The Involvement of FcR Mechanisms in Antibody-Mediated Rejection

• Published in: Transplantation Vol. 84; no. 10; pp. 1324 - 1334
• Main Authors: LEE, Chih-Yuan, LOTFI-EMRAN, Sahar, ERDINC, Melek, MURATA, Kazunori, VELIDEDEOGLU, Ergun, FOX-TALBOT, Karen, JINHUAN LIU, GARYU, Justin, BALDWIN, William M, WASOWSKA, Barbara A
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott 27-11-2007
• Subjects: Animals; Antibodies, Monoclonal - immunology; Biological and medical sciences; Cell Line, Transformed; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Graft Rejection - immunology; Heart Transplantation - immunology; Immunoglobulin G - immunology; Immunoglobulins - deficiency; Isoantibodies - immunology; Lymph Nodes - immunology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Receptors, Fc - immunology; Spleen - immunology; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Tissue, organ and graft immunology; Rejection; Graft(material); Graft; Antibody; Mechanism
• ISSN: 0041-1337; 1534-6080
• DOI: 10.1097/01.tp.0000287457.54761.53

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.
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.
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.
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.