Efomycine: Anti-entzündliche Therapie durch Hemmung der Leukozyten-Endothelzell-Interaktion

Zusammenfassung

Da Selektin-vermittelte Adhäsion an Endothelzellen (sog. Rollen) ein Schlüsselschritt bei der Rekrutierung von Leukozyten in entzündeten Geweben ist, ist die gezielte Hemmung dieser Interaktionen ein vielversprechender Ansatz zur gezielten Therapie entzündlicher Erkrankungen. E- und P-Selektin werden von Endothelzellen und L-Selektin wird von Leukozyten exprimiert. Auf der Suche nach kleinmolekularen Substanzen, die Selektin-vermittelte Leukozyten-Adhäsion an Endothelzellen gezielt beeinflussen, zeigte Efomycin M, ein halbsynthetisches Makrolid, eine sehr gute Hemmung der E- und P-Selektin-vermittelten Adhäsion. Dies resultierte in signifikant vermindertem Rollen von Lymphozyten in vivo sowie in einer sehr guten therapeutischen Wirksamkeit in zwei komplementären Mausmodellen der Psoriasis, einer häufigen chronisch entzündlichen Hauterkrankung. Auf molekularer Ebene konnte gezeigt werden, dass Efomycine, obwohl chemisch nicht verwandt, Strukturanaloga des natürlichen Selektin-Liganden Sialyl-LewisX sind und wahrscheinlich dadurch ihre anti-entzündliche und anti-adhäsive Wirkung entfalten. Insgesamt sind Efomycine eine interessante neue Substanzfamilie, deren Wirkprinzip eine selektive Beeinflussung verschiedener Entzündungsprozesse - nicht nur in der Haut - erwarten lässt.

Abstract

Given that selectin-mediated adhesive interactions between leukocytes and endothelial cells (i. e., rolling) are the crucial initial step in the cascade of events leading to leukocyte recruitment to inflammatory sites, selective inhibition of these interactions may be a promising target for selective anti-inflammatory therapies. E- and P-selectin are expressed by endothelial cells, while L-selectin is expressed by various leukocytes. When small-molecule compounds were screened for their capacity to inhibit selectin-mediated leukocyte-endothelial cell interactions, the macrolide, efomycine M, was found to exert profound inhibitory effects on both E- and P-selectin-mediated adhesion. This resulted in significantly diminished leukocyte rolling in vivo as well as in marked therapeutic efficacy in two complimentary mouse models of psoriasis, a common chronic inflammatory skin disorder. On the molecular level, efomycines are structural analogues of sialylated LewisX, a natural selectin ligand, although both compounds are chemically unrelated. Overall, efomycines are an interesting new family of compounds whose mode of action may prove relevant for selective therapies of various inflammatory disorders.

