Functional analysis of costimulatory molecules for autoimmune diseases

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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