Anti-CD44-mediated blockade of leukocyte migration in skin-associated immune diseases.
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.
Zöller
Margot
M
Department of Tumor Progression and Tumor Defense, German Cancer Research Center, Heidelberg, Germany. m.zoeller@dkfz.de
Gupta
Pooja
P
Marhaba
Rachid
R
Vitacolonna
Mario
M
Freyschmidt-Paul
Pia
P
D000485:Allergens / Q000494:pharmacology / Q000627:therapeutic use; D000506:Alopecia Areata / Q000188:drug therapy* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D015815:Cell Adhesion Molecules; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004485:Eczema / Q000188:drug therapy; D018960:Hyaluronan Receptors / Q000187:drug effects* / Q000276:immunology; D007154:Immune System Diseases / Q000188:drug therapy; D051379:Mice; D020033:Protein Isoforms / Q000276:immunology; D012871:Skin Diseases / Q000188:drug therapy
D000485:Allergens; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D018960:Hyaluronan Receptors; D020033:Protein Isoforms