Arima T, Rehman A, Hickey W F, Flye M W
Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
J Immunol. 1996 Jun 15;156(12):4916-24.
B7-1 and B7-2 are well characterized costimulatory ligands on Ag presentation cells for the CD28 and CTLA4 receptors on T cells. The fusion protein CTLA4Ig can block this interaction and prevent specific T cell activation. The development of fatal CD4+ T cell-mediated experimental allergic encephalomyelitis (EAE) in susceptible female Lewis rats was optimized by immunization with 20 mg of guinea pig spinal cord homogenate in CFA on day 0 with three doses of 1 microgram pertussis toxin given i.v. on days 0, 3, and 7. This immunization regimen uniformly resulted in the development of severe clinical neurologic signs of EAE with 100% mortality by day 17 postimmunization. Treatment with 0.5 mg/dose of rhCTLA4-Ig on days - 2, 0, 3, 6, 9, 12, 15 and 18 significantly decreased the incidence, delayed the onset, and reduced the severity of clinical EAE (p = 0.0002 vs control by the Mann-Whitney U test) enough to completely prevent fatal EAE, whereas treatment with control human IgG had no effect. Histologically, perivascular neutrophilic infiltrates were also dramatically decreased in the spinal cords of animals treated with CTLA4 but not in those treated with control human IgG. The proliferative response to encephalitogenic Ags (guinea pig myelin basic protein and proteolipid protein) by lymph node cells from animals immunized with guinea pig spinal cord 10 days before was also significantly suppressed in vitro by CTLA4Ig (1 microg/ml). However, the protective effect of CTLA4Ig could be completely prevented by the daily i.p. administration, from day 0 to 10, of exogenous human rIL-2 (180,000 IU). These results indicate a critical requirement of the costimulatory B7/CD28 pathway early in the development of CD4+ T cell-mediated EAE in the rat.
B7-1和B7-2是抗原呈递细胞上已被充分表征的共刺激配体，可作用于T细胞上的CD28和CTLA4受体。融合蛋白CTLA4Ig可阻断这种相互作用并防止特异性T细胞活化。通过在第0天用20mg豚鼠脊髓匀浆在弗氏完全佐剂中免疫，并在第0、3和7天静脉内给予三剂1微克百日咳毒素，优化了易感雌性Lewis大鼠中致命的CD4 + T细胞介导的实验性自身免疫性脑脊髓炎（EAE）的发病情况。这种免疫方案在免疫后第17天均导致严重的EAE临床神经学体征出现，死亡率达100%。在第-2、0、3、6、9、12、15和18天用0.5mg/剂量的重组人CTLA4-Ig进行治疗，可显著降低发病率、延迟发病并减轻临床EAE的严重程度（通过曼-惠特尼U检验，与对照组相比p = 0.0002），足以完全预防致命性EAE，而用对照人IgG治疗则无效。组织学上，用CTLA4治疗的动物脊髓中血管周围嗜中性粒细胞浸润也显著减少，而用对照人IgG治疗的动物则未减少。在体外，CTLA4Ig（1微克/毫升）也显著抑制了在10天前用豚鼠脊髓免疫的动物的淋巴结细胞对致脑炎抗原（豚鼠髓鞘碱性蛋白和蛋白脂蛋白）的增殖反应。然而，从第0天到第10天每天腹腔注射外源性人重组白细胞介素-2（180,000国际单位）可完全消除CTLA4Ig的保护作用。这些结果表明，在大鼠CD4 + T细胞介导的EAE发病早期，共刺激B7/CD28途径至关重要。
