| First Author | Zimmerer JM | Year | 2018 |
| Journal | J Immunol | Volume | 201 |
| Issue | 12 | Pages | 3731-3740 |
| PubMed ID | 30397035 | Mgi Jnum | J:268247 |
| Mgi Id | MGI:6269184 | Doi | 10.4049/jimmunol.1800333 |
| Citation | Zimmerer JM, et al. (2018) Critical Role of Macrophage FcgammaR Signaling and Reactive Oxygen Species in Alloantibody-Mediated Hepatocyte Rejection. J Immunol 201(12):3731-3740 |
| abstractText | Humoral alloimmunity negatively impacts both short- and long-term cell and solid organ transplant survival. We previously reported that alloantibody-mediated rejection of transplanted hepatocytes is critically dependent on host macrophages. However, the effector mechanism(s) of macrophage-mediated injury to allogeneic liver parenchymal cells is not known. We hypothesized that macrophage-mediated destruction of allogeneic hepatocytes occurs by cell-cell interactions requiring FcgammaRs. To examine this, alloantibody-dependent hepatocyte rejection in CD8-depleted wild-type (WT) and Fcgamma-chain knockout (KO; lacking all functional FcgammaR) transplant recipients was evaluated. Alloantibody-mediated hepatocellular allograft rejection was abrogated in recipients lacking FcgammaR compared with WT recipients. We also investigated anti-FcgammaRI mAb, anti-FcgammaRIII mAb, and inhibitors of intracellular signaling (to block phagocytosis, cytokines, and reactive oxygen species [ROS]) in an in vitro alloantibody-dependent, macrophage-mediated hepatocytoxicity assay. Results showed that in vitro alloantibody-dependent, macrophage-mediated hepatocytotoxicity was critically dependent on FcgammaRs and ROS. The adoptive transfer of WT macrophages into CD8-depleted FcgammaR-deficient recipients was sufficient to induce alloantibody-mediated rejection, whereas adoptive transfer of macrophages from Fcgamma-chain KO mice or ROS-deficient (p47 KO) macrophages was not. These results provide the first evidence, to our knowledge, that alloantibody-dependent hepatocellular allograft rejection is mediated by host macrophages through FcgammaR signaling and ROS cytotoxic effector mechanisms. These results support the investigation of novel immunotherapeutic strategies targeting macrophages, FcgammaRs, and/or downstream molecules, including ROS, to inhibit humoral immune damage of transplanted hepatocytes and perhaps other cell and solid organ transplants. |
