Xenotransplantation: Current Understanding of the Mechanism of Immune-Mediated Injury

The scarcity of transplantable organs represents a worldwide public health crisis, and as a result, thousands of people with kidney failure die waiting for a transplant each year. Xenotransplantation involves transplanting organs from an animal source into humans, offering a potential solution to this significant unmet need. Indeed, if there is a limitless supply of organs, many more patients who do not meet the current criteria for transplant eligibility could also be considered as candidates. Although there are examples of attempts to transplant animal tissues or organs into humans dating back over 300 years, none were successful due to cross-species immunologic incompatibility. Even so, significant advances in genetic engineering and the emergence of novel immunosuppressive agents have spurred impressive improvements in xenograft survival in preclinical studies involving nonhuman primates. Furthermore, recent reports of genetically modified pig kidney and heart xenotransplants in human decedents and living recipients on a compassionate use basis have provided impetus to advancing the field toward first-in-human trials. However, studies in nonhuman primates and humans thus far have described adaptive as well as innate immune-mediated xenograft injury. Understanding the mechanistic aspects of these responses at the cellular and molecular levels is critical to the development of targeted genetic modifications and innovative therapeutic strategies aimed at preventing rejection and inducing tolerance. Moreover, the physiologic components of the bidirectional communication between the human host and pig xenograft must also be understood and manipulated. Here, we review the breakthroughs in kidney xenotransplantation in the past few decades and highlight the immunologic hurdles that have yet to be overcome.