Mitigation of Delayed-Type Hypersensitivity Reactions by a CD44 Variant Isoform v3-Specific Antibody: Blockade of Leukocyte Egress

In allergic alterations of human skin the majority of infiltrated leukocytes express CD44v3, but no other CD44 variant isoform. Vessel endothelium, too, is brightly stained with a CD44v3-specific antibody. Being concerned about therapeutic intervention, it became of importance to define whether expression of CD44v3 on the endothelial cells or on the leukocytes or on both is of functional importance. As expression of CD44v3 in the mouse on activated endothelium and on subpopulations of activated CD4+ cells, B cells and monocytes was similar to the expression in the human, we answered the question in a mouse delayed-type hypersensitivity model. The effect of anti-CD44v3 was compared with the effect of anti-CD44s and anti-CD44v10, both known to suppress delayed-type hypersensitivity reactions. Anti-CD44v3 mitigated the delayed-type hypersensitivity reaction in dinitrofluorobenzene sensitized and challenged mice comparable with anti-CD44s and anti-CD44v10. The seemingly similar effects of CD44 isoform-specific antibodies, however, resulted from a distinct modulation of response. Anti-CD44s mainly suppressed T cell activation and interleukin-2 as well as interferon-γ expression. Anti-CD44v10 inhibited the activation of monocytes in the draining lymph nodes and in the infiltrate, which led to a strong reduction in the proinflammatory cytokines tumor necrosis factor-α and interleukin-12 and in edema formation. Anti-CD44v3 had only a weak effect on cytokine expression by isolated subpopulations of leukocytes, but suppressed cytokine production by helper T cells when cocultured with antigen-presenting cells, i.e., blocked an interaction between antigen-presenting cells and helper T cells. The dominating effect of anti-CD44v3, however, relied on a blockade of leukocyte extravasation. As leukocytes transferred into dinitrofluorobenzene sensitized, anti-CD44v3-treated and lethally irradiated mice did not infiltrate the sensitized skin, anti-CD44v3 most likely prevented leukocyte extravasation by blocking CD44v3 on endothelial cells