Targeting CLA/E-selectin interactions prevents CCR4-mediated recruitment of human Th2 memory cells to human skin in vivo.
Naive Th cells, bearing receptors for cutaneous antigens, become activated in skin-draining lymph nodes and express cutaneous lymphocyte antigen (CLA), which confers to these cells the capacity to migrate into the skin to exert their normal effector functions. In the case of atopic dermatitis (AD), allergen-specific Th2 cells generate exacerbated responses and induce skin inflammation. In such a situation, interfering with the specific mechanism of skin homing would provide a therapeutic benefit. Here we report that CLA+ Th2 memory cells, derived from skin lesions of AD patients, selectively migrate to human skin grafts transplanted onto SCID mice in response to CCR4 but not CCR3, CCR8 or CXCR3 ligands. Skin homing of human CCR4+ Th2 memory cells was Pertussis toxin sensitive and restricted to the CLA+ subset. Furthermore, treatment of these mice with anti-E-selectin monoclonal antibody was sufficient to prevent CCL22-mediated Th2 cell migration to human skin, which both, validates the model and highlights the importance of CLA/E-selectin interactions in the homing process of Th2 cells to the skin. Using this mechanistic model we demonstrate that skin homing of human Th2 memory cells can be efficiently suppressed using a low molecular weight E-selectin antagonist, which is of clinical relevance for the treatment of inflammatory skin diseases, including AD.
Biedermann
Tilo
T
Novartis Research Institute, Vienna, Austria.
Schwärzler
Christoph
C
Lametschwandtner
Günther
G
Thoma
Gebhard
G
Carballido-Perrig
Nicole
N
Kund
Julia
J
de Vries
Jan E
JE
Rot
Antal
A
Carballido
José M
JM
D000328:Adult; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; D002465:Cell Movement; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000502:physiology; D003876:Dermatitis, Atopic / Q000276:immunology; D019040:E-Selectin / Q000502:physiology*; D006801:Humans; D007156:Immunologic Memory; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D054398:Receptors, CCR4; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000502:physiology*; D012867:Skin / Q000276:immunology*; D016038:Skin Transplantation; D018418:Th2 Cells / Q000276:immunology*
D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; C106230:CCL17 protein, human; C515482:CCL22 protein, human; C515354:CCR4 protein, human; C063419:CTAGE1 protein, human; C515187:CXCR3 protein, human; C499538:Ccl17 protein, mouse; C515483:Ccl22 protein, mouse; C515355:Ccr4 protein, mouse; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D019742:Chemokines, CC; C515188:Cxcr3 protein, mouse; D019040:E-Selectin; D008562:Membrane Glycoproteins; D054398:Receptors, CCR4; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine