Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom.
Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):2289-94. doi: 10.1073/pnas.1321071111. Epub 2014 Jan 27.
An immune response is essential for protection against infection, but, in many individuals, aberrant responses against self tissues cause autoimmune diseases such as rheumatoid arthritis (RA). How to diminish the autoimmune response while not augmenting infectious risk is a challenge. Modern targeted therapies such as anti-TNF or anti-CD20 antibodies ameliorate disease, but at the cost of some increase in infectious risk. Approaches that might specifically reduce autoimmunity and tissue damage without infectious risk would be important. Here we describe that TNF superfamily member OX40 ligand (OX40L; CD252), which is expressed predominantly on antigen-presenting cells, and its receptor OX40 (on activated T cells), are restricted to the inflamed joint in arthritis in mice with collagen-induced arthritis and humans with RA. Blockade of this pathway in arthritic mice reduced inflammation and restored tissue integrity predominantly by inhibiting inflammatory cytokine production by OX40L-expressing macrophages. Furthermore, we identify a previously unknown role for OX40L in steady-state bone homeostasis. This work shows that more targeted approaches may augment the "therapeutic window" and increase the benefit/risk in RA, and possibly other autoimmune diseases, and are thus worth testing in humans.
免疫反应对于预防感染至关重要，但在许多个体中，针对自身组织的异常反应会导致自身免疫性疾病，如类风湿关节炎（RA）。如何在不增加感染风险的情况下减轻自身免疫反应是一个挑战。现代靶向治疗方法，如抗 TNF 或抗 CD20 抗体，可以改善疾病，但会增加一定的感染风险。因此，如果有一种方法可以特异性地减少自身免疫和组织损伤而不增加感染风险，那将是非常重要的。在这里，我们描述了 TNF 超家族成员 OX40 配体（OX40L；CD252），它主要表达在抗原呈递细胞上，其受体 OX40（在激活的 T 细胞上），在胶原诱导性关节炎小鼠和 RA 患者的关节炎中仅限于炎症关节。在关节炎小鼠中阻断该途径可减少炎症并恢复组织完整性，主要是通过抑制 OX40L 表达的巨噬细胞产生炎症细胞因子。此外，我们还发现了 OX40L 在稳态骨稳态中的一个先前未知的作用。这项工作表明，更有针对性的方法可能会增加 RA 及其他自身免疫性疾病的“治疗窗口”并增加获益/风险，因此值得在人类中进行测试。
