Functional analysis of costimulatory molecules for autoimmune diseases

1.ICOS/B7RP-1和OX40/OX40L在小鼠实验性自身免疫性葡萄膜视网膜炎中的作用抗B7RP-1单抗(MAb)处理的小鼠或ICOS缺陷小鼠的疾病评分显著降低。在效应期阻断ICOS/B7RP-1相互作用可改善病情，而在诱导期阻断ICOS/B7RP-1则无明显效果。在效应期阻断OX40/OX40L相互作用也可以缓解疾病，而在诱导期阻断OX40/OX40L的作用则加速。提示ICOS/B7RP-1和OX40/OX40L相互作用在葡萄膜炎发病机制中起重要作用。我们还指出，icos介导的共刺激在EAU和实验性自身免疫性脑脊髓炎中发挥着不同的作用，这也是一种由Thl引起的…。2.抗RANKL和抗TWINE单抗对胶原诱导性关节炎(CIA)的改善作用我们研究了抗RANKL和抗TWAINE单抗对类风湿关节炎(RA)小鼠模型CIA形成的影响。组织学分析显示，经抗RANKL治疗的CIA小鼠关节炎症部位破骨细胞形成受损。这些结果提示抗RANKL单抗可用于预防RA关节炎症相关的骨质疏松症。应用抗TWINE单抗后，大鼠足爪肿胀、滑膜增生和炎性细胞浸润明显减轻。血清和膝关节中促炎性趋化因子水平降低。组织学检查显示，抗TWINE单抗治疗可抑制滑膜组织中小血管的形成。这些结果表明TWEACK在CIA中具有抗炎和抗血管生成的作用，这可能也有利于RA的治疗。较少

1.The role of the ICOS/B7RP-1 and OX40/OX40L in murine experimental autoimmune uveoretinitis.We examined the role of ICOSB7RP-1 and OX40/OX40L pathways in the pathogenesis of mouse experimental autoimmune uveoretinitis (EAU) , an animal model of human autoimmune uveitis. The anti-B7RP-1 monoclonal antibody (mAb)-treated or ICOS-deficient mice showed a substantial reduction of disease scores. Blockade of ICOS/B7RP-1 interaction during the effector phase ameliorated the disease, whereas its blockade during the induction phase exhibited no significant effect. Blockade of OX40/OX40L interaction during the effector phase also ameliorated the disease, whereas its blockade during the induction phase accelerated. These results suggest that ICOS/B7RP-1 and OX40/OX40L interactions play a critical role in the pathogenesis of uveitis. We also indicated that ICOS-mediated costimulation plays differential roles in EAU and experimental autoimmune encephalomyelitis, which is also a Thl disease induced … More in the same manner as EAU.2.Amelioration of collagen-induced arthritis (CIA) by anti-RANKL and anti-TWEAK mAbs treatment.We have investigated the effect of anti-RANKL and anti-TWEAK mAbs on the development of CIA, a well-established murine model of rheumatoid arthritis (RA).Anti-RANKL mAb had no effect on immune responses or inflammation, it ameliorated bone loss at the site of inflammation. Histological analyses revealed that osteoclast formation was impaired at the site of joint inflammation in anti-RANKL-treated CIA mice. These results suggest the utility of anti-RANKL mAb for the prevention of osteoporosis associated with joint inflammation in RA. Administration of anti-TWEAK mAb significantly ameliorated paw swelling, synovial hyperplasia, and infiltration of inflammatory cells. The levels of proinflammatory chemokines in serum and knee joints were reduced. Histological examination revealed that the treatment with anti-TWEAK mAb suppressed the development of small vessels in synovial tissues. These results indicated anti-inflammatory and antiangiogenic effects of the TWEAK blockade in CIA, which may be also beneficial for the treatment of RA. Less