Literatur

• 1 Todderud G. et al . BMS-190 394, a selectin inhibitor, prevents rat cutaneous inflammatory reactions.  J Pharmacol Exp Ther. 1997;  282 1298-1304
• 2 Shimizu Y. et al . Four molecular pathways of T cell adhesion to endothelial cells: roles of LFA-1, VCAM-1, and ELAM-1 and changes in pathway hierarchy under different activation conditions.  J Cell Biol. 1991;  113 1203-1212
• 3 von Andrian U H. et al . Two-step model of leukocyte-endothelial cell interaction in inflammation: distinct roles for LECAM-1 and the leukocyte beta-2 integrins in vivo.  Proc Natl Acad Sci USA. 1991;  88 7538-7542
• 4 Springer T A. Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm.  Cell. 1994;  76 301-314
• 5 Smith C H. et al . Neuropeptides induce rapid expression of endothelial cell adhesion molecules and elicit granulocytic infiltration in human skin.  J Immunol. 1993;  151 3274-3282
• 6 Groves R W. et al . Endothelial leukocyte adhesion molecule-1 (ELAM-1) expression in cutaneous inflammation.  Br J Dermatol. 1991;  124 117-123
• 7 Butcher E, Picker L J. Lymphocyte homing and homeostasis.  Science. 1996;  272 60-66
• 8 Ley K. Functions of selectins.  Results Probl Cell Differ. 2001;  33 177-200
• 9 Feizi T. Carbohydrate ligands for the leukocyte-endothelium adhesion molecules, selectins.  Results Probl Cell Differ. 2001;  33 201-223
• 10 Varki A. Selectin ligands.  Proc Natl Acad Sci USA. 1994;  91 7390-7397
• 11 McEver R P, Beckstead J H. GMP-140, a platelet alpha granule membrane protein, is also synthesized by vascular endothelial cells and is localized in Waibel-Palade bodies.  J Clin Invest. 1989;  84 92-99
• 12 Bonfanti R, Furie B C. PADGEM (GMP140) is a component of Waibel-Palade bodies of human endothelial cells.  Blood. 1989;  73 1109-1112
• 13 Bevilacqua M P, Stengelin S. Endothelial leukocyte adhesion molecule-1: An inducible receptor for neutrophils related to complement regulatory proteins and lectins.  Science. 1989;  243 1160-1163
• 14 Cotran R S, Gimbrone M AJ. Induction and detection of a human endothelial activation antigen in vivo.  J Exp Med. 1986;  164 661-666
• 15 Grabovsky V, Dwir O, Alon R. Endothelial chemokines destabilize L-selectin-mediated lymphocyte rolling without inducing selectin shedding.  J Biol Chem. 2002;  277 20 640-20 650
• 16 Carlos T M, Harlan J M. Leukocyte-endothelial adhesion molecules.  Blood. 1994;  84 2068-2101
• 17 Bhushan M. et al . Anti-E-selectin is ineffective in the treatment of psoriasis: a randomized trial.  B J Dermatol. 2002;  146 824-831
• 18 Collins R G. et al . Dermal and pulmonary inflammatory disease in E-selectin and P-selectin double-null mice is reduced in triple-selectin-null mice.  Blood. 2001;  98 727-735
• 19 Jung U, Ley K. Mice lacking two or all three selectins demonstrate overlapping and distinct functions for each selectin.  J Immunol. 1999;  162 6755-6762
• 20 Labow M A. et al . Characterization of E-selectin-deficient mice: demonstration of overlapping function of the endothelial selectins.  Immunity. 1994;  1 709-720
• 21 Hwang S T. Mechanisms of T cell homing to skin.  Adv Dermatol. 2001;  17 211-241
• 22 Fors B P, Goodarzi K, von Andrian U H. L-selectin shedding is independent of its subsurface structures and topographic distribution.  J Immunol. 2001;  167 (7) 3642-3651
• 23 Zhao L C, Edgar J B, Dailey M O. Characterization of the rapid proteolytic shedding of murine L-selectin.  Dev Immunol. 2001;  8 (3 - 4) 267-277
• 24 Condon T P. et al . ADAM17 but not ADAM10 mediates tumor necrosis factor-alpha and L-selectin shedding from leukocyte membranes.  Antisense Nucleic Acid Drug Dev. 2001;  11 (2) 107-116
• 25 Hafezi-Moghadam A, Ley K. Relevance of L-selectin shedding for leukocyte rolling in vivo.  J Exp Med. 1999;  189 (6) 939-948
• 26 Hafezi-Moghadam A. et al . L-selectin shedding regulates leukocyte recruitment.  J Exp Med. 2001;  193 (7) 863-872
• 27 Fuhlbrigge R C. et al . Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells.  Nature. 1997;  389 978-981
• 28 Picker L J. et al . A unique phenotype of skin-associated lymphocytes in humans. Preferential expression of the HECA-425 epitope by benign and malignant T cells at cutaneous sites.  Am J Pathol. 1990;  136 1053-1068
• 29 Picker L J. et al . ELAM-1 is an adhesion molecule for skin-homing T-cells.  Nature. 1991;  349 796-799
• 30 Kunstfeld R. et al . HECA-452+ T cells migrate through superficial vascular plexus but not through deep vascular plexus endothelium.  J Invest Dermatol. 1997;  108 343-348
• 31 Reinhardt P H, Elliott J F, Kubes P. Neutrophils can adhere via alpha4beta1-integrin under flow conditions.  Blood. 1997;  89 (10) 3837-3846
• 32 Singbartl K. et al . A CD2-green fluorescence protein-transgenic mouse reveals very late antigen-4-dependent CD8+ lymphocyte rolling in inflamed venules.  J Immunol. 2001;  166 (12) 7520-7526
• 33 Berlin C. et al . alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow.  Cell. 1995;  80 (3) 413-422
• 34 Issekutz A C, Issekutz T B. The role of E-selectin, P-selectin, and very late activation antigen-4 in T lymphocyte migration to dermal inflammation.  J Immunol. 2002;  168 (4) 1934-1939
• 35 Schön M P. et al . Efomycine M, a new specific inhibitor of selectin, impairs leukocyte adhesion and alleviates cutaneous inflammation.  Nat Med. 2002;  8 366-372
• 36 Christophers E. The immunopathology of psoriasis.  Int Arch Allergy Immunol. 1996;  110 199-206
• 37 Powrie F. et al . Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity.  J Exp Med. 1994;  179 589-600
• 38 Schön M P, Detmar M, Parker C M. Murine psoriasis-like disorder induced by naive CD4+ T-cells.  Nature Med. 1997;  3 183-188
• 39 Boehncke W-H. et al . Pulling the trigger on psoriasis.  Nature. 1996;  379 777
• 40 Boehncke W-H. et al . The SCID-hu xenogeneic transplantation model allows screening of anti-psoriatic drugs.  Arch Dermatol Res. 1999;  291 104-106
• 41 Nickoloff B J. et al . Severe combined immunodeficiency mouse and human psoriatic skin chimeras. Validation of a new animal model.  Am J Pathol. 1995;  146 580-588