The Use of the Pig-to-Human Decedent Model to Optimize Future Results in Clinical Xenotransplantation Trials

– OVERALL Xenotransplantation has the potential to provide nearly unlimited organs for transplantation. Extension of xenograft survival in nonhuman primates (NHP) and xenotransplants to living and brain-dead humans have advanced the field toward clinical trials. Four gaps in knowledge remain to be filled before any human clinical trials of xenotransplantation can begin. We must first define the: 1) optimal immunosuppression regimen, 2) optimal genetics of the source animal, 3) humoral and cellular response to xenografts in humans, and 4) ability of the pig kidney to appropriately regulate human physiology. Only pig-to-human xenotransplants can provide this information. At NYU Langone, we developed an innovative decedent model to study the results of xenografts transplanted to humans and gain experience in the clinical management of xenograft recipients. We have now performed five decedent xenotransplants and monitored them up to 61 days after the transplant. Our preliminary data show that decedents have normal immune responses to xenografts, and that we can diagnose and treat antibody-mediated rejection of Gal-knockout thymokidneys. We now propose to perform 20 thymokidney xenotransplants and monitor the clinical, immunological, and physiological results in the decedents for up to 60 days, studying the human adaptive immune response to xenografts for the first time. Our program’s overarching hypothesis is that the decedent model will reveal critical information on the immune response to xenografts and the physiologic function of pig kidneys in recipient humans. Our program consists of four projects: Project 1 will study the effect of different immunosuppression regimens and different genetic modifications to the pigs on xenograft function and survival; Project 2 will use an innovative multi-omic approach to profile the human immune response to xenografts and assess physiologic changes in the decedent; Project 3 will examine the donor-specific T-cell response to xenografts (effector and regulatory T cells) and study the role of follicular T cells on potentiating the humoral immune response; and Project 4 will study the physiologic function of the pig kidney in the human milieu and in the context of possible immunologic injury. Findings in each project will inform, extend or complement studies pursued by other projects. The projects will be supported by a Molecular Science Core that will standardize and support multi-omic data collection and analysis. We also have an Administrative Core providing budgetary, logistical, and scientific oversight and statistical guidance. Collectively, these projects will provide a new level of understanding of the management of xenograft recipients and the human immune response to xenografts. Upon successful completion of the proposed research, we expect to be able to appropriately define the donor pig and treatment approach for the first clinical trials of kidney xenotransplantation, with the long-term goal of developing xenotransplantation into a standard clinical treatment option for organ failure. Project Number: 1P01AI181994-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: ROBERT MONTGOMERY (+1 co-PI) | Institution: NEW YORK UNIVERSITY SCHOOL OF MEDICINE, NEW YORK, NY | Award Amount: $2,064,597 | Activity Code: P01 | Study Section: Special Emphasis Panel[ZRG1 DCAI-V (42)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1P01AI18199401A1