title: Blockade of p-selectin is sufficient to reduce MHC I antibody-elicited monocyte recruitment in vitro and in vivo.
abstract: Donor-specific HLA antibodies significantly lower allograft survival, but as yet there are no satisfactory therapies for prevention of antibody-mediated rejection. Intracapillary macrophage infiltration is a hallmark of antibody-mediated rejection, and macrophages are important in both acute and chronic rejection. The purpose of this study was to investigate the Fc-independent effect of HLA I antibodies on endothelial cell activation, leading to monocyte recruitment. We used an in vitro model to assess monocyte binding to endothelial cells in response to HLA I antibodies. We confirmed our results in a mouse model of antibody-mediated rejection, in which B6.RAG1(-/-)  recipients of BALB/c cardiac allografts were passively transferred with donor-specific MHC I antibodies. Our findings demonstrate that HLA I antibodies rapidly increase intracellular calcium and endothelial presentation of P-selectin, which supports monocyte binding. In the experimental model, donor-specific MHC I antibodies significantly increased macrophage accumulation in the allograft. Concurrent administration of rPSGL-1-Ig abolished antibody-induced monocyte infiltration in the allograft, but had little effect on antibody-induced endothelial injury. Our data suggest that antagonism of P-selectin may ameliorate accumulation of macrophages in the allograft during antibody-mediated rejection.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: N M
authors.initials: NM
authors.lastname: Valenzuela
authors.forename: L
authors.initials: L
authors.lastname: Hong
authors.forename: X-Da
authors.initials: XD
authors.lastname: Shen
authors.forename: F
authors.initials: F
authors.lastname: Gao
authors.forename: S H
authors.initials: SH
authors.lastname: Young
authors.forename: E
authors.initials: E
authors.lastname: Rozengurt
authors.forename: J W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
authors.forename: M C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: E F
authors.initials: EF
authors.lastname: Reed
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001011:Aorta / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology; D005089:Exocytosis; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000379:methods; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology*; D019007:P-Selectin / Q000037:antagonists & inhibitors*; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D019007:P-Selectin; D017493:Leukocyte Common Antigens; D002118:Calcium