Xenotransplantation: immunological hurdles and progress toward tolerance

Abstract

The discrepancy between organ need and organ availability represents one of the major limitations in the field of transplantation. One possible solution to this problem is xenotransplantation. Research in this field has identified several obstacles that have so far prevented the successful development of clinical xenotransplantation protocols. The main immunologic barriers include strong T-cell and B-cell responses to solid organ and cellular xenografts. In addition, components of the innate immune system can mediate xenograft rejection. Here, we review these immunologic and physiologic barriers and describe some of the strategies that we and others have developed to overcome them. We also describe the development of two strategies to induce tolerance across the xenogeneic barrier, namely thymus transplantation and mixed chimerism, from their inception in rodent models through their current progress in preclinical large animal models. We believe that the addition of further beneficial transgenes to Gal knockout swine, combined with new therapies such as Treg administration, will allow for successful clinical application of xenotransplantation.

Keywords: NK cells; genetically modified swine; mixed chimerism; thymus transplant; tolerance; xenotransplantation.

Figure 1

Model for NK cell responses in mixed allogeneic and xenogeneic chimeras. Licensing model requires an inhibitory ligand-receptor interaction to activate an NK cell, whereas the anergy or disarming model predicts that persistent unopposed activation renders an NK cell anergic (A). In mixed xenogeneic chimeras, donor cells present activating ligands, but not inhibitory ligands, leading to unopposed NK cell activation and global unresponsiveness, consistent with the disarming model of NK cell tolerance (B). In mixed allogeneic chimeras, autologous and allogeneic cells both display inhibitory ligands, resulting in NK cell function with specific tolerance to donor and recipient (C). Dashed line indicates lack of inhibitory receptor-ligand interaction.