Premium
Blockade of P‐Selectin Is Sufficient to Reduce MHC I Antibody‐Elicited Monocyte Recruitment In Vitro and In Vivo
Author(s) -
Valenzuela N. M.,
Hong L.,
Shen X.Da,
Gao F.,
Young S. H.,
Rozengurt E.,
KupiecWeglinski J. W.,
Fishbein M. C.,
Reed E. F.
Publication year - 2013
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.12016
Subject(s) - medicine , blockade , in vivo , monocyte , in vitro , immunology , antibody , pharmacology , receptor , biology , biochemistry , microbiology and biotechnology
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.