transgenic mice. Methods Human HLA DRα + 4β gene was transfected into C57BL / 6 × DBA / 1F1 mice to produce transgenic arthritis model by immunization with collagen and adjuvant. Molecular biology techniques were used to detect the integration and expression of exogenous genes. The onset time, pathological score and serum level of type II collagen antibody were used to study the effect of HLADR4 on arthritis susceptibility and methotrexate treatment. Lymphocyte proliferation was induced by type Ⅱ collagen and anti-HLADR, Lyt2 and L3T4 monoclonal antibodies in vitro by lymphocyte proliferation and blocking experiments. Results ① Human HLADR4 gene was stably integrated in C57BL / 6 × DBA / 1F1 mice and mainly expressed in spleen and kidney. ② HLA-DR4 transgenic mice in the control group onset time earlier than non-transgenic mice (P <0 05). ③ The total pathological score and cartilage destruction score of the HLA-DR4 transgenic mice were higher than those of the corresponding methotrexate-treated mice (P <005), while those of the non-transgenic mice in the control group were significantly lower than those of the untreated mice Bone erosion score was higher than the corresponding methotrexate treatment group (P <0 05, P <0 01). ④ HLA-DR4 transgenic mouse control group and methotrexate treatment group collagen type Ⅱ antibody levels than the corresponding non-transgenic mice group (P <0 05, P <0 001), and were higher than the two groups Normal serum control group (P <?