VCAM-1 and VLA-4 modulate dendritic cell IL-12p40 production in experimental visceral leishmaniasis.
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.
Stanley
Amanda C
AC
Queensland Institute of Medical Research, Herston, Queensland, Australia.
Dalton
Jane E
JE
Rossotti
Susanna H
SH
MacDonald
Kelli P
KP
Zhou
Yonghong
Y
Rivera
Fabian
F
Schroder
Wayne A
WA
Maroof
Asher
A
Hill
Geoff R
GR
Kaye
Paul M
PM
Engwerda
Christian R
CR
D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000378:metabolism*; D039041:Integrin alpha4beta1 / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis*; D007893:Leishmania donovani; D007898:Leishmaniasis, Visceral / Q000276:immunology*; D008099:Liver / Q000469:parasitology; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D013154:Spleen / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology*
D000913:Antibodies, Protozoan; D039041:Integrin alpha4beta1; D053762:Interleukin-12 Subunit p40; D019010:Vascular Cell Adhesion Molecule-1