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ACTIVATION OF INTRAGRAFT ENDOTHELIAL AND MONONUCLEAR CELLS DURING DISCORDANT XENOGRAFT REJECTION
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1994
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ImmunologyTransplantation MedicineCellular PhysiologyAngiogenesisHematologyCardiac XenotransplantationGraft SurvivalEndothelial Cell ActivationCell TransplantationCell SignalingHealth SciencesTransplantation SurgeryXenotransplantationTransplantationVascular PharmacologyAutoimmunityVascular BiologyHyperacute RejectionDiscordant Xenograft RejectionNeovascularizationCell BiologyTransplant RejectionDevelopmental BiologyPhysiologyEndothelial DysfunctionCell MigrationMedicineGraft Rejection
Discordant xenograft rejection studies have largely examined antibody and complement‑mediated hyperacute rejection, with little in vivo evidence on endothelial cell contributions. The study aimed to test whether recipient natural antibodies and complement trigger donor endothelial cell activation that drives rejection of discordant vascularized xenografts. The authors conducted a kinetic analysis of guinea pig heart rejection in Lewis rats, comparing untreated animals to complement‑depleted recipients to assess delayed rejection dynamics. Both hyperacute and delayed rejection of guinea pig hearts showed extensive endothelial activation (P‑selectin, E‑selectin, tissue factor up‑regulation, thrombomodulin and antithrombin III down‑regulation) occurring early post‑transplant, accompanied by a dense infiltrate of activated macrophages and NK cells with pro‑inflammatory cytokine expression, indicating that endothelial activation and innate immune cell infiltration are key drivers of xenograft rejection and potential therapeutic targets.
Most studies of discordant xenograft rejection have focused on the roles of recipient xenoreactive antibody and complement as mediators of hyperacute rejection; there are essentially no data from in vivo studies as to the contribution of endothelial cell responses to the pathobiology of xenograft rejection. We hypothesized that the mechanism by which xenoreactive natural antibodies and complement of the recipient are involved in rejection of a discordant, immediately vascularized xenograft involves donor organ endothelial cell activation, with the consequences of such activation contributing significantly to the rejection process. We performed a kinetic analysis of rejection of guinea pig hearts by untreated Lewis rats or recipients depleted of complement activity that underwent delayed xenograft rejection. We report that in both hyperacute rejection and delayed xenograft rejection there is widespread evidence of endothelial cell activation, including expression of P-selectin and E-selectin, upregulation of tissue factor, and downregulation of thrombomodulin and antithrombin III expression. Many of these changes occur very early posttransplantation in grafts that are not completely rejected until approximately 3 days. In delayed xenograft rejection, an intense cellular infiltrate is seen that results from progressive accumulation of activated macrophages and natural killer cells. T cell receptor α/β+ T cells are present only at relatively low levels. This cellular infiltrate is associated with dense expression of pro-inflammatory cytokines, including interferon gamma, interleukin 1, and tumor necrosis factor-alpha. We conclude that both endothelial cell activation and infiltration by activated macrophages and natural killer cells may play an important role in xenograft rejection. These newly described features of the xenogeneic rejection response may require targeting by future therapeutic regimens aimed at prolonging xenograft survival.