Mackay F, Browning J L, Lawton P, Shah S A, Comiskey M, Bhan A K, Mizoguchi E, Terhorst C, Simpson S J
Department of Immunology, Inflammation and Cell Biology, Biogen, Cambridge, MA 02142, USA.
Gastroenterology. 1998 Dec;115(6):1464-75. doi: 10.1016/s0016-5085(98)70025-3.
BACKGROUND & AIMS: Membrane lymphotoxin (LT) alpha/beta, a member of the tumor necrosis factor (TNF) family of immune regulatory molecules, is involved both in the development of secondary lymphoid tissues and the maintenance of organized lymphoid tissues in the adult. Defects observed in the mucosal immune system in animals with a genetically disrupted LTalpha/beta pathway coupled with the expression of LTalpha/beta in activated T cells motivated an examination of the importance of this pathway in experimental colitis.
Soluble LTbeta receptor (LTbetaR) immunoglobulin fusion protein was used to inhibit the LTalpha/beta/light axis in two independent rodent models of colitis: CD45RBhi CD4(+)-reconstituted SCID mice and bone marrow-transplanted tg26 mice (BM --> tg26).
Treatment with LTbetaR immunoglobulin attenuated the development of both the clinical and histological manifestations of the disease in these two murine models of colitis. Given the success of TNF inhibitors in the treatment of human Crohn's disease, the effects of LTbetaR immunoglobulin have been compared with antibody to TNF in the BM --> tg26 model, and both treatments were equally efficacious.
The LT pathway plays a role in the development of colitis as important as that of the TNF system and, therefore, represents a potential novel intervention point for the treatment of inflammatory bowel disease.
膜淋巴毒素（LT）α/β是免疫调节分子肿瘤坏死因子（TNF）家族的成员，参与次级淋巴组织的发育以及成体中有序淋巴组织的维持。在LTα/β途径发生基因破坏的动物的黏膜免疫系统中观察到的缺陷，以及活化T细胞中LTα/β的表达，促使人们研究该途径在实验性结肠炎中的重要性。
在两种独立的啮齿动物结肠炎模型中，使用可溶性LTβ受体（LTβR）免疫球蛋白融合蛋白来抑制LTα/β/轻链轴：CD45RBhi CD4(+)重建的SCID小鼠和骨髓移植的tg26小鼠（BM→tg26）。
在这两种小鼠结肠炎模型中，用LTβR免疫球蛋白治疗可减轻疾病的临床和组织学表现的发展。鉴于TNF抑制剂在治疗人类克罗恩病方面的成功，在BM→tg26模型中比较了LTβR免疫球蛋白与抗TNF抗体的效果，两种治疗同样有效。
LT途径在结肠炎的发展中所起的作用与TNF系统一样重要，因此代表了治疗炎症性肠病的一个潜在的新干预点。
