Pan-selectin antagonism improves psoriasis manifestation in mice and man.
The selectin family of vascular cell adhesion molecules is comprised of structurally related carbohydrate binding proteins, which mediate the initial rolling of leukocytes on the activated vascular endothelium. Because this process is one of the crucial events in initiating and maintaining inflammation, selectins are proposed to be an attractive target for the development of new antiinflammatory therapeutics. Here, we demonstrate that the synthetic pan-selectin antagonist bimosiamose is effective in pre-clinical models of psoriasis as well as in psoriatic patients. In vitro bimosiamose proved to be inhibitory to E- or P-selectin dependent lymphocyte adhesion under flow conditions. Using xenogeneic transplantation models, bimosiamose reduced disease severity as well as development of psoriatic plaques in symptomless psoriatic skin. The administration of bimosiamose in patients suffering from psoriasis resulted in a reduction of epidermal thickness and lymphocyte infiltration. The clinical improvement was statistically significant (P=0.02) as analyzed by comparison of psoriasis area and severity index before and after treatment. Assessment of safety parameters showed no abnormal findings. These data suggest that pan-selectin antagonism may be a promising strategy for the treatment of psoriasis and other inflammatory diseases.
Friedrich
Markus
M
Department of Dermatology and Allergy, University Hospital Charité, Schumannstr. 20/21, 10117 Berlin, Germany.
Bock
Daniel
D
Philipp
Sandra
S
Ludwig
Nina
N
Sabat
Robert
R
Wolk
Kerstin
K
Schroeter-Maas
Sabine
S
Aydt
Ewald
E
Kang
Sewon
S
Dam
Tomas Norman
TN
Zahlten
Rainer
R
Sterry
Wolfram
W
Wolff
Gerhard
G
D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D004817:Epidermis / Q000737:chemistry / Q000473:pathology; D005260:Female; D018922:HL-60 Cells; D006586:Hexanes / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D019169:Jurkat Cells; D007962:Leukocytes / Q000473:pathology / Q000502:physiology; D008297:Male; D008358:Mannose / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D019007:P-Selectin / Q000032:analysis / Q000502:physiology*; D010865:Pilot Projects; D011565:Psoriasis / Q000097:blood / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D013601:T-Lymphocytes / Q000473:pathology
D000893:Anti-Inflammatory Agents; D006586:Hexanes; D019007:P-Selectin; C496819:bimosiamose; D008358:Mannose