The involvement of FcR mechanisms in antibody-mediated rejection.
BACKGROUND
Antibody-mediated rejection is characterized by macrophage margination against vascular endothelium. The potential interactions triggered by antibodies between endothelial cells (EC) and macrophages have not been examined thoroughly in transplants. We used in vivo and in vitro models of antibody-mediated rejection.


METHODS
Passive transfer of monoclonal alloantibodies (Allo-mAbs) to donor major histocompatibility complex-class I antigens was used to restore acute rejection of B10.A (H-2a) hearts to C57BL/6 (H-2b) immunoglobulin knockout (IgKO) recipients. Intragraft cytokine mRNA expression was measured by real-time polymerase chain reaction. In vitro, mouse EC were cultured in the presence of Allo-mAbs to donor major histocompatibility complex class I antigens and mononuclear cells. Levels of cytokines in culture supernatants were determined in enzyme-linked immunosorbent assay.


RESULTS
Expression of MCP-1, IL-6 and IL-1alpha mRNA was higher in rejecting transplants from recipients treated with Allo-mAbs compared to non-rejecting transplants. EC sensitized with Allo-mAbs produced high levels of MCP-1 and KC. The addition of macrophages to sensitized EC stimulated high levels of IL-6 in addition to MCP-1, KC, Rantes, and TIMP-1. The levels of MCP-1 and IL-6 were significantly lower in co-cultures of EC sensitized with IgG1 Allo-mAbs in the presence of mononuclear cells from Fcgamma-Receptor III KO (FcgammaRIII-KO) graft recipients compared to co-cultures with wild-type cells. The levels of both cytokines were also lower in co-cultures of EC stimulated with F(ab')2 fragments of antibody.


CONCLUSIONS
Our findings indicate that IgG1 Allo-mAbs to major histocompatibility complex class I antigens can augment graft injury by stimulating EC to produce MCP-1 and by activating mononuclear cells through their Fc receptors.
Lee
Chih-Yuan
CY
Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
Lotfi-Emran
Sahar
S
Erdinc
Melek
M
Murata
Kazunori
K
Velidedeoglu
Ergun
E
Fox-Talbot
Karen
K
Liu
Jinhuan
J
Garyu
Justin
J
Baldwin
William M
WM
Wasowska
Barbara A
BA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002461:Cell Line, Transformed; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D007136:Immunoglobulins / Q000172:deficiency*; D007518:Isoantibodies / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D011961:Receptors, Fc / Q000276:immunology*; D013154:Spleen / Q000276:immunology
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007136:Immunoglobulins; D007518:Isoantibodies; D011961:Receptors, Fc