Diminished lymphocyte adhesion and alleviation of allergic responses by small-molecule- or antibody-mediated inhibition of L-selectin functions.
Selectins are attractive targets for specific anti-inflammatory therapies. Using human lymphocytes as well as an L-selectin-transfected pre-B-cell line in dynamic flow chamber experiments, we could demonstrate that the small-molecule compound efomycine M blocks L-selectin-mediated lymphocyte rolling on sialylated Lewis(X), an action that was confirmed by plasmon resonance spectroscopy. Recruitment of naive lymphocytes to peripheral lymph nodes depends on L-selectin-mediated adhesion to high endothelial venules. We performed intravital microscopy studying lymphocyte rolling in peripheral lymph nodes and showed a 53% reduction (P=0.0006) of lymphocyte rolling in mice treated with efomycine M or a function-blocking antibody against L-selectin. In addition, the number of lymph node-homing T cells was reduced by >60% using either efomycine M or L-selectin-blocking antibodies. As recruitment of naive lymphocytes is a prerequisite for sensitization in T-cell-mediated immune reactions and allergic responses, mice were treated with efomycine M or an L-selectin-specific antibody during contact sensitization with DNFB. After adoptive transfer of corresponding T cells into non-sensitized recipient mice, the capacity of these cells to induce contact hypersensitivity was significantly reduced (P=0.0002 and P=0.0001, respectively). Our data demonstrate that it is possible, in principle, to diminish T-cell-mediated allergic reactions through interference with L-selectin functions during the early sensitization phase.
Oostingh
Gertie J
GJ
Rudolf Virchow Center, and Department of Dermatology, Julius Maximilians University, Würzburg, Germany.
Ludwig
Ralf J
RJ
Enders
Sven
S
Grüner
Sabine
S
Harms
Gesche
G
Boehncke
W Henning
WH
Nieswandt
Bernhard
B
Tauber
Rudolf
R
Schön
Michael P
MP
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D002448:Cell Adhesion; D002465:Cell Movement; D003877:Dermatitis, Contact / Q000517:prevention & control; D006801:Humans; D006967:Hypersensitivity / Q000517:prevention & control*; D019041:L-Selectin / Q000276:immunology / Q000502:physiology*; D008214:Lymphocytes / Q000502:physiology*; D018942:Macrolides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D033081:Shear Strength
D000906:Antibodies; D018942:Macrolides; C453219:efomycine M; D019041:L-Selectin