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Critical Role of Effector Macrophages in Mediating CD4-Dependent Alloimmune Injury of Transplanted Liver Parenchymal Cells¹

Phillip H. Horne^*,, Jason M. Zimmerer^*, Mason G. Fisher^*, Keri E. Lunsford, Gyongyi Nadasdy, Tibor Nadasdy, Nico van Rooijen and Ginny L. Bumgardner^2,*

^* Department of Surgery, Comprehensive Transplant Center, Integrated Biomedical Science Graduate Program, College of Medicine, and Department of Pathology, Ohio State University Medical Center, Columbus, OH 43210; and Department of Molecular Cell Biology, Vrije University Medical Center, Amsterdam, The Netherlands

Despite the recognition that humoral rejection is an important cause of allograft injury, the mechanism of Ab-mediated injury to allograft parenchyma is not well understood. We used a well-characterized murine hepatocellular allograft model to determine the mechanism of Ab-mediated destruction of transplanted liver parenchymal cells. In this model, allogeneic hepatocytes are transplanted into CD8-deficient hosts to focus on CD4-dependent, alloantibody-mediated rejection. Host serum alloantibody levels correlated with in vivo allospecific cytotoxic activity in CD8 knockout hepatocyte rejector mice. Host macrophage depletion, but not CD4⁺ T cell, NK cell, neutrophil, or complement depletion, inhibited in vivo allocytotoxicity. Recipient macrophage deficiency delayed CD4-dependent hepatocyte rejection and inhibited in vivo allocytotoxicity without influencing alloantibody production. Furthermore, hepatocyte coincubation with alloantibody and macrophages resulted in Ab-dependent hepatocellular cytotoxicity in vitro. These studies are consistent with a paradigm of acute humoral rejection in which CD4⁺ T cell-dependent alloantibody production results in the targeting of transplanted allogeneic parenchymal cells for macrophage-mediated cytotoxic immune damage. Consequently, strategies to eliminate recipient macrophages during CD4-dependent rejection pathway may prolong allograft survival.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from the American Society of Transplantation Basic Science Physician Scientist Award, Roche Organ Transplantation Research Foundation, American Society of Transplant Surgeons, and National Institutes of Health (Grant DK072262).

² Address correspondence and reprint requests to Dr. Ginny L. Bumgardner, Department of Surgery, Division of Transplant, Ohio State University Medical Center, 1654 Upham Drive, 373 Means Hall, Columbus, OH 43210. E-mail address: ginny.bumgardner{at}osumc.edu

³ Abbreviations used in this paper: ADCC, Ab-dependent cellular cytotoxicity; KO, knockout; ALT, alanine transaminase; MST, median survival time; AAMR, Ab-mediated allograft rejection.