Abstract
Pig-to-human xenotransplantation offers a potential bridge to the growing disparity between patients with end-stage organ failure and graft availability. Early studies attempting to overcome cross-species barriers demonstrated robust humoral immune responses to discordant xenoantigens. Recent advances have led to highly efficient and targeted genomic editing, drastically altering the playing field towards rapid production of less immunogenic porcine tissues and even the discussion of human xenotransplantation trials. However, as these humoral immune barriers to cross-species transplantation are overcome with advanced transgenics, cellular immunity to these novel xenografts remains an outstanding issue. Therefore, understanding and optimizing immunomodulation will be paramount for successful clinical xenotransplantation. Costimulation blockade agents have been introduced in xenotransplantation research in 2000 with anti-CD154mAb. Most recently, prolonged survival has been achieved in solid organ (kidney xenograft survival > 400 days with anti-CD154mAb, heart xenograft survival > 900 days, and liver xenograft survival 29 days with anti-CD40mAb) and islet xenotransplantation (>600 days with anti-CD154mAb) with the use of these potent experimental agents. As the development of novel genetic modifications and costimulation blocking agents converges, we review their impact thus far on preclinical xenotransplantation and the potential for future application.
Highlights
Organ transplantation remains the definitive treatment for patients suffering from end-stage organ failure
Residual preformed human antibodies to GTKO pig antigens suggested additional major barriers, which would hinder progress towards clinical application. This remains a major breakthrough as the identification of Gal α(1 (Gal) and production of GTKO pigs demonstrated the potential of reducing porcine antigenicity through genetic modification
A feedback mechanism occurs at this juncture by which CD28 is downregulated and the T cell increases expression of CTLA4-Ig. This molecule binds CD80/CD86 with much higher affinity than CD28 and produces an inhibitory signal as a highly evolved feedback mechanism [34]. Another increasingly significant costimulation pathway is the CD40/CD154 (CD40 ligand) interaction, which has been shown to be a potent stimulator of T and B cell activation through conventional antigen-presenting cell (APC) interactions and through interactions with innate immune cells and endothelium [35,36,37,38]
Summary
Organ transplantation remains the definitive treatment for patients suffering from end-stage organ failure. Residual preformed human antibodies to GTKO pig antigens suggested additional major barriers (i.e., anti-non-Gal antibodies), which would hinder progress towards clinical application This remains a major breakthrough as the identification of Gal and production of GTKO pigs demonstrated the potential of reducing porcine antigenicity through genetic modification. Much work over the past decade has defined costimulation signals, which regulate T cell activation and immune tolerance [17] Most of these agents are still experimental and early in the development pathway, preclinical studies utilizing experimental costimulation blockade agents have demonstrated prolonged engraftment of both solid organ and islet xenografts [18,19,20,21,22,23,24,25]. As discussions of pig-to-human xenotransplantation trials are underway [30, 31], we provide an overview of costimulation pathways, the current standing of clinical and preclinical development of these agents, and the preclinical data regarding their use in xenotransplantation
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