University of Rochester School of Medicine and Dentistry, Rochester, New York.
Cooper Medical School of Rowan University, Camden, New Jersey.
Arthritis Rheumatol. 2017 Jun;69(6):1187-1193. doi: 10.1002/art.40047. Epub 2017 Apr 4.
Recent studies have demonstrated that there is an inverse relationship between lymphatic egress and inflammatory arthritis in affected joints. As a model, tumor necrosis factor (TNF)-transgenic mice develop advanced arthritis following draining lymph node (LN) collapse, and loss of lymphatic contractions downstream of inflamed joints. It is unknown if these lymphatic deficits are reversible. This study was undertaken to test the hypothesis that anti-TNF therapy reduces advanced erosive inflammatory arthritis, associated with restoration of lymphatic contractions, repair of damaged lymphatic vessels, and evidence of increased monocyte egress.
TNF-transgenic mice with advanced arthritis and collapsed popliteal LNs were treated with anti-TNF monoclonal antibody (10 mg/kg weekly) or placebo for 6 weeks, and effects on knee synovitis, lymphatic vessel ultrastructure and function, and popliteal LN cellularity were assessed by ultrasound, histology, transmission electron microscopy (TEM), near-infrared indocyanine green imaging, and flow cytometry.
Anti-TNF therapy significantly decreased synovitis (∼5-fold; P < 0.05 versus placebo), restored lymphatic contractions, and significantly increased the number of popliteal LN monocyte/macrophages (∼2-fold; P < 0.05 versus placebo). TEM demonstrated large activated macrophages attached to damaged lymphatic endothelium in mice with early arthritis, extensively damaged lymphatic vessels in placebo-treated mice with advanced arthritis, and rolling leukocytes in repaired lymphatic vessels in mice responsive to anti-TNF therapy.
These findings support the concept that anti-TNF therapy ameliorates erosive inflammatory arthritis, in part via restoration of lymphatic vessel contractions and potential enhancement of inflammatory cell egress.
最近的研究表明，在受影响的关节中，淋巴流出与炎症性关节炎呈负相关。作为一个模型，肿瘤坏死因子（TNF）转基因小鼠在引流淋巴结（LN）塌陷后发展为晚期关节炎，并在发炎关节下游失去淋巴收缩。尚不清楚这些淋巴缺陷是否可逆。本研究旨在检验以下假设：抗 TNF 治疗可减少晚期侵蚀性炎症性关节炎，同时伴有淋巴收缩恢复、受损淋巴管修复以及单核细胞流出增加的证据。
接受过抗 TNF 单克隆抗体（10 mg/kg 每周）或安慰剂治疗 6 周的晚期关节炎和腘窝 LN 塌陷的 TNF 转基因小鼠，通过超声、组织学、透射电子显微镜（TEM）、近红外吲哚菁绿成像和流式细胞术评估膝关节滑膜炎、淋巴管超微结构和功能以及腘窝 LN 细胞数。
抗 TNF 治疗显著降低滑膜炎（约 5 倍；P<0.05 与安慰剂相比），恢复淋巴收缩，并显著增加腘窝 LN 单核细胞/巨噬细胞数量（约 2 倍；P<0.05 与安慰剂相比）。TEM 显示，在早期关节炎的小鼠中，大量活化的巨噬细胞附着在受损的淋巴管内皮上，在接受安慰剂治疗的晚期关节炎小鼠中，广泛受损的淋巴管，以及在对抗 TNF 治疗有反应的小鼠中修复的淋巴管中滚动的白细胞。
这些发现支持这样一种观点，即抗 TNF 治疗通过恢复淋巴管收缩和潜在增强炎症细胞流出，改善侵蚀性炎症性关节炎。
