Journal of Leukocyte Biology
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Originally published online as doi:10.1189/jlb.0107063 on April 18, 2007

Published online before print April 18, 2007
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(Journal of Leukocyte Biology. 2007;82:57-71.)
© 2007 by Society for Leukocyte Biology

Anti-CD44-mediated blockade of leukocyte migration in skin-associated immune diseases

Margot Zöller*,{dagger},1, Pooja Gupta*, Rachid Marhaba*, Mario Vitacolonna* and Pia Freyschmidt-Paul{ddagger}

* Department of Tumor Progression and Tumor Defense, German Cancer Research Center, Heidelberg, Germany;
{dagger} Department of Applied Genetics, University of Karlsruhe, Germany; and
{ddagger} Department of Dermatology, University Hospital Marburg, Germany

1 Correspondence: Department of Tumor Progression and Immune Defense, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. E-mail: m.zoeller{at}dkfz.de

ABSTRACT

CD44 plays an important role in leukocyte extravasation, which is fortified in autoimmune diseases and delayed-type hypersensitivity (DTH) reactions. There is additional evidence that distinct CD44 isoforms interfere with the extravasation of selective leukocyte subsets. We wanted to explore this question in alopecia areata (AA), a hair-follicle centric autoimmune disease, and in a chronic eczema. The question became of interest because AA is treated efficiently by topical application of a contact sensitizer, such that a mild DTH reaction is maintained persistently. Aiming to support the therapeutic efficacy of a chronic eczema in AA by anti-CD44 treatment, it became essential to control whether a blockade of migration, preferentially of AA effector cells, could be achieved by CD44 isoform-specific antibodies. Anti-panCD44 and anti-CD44 variant 10 isoform (CD44v10) inhibited in vitro migration of leukocytes from untreated and allergen-treated, control and AA mice. In vivo, both antibodies interfered with T cell and monocyte extravasation into the skin; only anti-panCD44 prevented T cell homing into lymph nodes. Contributing factors are disease-dependent alterations in chemokine/chemokine receptor expression and a blockade of CD44 on endothelial cells and leukocytes. It is important that CD44 can associate with several integrins and ICAM-1. Associations depend on CD44 activation and vary with CD44 isoforms and leukocyte subpopulations. CD44 standard isoform preferentially associates with CD49d in T cells and CD44v10 with CD11b in monocytes. Accordingly, anti-panCD44 and anti-CD49d inhibit T cell, anti-CD11b, and anti-CD44v10 macrophage migration most efficiently. Thus, allergen treatment of AA likely can be supported by targeting AA T cells selectively via a panCD44-CD49d-bispecific antibody.

Key Words: rodent • autoimmunity • adhesion molecules • cell trafficking






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