The Role of Macrophages in Xenograft Rejection A. Cadili and N. Kneteman ABSTRACT Safe and effective xenotransplantation would provide a valuable answer to many of the limitations of allogenic transplantation. Such limitations include scarcity of organ supply and morbidity to donors in cases of living-related donor transplantation. The main hurdle to the efficacious application of xenotransplantation in clinical medicine is the fierce host immune response to xenografts. This immune response is embodied in 3 different types of xenograft rejection. Both hyperacute rejection and delayed xenograft rejection are mediated by natural antibodies and are concerned primarily with whole organ rejection. Cellular xenograft rejection (CXR), on the other hand, is concerned with both whole organ and CXR and is mediated by innate immunity rather than natural antibodies. Macro- phages, which are cells of the innate immune system, play a role in all 3 types of xenograft rejection (not just CXR). They impart their effects both directly and through T-cell activation. T RANSPLANTATION is the only effective therapy in many disease states involving end-organ failure. One of the major limitations of this therapy, however, is the severe shortage of allogenic donor grafts available for transplantation. 1,2 One of the solutions being explored to deal with this problem is the use of xenogenic grafts. Xenografts, in the form of both whole organ and cellular grafts, carry the potential for providing an unlimited supply of grafts. To date, xenotransplantation has not entered clinical use as a viable option because xenografts are faced with a more intense immune reaction from the body than allografts, thus decreasing their clinical utility. This heightened immune reaction against xenografts may be due to the greater antigenic disparities across different species (compared with different members of the same species). 3–6 With improved supportive medical therapy, many more patients are reaching a stage in their disease where trans- plantation should be considered. Hence, the need for transplantation as a therapeutic option is increasing, while rates of donor organ availability are not. Success in xeno- transplantation, therefore, would enhance our ability to provide effective care to an increasing number of patients in critical need. The main impediment to achieving this goal of safe, effective, and durable xenotransplantation is the host’s immune rejection. The negative effects of the host’s im- mune reaction against xenografts fall under 2 main catego- ries: graft failure and side effects of immunosuppressive therapy. Unraveling, and effectively countering, the im- mune mechanisms directed against xenografts will, no doubt, help to make xenotransplantation a viable clinical option. IMMUNOLOGIC BARRIERS TO XENOTRANSPLANTATION There are multiple immunologic barriers to successful transplantation of xenografts. The first is hyperacute rejec- tion (HAR), which is also termed acute humoral rejection. HAR is mediated by xenoreactive natural antibodies. These natural antibodies are directed against the -galactosyl xenoantigen (-Gal) carbohydrate epitopes present on the vascular endothelium of all species except humans and old world monkeys. 7 HAR, which results in graft destruction within minutes to hours, is ultimately mediated by activa- tion of the recipient’s complement. Complement activation may occur through the classical pathway, as is the case with pig to primate transplantation. 8 Complement activation also may occur through the alternate pathway, as has been shown to be the case in guinea pig to rat and pig to dog transplantation. 9,10 The second barrier to xenotransplantion is termed de- layed xenograft rejection (DXR). This type of rejection From the Department of Surgery, University of Alberta, Edm- onton, Alberta, Canada. Address reprint requests to Dr Ali Cadili, Department of Surgery, University of Alberta, 8440-112 Street, Edmonton, Alberta, Canada. © 2008 by Elsevier Inc. All rights reserved. 0041-1345/08/$–see front matter 360 Park Avenue South, New York, NY 10010-1710 doi:10.1016/j.transproceed.2008.08.125 Transplantation Proceedings, 40, 3289 –3293 (2008) 3289