Leukocyte recruitment into human skin transplanted onto severe combined immunodeficient mice induced by TNF-alpha is dependent on E-selectin.
In order to study the in vivo role of E-selectin in human inflammation, we have developed a model in which human skin is transplanted onto severe combined immunodeficient (SCID) mice. The grafted skin closely resembles normal skin and retains its human vasculature. After intradermal injection of rTNF-alpha, human E-selectin was rapidly up-regulated on dermal microvessels, with significant expression (determined immunohistochemically) at 1 h postinjection and maximum expression at 2 h postinjection. To study the functional role of E-selectin, a murine Ab against human E-selectin (mAb HEL 3/2) was developed that inhibited the in vitro adhesion of both human U937 cells and murine 32D cells to TNF-alpha-stimulated human endothelial cells. After intradermal injection of TNF-alpha, large numbers of murine leukocytes migrated into the grafts within 2 h. Intravenous injection of the antihuman E-selectin mAb 3/2 completely inhibited murine white blood cell (WBC) transmigration into the skin grafts, but an isotype-matched control Ab that also bound to human endothelium had no effect. Antihuman E-selectin mAb 3/2 was also able to inhibit the migration of i.v. 51Cr-labeled human neutrophils. These findings demonstrate that E-selectin is important in early white blood cell adhesion events and is required for TNF-alpha-induced white blood cell transmigration in the human/SCID mouse chimeric model.
Yan
H C
HC
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104.
Delisser
H M
HM
Pilewski
J M
JM
Barone
K M
KM
Szklut
P J
PJ
Chang
X J
XJ
Ahern
T J
TJ
Langer-Safer
P
P
Albelda
S M
SM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000502:physiology*; D002465:Cell Movement; D019040:E-Selectin; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D007962:Leukocytes / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D016038:Skin Transplantation / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D014409:Tumor Necrosis Factor-alpha