Pig-to-human xenotransplantation offers a potential bridge to the growing disparity between patients with end-stage organ failure\nand graft availability. Early studies attempting to overcome cross-species barriers demonstrated robust humoral immune\nresponses to discordant xenoantigens. Recent advances have led to highly efficient and targeted genomic editing, drastically\naltering the playing field towards rapid production of less immunogenic porcine tissues and even the discussion of human\nxenotransplantation trials. However, as these humoral immune barriers to cross-species transplantation are overcome with\nadvanced transgenics, cellular immunity to these novel xenografts remains an outstanding issue. Therefore, understanding and\noptimizing immunomodulation will be paramount for successful clinical xenotransplantation. Costimulation blockade agents\nhave been introduced in xenotransplantation research in 2000 with anti-CD154mAb. Most recently, prolonged survival has been\nachieved in solid organ (kidney xenograft survival > 400 days with anti-CD154mAb, heart xenograft survival > 900 days, and liver\nxenograft survival 29 days with anti-CD40mAb) and islet xenotransplantation (>600 days with anti-CD154mAb) with the use of\nthese potent experimental agents. As the development of novel genetic modifications and costimulation blocking agents\nconverges, we review their impact thus far on preclinical xenotransplantation and the potential for future application.
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