Speeding Immune Reconstitution after Thymus Transplantation

Speeding Immune Reconstitution after Thymus Transplantation Pivotal prior work by our team showed that cultured thymus tissue implantation (CTTI; also called thymus transplantation) into athymic humans generates a functional immune system where T cells protect against infection and are tolerant to both recipient (self) and to donor MHC antigens on the implanted thymus. We have extended these findings to reprogram the immune system of immunocompetent rats to recognize a transplanted allogeneic heart as self, then translated this paradigm-changing proof of concept via the successful first human CTTI/heart co-transplantation into an infant with both a damaged heart and very low T cell numbers. However, therapies that can drive more rapid T cell reconstitution are urgently needed to prevent unnecessary early deaths post-CTTI from infection before immune reconstitution has occurred, in order to extend this potentially life-saving method for inducing tolerance to a broader range of recipients. Using single cell RNA sequencing and spatial profiling of murine and human thymus, our team has identified multiple separately targetable pathways that regulate the transition of the thymus from its robust growth during the perinatal period to the homeostasis that is observed in juveniles. In this proposal, two of these pathways will be manipulated in murine models via either ex vivo gene therapy using adeno- associated virus vectors or pharmaceutical intervention. Impacts of these interventions on growth of implanted thymus and the speed and quality of immune reconstitution post-CTTI will be determined. As developers of CTTI with expertise in thymus biology and gene therapy, our research team is extraordinarily well-qualified to lead this study. The potential impact is large, since these rapidly translatable approaches may also speed T cell reconstitution after cancer treatment, advance progress toward the long sought-after goal of generating donor-specific tolerance to transplanted organs, improve treatment of autoimmunity, and even potentially ameliorate age-related declines in immunity. Project Number: 1R21AI196275-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Dawn Bowles (+1 co-PI) | Institution: DUKE UNIVERSITY, DURHAM, NC | Award Amount: $444,125 | Activity Code: R21 | Study Section: Immunobiology of Transplantation and Alloimmunity Study Section[ITA] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI19627501