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 s evere combined immunodeficient (SCID) mice. The grafted skin closely r esembles normal skin and retains its human vasculature. After intrader mal injection of rTNF-alpha, human E-selectin was rapidly up-regulated on dermal microvessels, with significant expression (determined immun ohistochemically) at 1 h postinjection and maximum expression at 2 h p ostinjection. To study the functional role of E-selectin, a murine Ab against human E-selectin (mAb HEL 3/2) was developed that inhibited th e in vitro adhesion of both human U937 cells and murine 32D cells to T NF-alpha-stimulated human endothelial cells. After intradermal injecti on of TNF-alpha, large numbers of murine leukocytes migrated into the grafts within 2 h. Intravenous injection of the antihuman E-selectin m Ab 3/2 completely inhibited murine white blood cell (WBC) transmigrati on into the skin grafts, but an isotype-matched control Ab that also b ound to human endothelium had no effect. Antihuman E-selectin mAb 3/2 was also able to inhibit the migration of i.v. Cr-51-labeled human neu trophils. These findings demonstrate that E-selectin is important in e arly white blood cell adhesion events and is required for TNF-alpha-in duced white blood cell transmigration in the human/SCID mouse chimeric model.