Cross-Species Chemoattraction and Xenograft Failure: Do Neutrophils Play a Role?

Abstract

Polymorphonuclear granulocytes (PMN, neutrophils) are well known to contribute to the pathogenesis of many congenital disorders (e.g., CR3 deficiency, chronic granulomatous disease, myeloperoxidase deficiency) and acquired disease states (e.g., inflammatory bowel disease, glomerulonephritis, immune vasculitis, rheumatoid arthritis, neutrophil dermatoses, sepsis). They play a key role in mediating ischemia-reperfusion injury following solid organ allotransplantation,andmorerecentevidencesuggeststhat,following early migration into the allograft, neutrophils are capable of amplifying T-cell mediated allograft rejection (1). In xenotransplantation, the major hurdle of hyperacute rejection (HAR) has led research efforts to focus on the role of natural xenoantibodies and complement activation, while the neutrophilwasconsideredtoplayasecondaryroleandwastherefore given little attention. Meanwhile, it seems that experimental prevention of HAR becomes feasible thanks to the genetic modification of donor animals (DAF/CD55 transgenicpigs,-Galknockoutpigsandmice)and,consequently, the mechanism of acute vascular rejection (AVR) and the cellular aspects of xenograft rejection now receive full attention. AVR is characterized by a dense cellular infiltrate, which is dominated not only by natural killer (NK) cells and macrophages, but also by PMN. It is therefore plausible to assume that neutrophils take an active part in the rejection process and this hypothesis is gaining increasing interest. Vercellotti et al. (2) showed that the adhesion of human neutrophils to porcine endothelial cells (PECs) was promoted by humannaturalxenoantibodiesandcomplement,and,particularly, that endothelial deposition of iC3b was critically involvedintheadhesionprocess.Ehrnfeltetal.(3)showedthat humanPMNsadheretoPECs,providedtheseareactivatedby human natural xenoantibodies. These studies indicate that the interaction between neutrophils and xenoendothelium requires preactivation of endothelial cells by complement and/or natural xenoantibodies and, consequently, that the PMN plays a secondary role in HAR. In contrast, others have providedevidencethathumanPMNhavetheinherentcapac