Stanley Amanda C, Dalton Jane E, Rossotti Susanna H, MacDonald Kelli P, Zhou Yonghong, Rivera Fabian, Schroder Wayne A, Maroof Asher, Hill Geoff R, Kaye Paul M, Engwerda Christian R
Queensland Institute of Medical Research, Herston, Queensland, Australia.
PLoS Pathog. 2008 Sep 19;4(9):e1000158. doi: 10.1371/journal.ppat.1000158.
Vascular cell adhesion molecule-1 (VCAM-1) interacts with its major ligand very late antigen-4 (VLA-4) to mediate cell adhesion and transendothelial migration of leukocytes. We report an important role for VCAM-1/VLA-4 interactions in the generation of immune responses during experimental visceral leishmaniasis caused by Leishmania donovani. Our studies demonstrate that these molecules play no direct role in the recruitment of leukocytes to the infected liver, but instead contribute to IL-12p40-production by splenic CD8(+) dendritic cells (DC). Blockade of VCAM-1/VLA-4 interactions using whole antibody or anti-VCAM-1 Fab' fragments reduced IL-12p40 mRNA accumulation by splenic DC 5 hours after L. donovani infection. This was associated with reduced anti-parasitic CD4(+) T cell activation in the spleen and lowered hepatic IFNgamma, TNF and nitric oxide production by 14 days post infection. Importantly, these effects were associated with enhanced parasite growth in the liver in studies with either anti-VCAM-1 or anti-VLA-4 antibodies. These data indicate a role for VCAM-1 and VLA-4 in DC activation during infectious disease.
血管细胞黏附分子-1（VCAM-1）与其主要配体极迟抗原-4（VLA-4）相互作用，介导白细胞的细胞黏附和跨内皮迁移。我们报告了VCAM-1/VLA-4相互作用在杜氏利什曼原虫引起的实验性内脏利什曼病免疫反应产生中的重要作用。我们的研究表明，这些分子在白细胞募集到受感染肝脏的过程中不发挥直接作用，而是有助于脾脏CD8(+)树突状细胞（DC）产生IL-12p40。在杜氏利什曼原虫感染5小时后，使用全抗体或抗VCAM-1 Fab'片段阻断VCAM-1/VLA-4相互作用，可减少脾脏DC的IL-12p40 mRNA积累。这与感染后14天时脾脏中抗寄生虫CD4(+) T细胞活化减少以及肝脏中IFNγ、TNF和一氧化氮产生降低有关。重要的是，在使用抗VCAM-1或抗VLA-4抗体的研究中，这些效应与肝脏中寄生虫生长增强有关。这些数据表明VCAM-1和VLA-4在传染病期间DC活化中发挥作用。
