Targeting IL-15 receptor-bearing cells with an antagonist mutant IL-15/Fc protein prevents disease development and progression in murine collagen-induced arthritis
Targeting IL-15 receptor-bearing cells with an antagonist mutant IL-15/Fc protein prevents disease development and progression in murine collagen-induced arthritis
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DOI：
10.4049/jimmunol.173.9.5818
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发表时间：
2004-11-01
影响因子：
4.4
通讯作者：
Moll, T
中科院分区：
文献类型：
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作者：
Ferrari-Lacraz, S;Zanelli, E;Moll, T
已经表明炎性细胞因子IL-15在包括类风湿性关节炎在内的几种自身免疫性疾病的发展中起重要作用。我们已经产生了靶向IL-15 R的独特的裂解性和拮抗性IL-15突变体/Fc γ 2a融合蛋白（CRB-15）。在本研究中，我们检查了靶向IL-15 R对预防和治疗小鼠胶原诱导的关节炎（CIA）的作用，并探讨了这种IL-15突变体/Fc γ 2a蛋白的可能作用机制。在用II型胶原免疫后，DBA/1小鼠发生严重的关节炎症和破坏。在II型胶原蛋白激发时用CRB-15短暂治疗DBA/1小鼠显著抑制关节炎的发生率和严重程度。此外，与对照治疗的动物相比，在患有持续建立的关节炎的动物中，用CR-B-15治疗有效地阻断了疾病进展。CRB-15对疾病发展或疾病进展的治疗效果非常稳定，因为停止治疗不会导致疾病复发。一项详细的分析显示，CRB-15治疗减少了关节滑膜炎;减少了骨侵蚀和软骨破坏;减少了促炎细胞因子TNF-α、IL-1 β、IL-6和IL-17的原位产生;并降低了自身反应性T细胞的应答频率。我们的研究表明，CRB-15有效靶向IL-15 R触发的事件在类风湿性关节炎的治疗中具有重要的治疗意义。
It has been suggested that the inflammatory cytokine IL-15 plays an important role in the development of several autoimmune diseases, including rheumatoid arthritis. We have generated a unique lytic and antagonistic IL-15 mutant/Fcgamma2a fusion protein (CRB-15) that targets the IL-15R. In the present study we examined the effects of targeting the IL-15R on the prevention and treatment of collagen-induced arthritis (CIA) in mice and probed the possible mechanisms of action of this IL-15 mutant/Fcgamma2a protein. Upon immunization with type II collagen, DBA/1 mice develop severe articular inflammation and destruction. Treatment of DBA/1 mice with a brief course of CRB-15 at the time of type II collagen challenge markedly inhibited the incidence and severity of arthritis. Moreover, in animals with ongoing established arthritis, treatment with CR-B-15 effectively blocked disease progression compared with that in control-treated animals. The therapeutic effect of CRB-15 on either disease development or disease progression is remarkably stable, because withdrawal of treatment did not lead to disease relapse. A detailed analysis revealed that treatment with CRB-15 decreased synovitis in the joints; reduced bone erosion and cartilage destruction; reduced in situ production of the proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, and IL-17; and decreased the responder frequency of autoreactive T cells. Our study suggests that the effective targeting of IL-15R-triggered events with CRB-15 can be of therapeutic importance in the treatment of rheumatoid arthritis.