Macphee I A M, Turner D R, Yagita H, Oliveira D B G
Department of Renal Medicine, St. George's Hospital Medical School, London, UK.
Clin Exp Immunol. 2002 Sep;129(3):405-10. doi: 10.1046/j.1365-2249.2002.01928.x.
Mercuric chloride (HgCl2)-induced autoimmunity in Brown Norway (BN) rats is a highly polarized polyclonal Th2-driven autoimmune response with increased IgE production, lymphoproliferation, vasculitis and proteinuria. The increase in serum IgE concentration is clearly measurable by day 4 after the first HgCl2 injection and peaks between days 15 and 20. Treatment with CD80 and CD86 antibodies prior to administration of HgCl2 completely suppresses the autoimmune process. To determine whether interruption of CD28 signalling after initial stimulation of the Th2-response would be suppressive, antibody treatment was delayed. BN rats were given 5 doses of HgCl2 subcutaneously on alternate days. CD80 and CD86 antibodies, or an isotype control, were given daily for 3 days and then on alternate days until day 12 commencing either on the day of the first HgCl2 injection (day 0) or on days 4 or 8. Treatment from day 0 reduced serum IgE concentrations to below baseline (median 9.34 microg/ml on day 0 versus 4.6 microg/ml, on day 5, P = 0.03) suggesting that ongoing costimulation via CD28 is required to maintain basal serum IgE production. Delaying treatment until day 4 or day 8 after the first HgCl2 injection resulted in significant inhibition of IgE secretion, lymphoproliferation, and vasculitis, although less markedly than when treatment was commenced on day 0. These data indicate that CD28-mediated costimulation is not only required for the initiation of the Th2-response but is required for maintenance of a maximal response, making this an attractive therapeutic target for antibody-mediated autoimmune diseases.
氯化汞（HgCl2）诱导的棕色挪威（BN）大鼠自身免疫是一种高度极化的多克隆Th2驱动的自身免疫反应，伴有IgE产生增加、淋巴细胞增殖、血管炎和蛋白尿。首次注射HgCl2后第4天，血清IgE浓度的升高就可明显检测到，并在第15至20天达到峰值。在给予HgCl2之前用CD80和CD86抗体治疗可完全抑制自身免疫过程。为了确定在Th2反应初始刺激后中断CD28信号是否具有抑制作用，抗体治疗被延迟。BN大鼠每隔一天皮下注射5剂HgCl2。每天给予CD80和CD86抗体或同型对照，共3天，然后每隔一天给药，直到第12天，从首次注射HgCl2的当天（第0天）或第4天或第8天开始。从第0天开始治疗可使血清IgE浓度降至基线以下（第0天中位数为9.34μg/ml，第5天为4.6μg/ml，P = 0.03），这表明需要通过CD28进行持续的共刺激来维持基础血清IgE的产生。将治疗延迟到首次注射HgCl2后的第4天或第8天，可显著抑制IgE分泌、淋巴细胞增殖和血管炎，尽管其抑制程度不如从第0天开始治疗时明显。这些数据表明，CD28介导的共刺激不仅是Th2反应启动所必需的，也是维持最大反应所必需的，这使其成为抗体介导的自身免疫性疾病有吸引力的治疗靶点。
