NIH grant: Xenotransplantation without Immunosuppressive Maintenance (XTWIM) (1P01AI198696-01)

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NIH grant 1P01AI198696-01: Xenotransplantation without Immunosuppressive Maintenance (XTWIM)
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: DAVID H SACHS. Award: $3040700.
Start: 2026-08-01T00:00:00.
PROJECT SUMMARY
Xenotransplantation currently utilizes heavy immunosuppression (IS) with severe toxic side effects. Our
program uniquely employs histocompatible inbred pigs with genetic modifications (GMs) aimed at
achieving donor-specific immunologic unresponsiveness (DSU) by first transplanting cells and tissues, followed
by transplantation of histocompatible organs from the same pig line. In two highly integrated Projects and three
Cores, we will utilize two unique platforms for inducing DSU, namely xenogeneic mixed hematopoietic
chimerism (MC) and porcine thymus (THY) transplantation. Using these, we have achieved
Xenotransplantation Without Immunosuppressive Maintenance (XTWIM) in human immune system (HIS) mice
and IS weaning to monotherapy in non-human primates (NHPs). In Project 1, “Re-education of Adaptive and
Innate Human Anti-Pig Immune Responses in Human Immune System Mice”, we will optimize XTWIM in
human immune systems by combining porcine THY transplantation and xenogeneic MC. While both
approaches centrally tolerize human T cells to the source pig, xenogeneic MC also tolerizes human NK cells
and nAb-producing B cells. THY transplantation generates Tregs to overcome residual peripheral immunity to
the pig. We have now demonstrated that combined MC and porcine THY transplantation can overcome
limitations in interactions with human APCs in the periphery if a human thymus is also present. We will
characterize the human immune systems developed with this approach, determine the mechanisms of DSU
and optimize conditioning for translation into the large animal models in Project 2 and ultimately patients.
Project 2, “Achieving XTWIM Through Thymic Transplantation and Mixed Chimerism in NHPs”, will advance
THY transplantation and xenogeneic MC to achieve XTWIM in NHPs. We have achieved remarkable long-term
survival of GalT knockout porcine kidneys grafted as composite thymokidney (TK) grafts. Project 2 will optimize
XTWIM induction by combining this approach with MC in a pre-clinical NHP model. We will modify IS induction,
aiming to enhance Treg-mediated suppression of pre-existing responses. We will explore the use of fetal THY
tissue, capitalizing on our inbred pig line, aiming to accelerate recipient thymopoiesis and DSU in TK grafts.
For animals with higher nAb levels, we will utilize GalT KO pigs with additional GMs and use a normothermic
perfusion (NMP) device to investigate novel GMs. We will evaluate strategies (from Project 1 and Core C) to
protect pig BM from baboon innate immunity, thereby combining MC and TK transplantation. Core A, will
provide administrative coordination of the program. Core B will provide quality-controlled animals, porcine cells
and tissues to both projects and produce new, highly inbred histocompatible and GM pigs. Core C constructs
unique GM pigs aimed at promoting XTWIM. Collectively, these projects and cores will synergize to advance
clinical XTWIM.

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