279 © Springer Nature Switzerland AG 2021 N. Hakim et al. (eds.), Transplantation Surgery, Springer Specialist Surgery Series, https://doi.org/10.1007/978-3-030-55244-2_18 Xenotransplantation 1.0 to 2.0 Omar Haque, Daniel Cloonan, Erin E. McIntosh, and Christiane Ferran 18.1 Introduction and Historic Perspective The shortage of organs for transplantation is the single most important impediment to broad implementation of these life-saving proce- dures. Numerous efforts to expand the donor pool, including the use of living donors where possible, of extended criteria donor organs, and most recently of machine perfusion to improve organ quality of suboptimal allografts, have somewhat improved the numbers, yet the need is far from being met. In the United States alone, over 113,000 patients were listed for organ transplantation in 2019, with sadly 20 of them dying each day while awaiting transplan- tation [1]. Utilizing nonhuman tissue to replace a failing organ is not novel, with the frst trials dating back to the 1600s [2–4]. In the absence of advanced surgical techniques and of any knowledge of the immunologic response to xenotransplantation, these initial attempts promptly failed. It took over 3 centuries for xenotransplantation to resurface in the 1960s, around the time allotransplantation was also taking off thanks to the recognition of the immunosuppressive properties of steroids and of drugs such as Azathioprine [5]. Several pioneering attempts using kidney xenografts in 1963 [6], heart xenografts in 1964 [7], and liver xenografts in 1969 [8] failed within minutes to days due to hyperacute (HAR) and acute vascular rejection, AKA delayed xenograft rejection (AVR/DXR). The advent of cyclosporine A (CsA) in 1976 marked a signifcant turning point for allotrans- plantation, but also xenotransplantation [9]. O. Haque · D. Cloonan Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA e-mail: ojhaque@bidmc.harvard.edu; dcloonan@ bidmc.harvard.edu E. E. McIntosh Department of Surgery, Harvard Medical School, Boston, MA, USA Division of Vascular and Endovascular Surgery, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA C. Ferran (*) Department of Surgery, Harvard Medical School, Boston, MA, USA Division of Vascular and Endovascular Surgery, Center for Vascular Biology Research, Harvard Medical School, Boston, MA, USA Division of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA The Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA e-mail: cferran@bidmc.harvard.edu 18 Omar Haque and Daniel Cloonan equally contributed to this manuscript as frst co-authors. Christiane Ferran is last and corresponding author.