Absence of FcγRIII Results in Increased Proinflammatory Response in FcγRIII-KO Cardiac Recipients

Abstract

Background Alloantibody can contribute significantly to rejection of heart transplants by activation of complement and interactions with a variety of effector cells, including macrophages and monocytes through activating FcγRI, FcγRIII, FcγRIV, the inhibitory FcγRIIB and complement receptors. These receptors link cellular and humoral immunity by bridging the antibody specificity to effector cells. Activating FcγRs are also involved in serum amyloid P component (SAP)-mediated clearance of apoptotic bodies. Methods B10.A (H-2a) hearts were transplanted into WT or FcγRIII-KO C57BL/6 (H-2b) mouse recipients. Levels of alloantibodies and SAP in the circulation were determined by flow cytometry and ELISA, respectively. Intragraft cytokine mRNA expression was measured by real-time PCR. Intragraft deposition of C4d, von-Willebrand factor (vWF), SAP and activated caspase 3 was visualized by immunochemistry. Results B10.A hearts in C57BL/6 FcγRIII-KO recipients were rejected acutely within 6-8 days as compared to 10-14 days in WT. The rejection in FcγRIII-KO was accompanied by higher levels of circulating IgM/IgG alloantibodies and SAP than in WT recipients. Histology in FcγRIII-KO cardiac allograft recipients indicated: perivascular margination of monocytes and neutrophils, vascular endothelial cell injury, intense vasculocentric infiltrates with extensive apoptosis. Higher numbers of apoptotic cells, stronger C4d and SAP deposition and extensive activated caspase 3 were found in areas of dense pockets of apoptotic blebs in FcγRIII-KO. Conclusions We propose that absence of FcγRIII is associated with the lack of efficient SAP-mediated clearance of apoptotic cells through FcγRs. Apoptotic cells become immunogenic, induce enhanced inflammation, AlloAb production and complement activation leading to accelerated cardiac allograft rejection.

Contribution of Fcγ receptors to human respiratory syncytial virus pathogenesis and the impairment of T‐cell activation by dendritic cells

“…It is important to point out that other groups have reported that Fc γ RIII‐deficient mice display difficulties at eliminating immune complexes, such as IgG1‐coated particles by macrophages . Yet, these animals have been described overall as responding in a similar way to WT mice in IgG‐independent inflammatory processes . However, we cannot rule out that this knockout mouse may harbour uncharacterized immune abnormalities that could influence the results observed.…”

Acute and Chronic Rejection: Compartmentalization and Kinetics of Counterbalancing Signals in Cardiac Transplants

“…Full cross‐sections through cardiac grafts were fixed in methanol acetic acid and immunohistology was performed as previously described . The following primary reagents were used: polyclonal rabbit antibody to CD3 (Abcam, Cambridge, MA), rat mAb to Galectin‐3 (Mac‐2; Cedarlane, Burlington, NC), rabbit polyclonal antibody to Ym1 (Stem Cell Technologies, Vancouver, Canada), polyclonal goat antibody to PD1 (R&D Systems Inc, Minneapolis, MN), rat mAb to mouse Foxp3 (eBioscience, San Diego, CA), and biotinylated hyaluronic acid binding protein (Millipore, Billerica, MA).…”

FcγR requirements leading to successful immunotherapy

“…Human recipients of renal transplants, carrying the rare FcγRIIB T232 SNP associated with dysfunction of inhibitory signaling, did not reject grafts and the SNP had no effect on graft function at 1 or 10 years post‐transplant or on patient survival . In another study, MHC mismatch heart transplants were rejected faster in FcγRIII‐KO recipient mice compared to WT recipients, and lack of activating FcγRIII led to a defect in clearance of apoptotic cells and increase alloantibody production .…”