vcam-1 and vla-4 modulate dendritic cell il-12p40 production in experimental visceral leishmaniasisvcam-1和vla-4调节树突细胞il-12p40生产实验内脏利什曼病.pdfVIP

VCAM-1 and VLA-4 Modulate Dendritic Cell IL-12p40 Production in Experimental Visceral Leishmaniasis 1 2 1 1 1 Amanda C. Stanley , Jane E. Dalton , Susanna H. Rossotti , Kelli P. MacDonald , Yonghong Zhou , 1 1 2 1 2 Fabian Rivera , Wayne A. Schroder , Asher Maroof , Geoff R. Hill , Paul M. Kaye , Christian R. Engwerda1* 1 Queensland Institute of Medical Research, Herston, Queensland, Australia, 2 Immunology and Infection Unit, Department of Biology, University of York, and The Hull York Medical School, York, United Kingdom Abstract 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 Fab9 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 IFNc, TNF and nitric oxide production by 14 days post infection. Importantly, these effects were associated with enhanced parasite growth in