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

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.

CD44 is highly expressed on milk neutrophils in bovine mastitis and plays a role in their adhesion to matrix and mammary epithelium

“…This isoform was previously shown to be expressed on bovine endothelial cells and might play a role in HA-mediated migration of these cells [15]. Furthermore, anti-CD44v10 antibodies specifically affected macrophage recruitment into inflamed skin [22]. In this work we demonstrated adhesion of CD44v10-negative blood PMN to HA.…”

Effects of diphencyprone on expression of Bcl-2 protein in patients with Alopecia areata

“…(14) It has been shown that after treatment with DPCP, anti-panCD44 inhibits the immigration of T cells toward lymph nodes and causes disease improvement. (16) This study showed increased level of Bcl-2 expression in patients with AA who had improvement in hair growth after treatment with DPCP. Whether this increase in Bcl-2 expression is due to DPCP effect, or is it something that occurs with improvement in AA regardless of any particular treatment should be addressed in future studies including AA patients with spontaneous hair regrowth.…”

Alopecia areata update

“…All of these disease models have significantly helped in understanding the pathogenesis of AA, and they should prove invaluable in the development of new treatments 63 and understanding the mechanisms by which current treatments are effective. 64,65 …”