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 leukocyte s express CD44v3, but no other CD44 variant isoform, Vessel endothelium, to o, is brightly stained with a CD44v3-specific antibody. Being concerned abo ut therapeutic intervention, it became of importance to define whether expr ession of CD44v3 on the endothelial cells or on the leukocytes or on both i s of functional importance. As expression of CD44v3 in the mouse on activat ed endothelium and on subpopulations of activated CD4(+) cells, B cells and monocytes was similar to the expression in the human, we answered the ques tion in a mouse delayed-type hypersensitivity model. The effect of anti-CD4 4v3 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 sensiti zed and challenged mice comparable with anti-CD44s and anti-CD44v10. The se emingly similar effects of CD44 isoform-specific antibodies, however, resul ted from a distinct modulation of response. Anti-CD44s mainly suppressed T cell activation and interleukin-2 as well as interferon-gamma expression. A nti-CD44v10 inhibited the activation of monocytes in the draining lymph nod es and in the infiltrate, which led to a strong reduction in the proinflamm atory cytokines tumor necrosis factor-a and interleukin-12 and in edema for mation. AntiCD44v3 had only a weak effect on cytokine expression by isolate d subpopulations of leukocytes, but suppressed cytokine production by helpe r T cells when cocultured with antigen-presenting cells, i.e., blocked an i nteraction between antigen-presenting cells and helper T cells. The dominat ing effect of anti-CD44v3, however, relied on a blockade of leukocyte extra vasation, As leukocytes transferred into dinitrofluorobenzene sensitized, a nti-CD44v3-treated and lethally irradiated mice did not infiltrate the sens itized skin, anti-CD44v3 most likely prevented leukocyte extravasation by b locking CD44v3 on endothelial cells.