Gonzalez-Rey Elena, Chorny Alejo, Varela Nieves, O'Valle Francisco, Delgado Mario
Instituto de Parasitologia y Biomedicina, CSIC, Granada, Spain.
Arthritis Rheum. 2007 Feb;56(2):531-43. doi: 10.1002/art.22394.
To investigate the potential therapeutic action of the immunomodulatory neuropeptide urocortin (UCN) in an experimental model of rheumatoid arthritis (RA).
After disease onset, DBA/1J mice with collagen-induced arthritis (CIA) were treated with UCN, and the incidence, severity (clinical score), and joint histopathology were evaluated. The inflammatory response was determined by measuring the levels of different mediators of inflammation (cytokines and chemokines) in the joints and sera. The Th1-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with the autoantigen and by assaying the content of serum autoantibodies. The number of regulatory CD4+,CD25+ T cells and their capacity to suppress self-reactive Th1 cells were determined in joints and lymph nodes.
UCN treatment significantly reduced the incidence and severity of CIA, completely abrogating joint swelling and cartilage and bone destruction. The therapeutic effect of UCN was associated with a striking reduction of the 2 deleterious components of the disease: the Th1-driven autoimmune response and the inflammatory response. UCN also induced the generation and/or activation of efficient interleukin-10/transforming growth factor beta1-producing Treg cells in arthritis with the capacity to suppress the autoreactive response and to restore immune tolerance, thus playing a pivotal role in the therapeutic effect of UCN.
Our findings provide a powerful rationale for assessing the efficacy of UCN as a novel multistep therapeutic approach to the treatment of RA in humans.
在类风湿性关节炎（RA）实验模型中研究免疫调节神经肽尿皮质素（UCN）的潜在治疗作用。
胶原诱导性关节炎（CIA）发病后，对DBA/1J小鼠用UCN进行治疗，并评估发病率、严重程度（临床评分）及关节组织病理学。通过测量关节和血清中不同炎症介质（细胞因子和趋化因子）的水平来确定炎症反应。通过测定经自身抗原刺激的引流淋巴结细胞的增殖反应和细胞因子谱以及检测血清自身抗体含量来评估Th1介导的自身反应性应答。测定关节和淋巴结中调节性CD4⁺、CD25⁺ T细胞的数量及其抑制自身反应性Th1细胞的能力。
UCN治疗显著降低了CIA的发病率和严重程度，完全消除了关节肿胀以及软骨和骨破坏。UCN的治疗效果与该疾病的2种有害成分显著减少有关：Th1驱动的自身免疫反应和炎症反应。UCN还在关节炎中诱导产生和/或激活了高效产生白细胞介素-10/转化生长因子β1的调节性T细胞，其具有抑制自身反应性应答和恢复免疫耐受的能力，因此在UCN的治疗效果中起关键作用。
我们的研究结果为评估UCN作为治疗人类RA的新型多步骤治疗方法的疗效提供了有力依据。
