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Blood, 1 October 2005, Vol. 106, No. 7, pp. 2424-2432.
Prepublished online as a Blood First Edition Paper on June 23, 2005; DOI 10.1182/blood-2005-01-0342.
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IMMUNOBIOLOGY
Systemic administration of a TLR7 ligand leads to transient immune incompetence due to peripheral-blood leukocyte depletion
Matthias Gunzer,
Helge Riemann,
Yasmin Basoglu,
Anja Hillmer,
Carsten Weishaupt,
Sandra Balkow,
Bernd Benninghoff,
Beat Ernst,
Meike Steinert,
Thomas Scholzen,
Cord Sunderkötter, and
Stephan Grabbe
From the German Research Centre for Biotechnology, Braunschweig, Germany; Department of Dermatology, University of Münster, Germany; 3M Medica, Neuss, Germany; University of Basel Institute of Molecular Pharmacy, Switzerland; and Department of Dermatology, University of Essen, Germany.
Toll-like receptor (TLR) ligands lead to the induction of proinflammatory cytokines and are potent enhancers of specific immune responses. We show here that a single systemic dose of R-848, a ligand for TLR7, potently enhanced hapten sensitization during the induction of contact hypersensitivity (CHS). However, R-848 administration also resulted in a rapid and almost complete depletion of leukocytes from the blood. This effect was transient and was associated with general induction of endothelial adhesiveness. In response to R-848, endothelial cells up-regulated adhesion molecules in vitro and in vivo and leukocytes exhibited increased rolling on endothelia in R-848-treated animals. Adhesion molecule induction appeared to be a direct effect, because endothelial cells expressed TLR7 in vitro and in vivo. After R-848 treatment, the tissue residence time of leukocytes was markedly prolonged in all major peripheral organs. The resulting transiently reduced availability of peripheral-blood leukocytes (PBLs) (TRAP) significantly inhibited otherwise potent CHS responses until the effector cells returned. Thus, although TLR7 ligands are effective adjuvants for the induction of cell-mediated immunity, they can transiently inhibit the elicitation of localized immune responses, possibly due to a systemic endothelial activation throughout the vasculature. (Blood. 2005;106:2424-2432)
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