Project Summary/Abstract The ultimate goal in clinical transplantation is robust and specific host immunological tolerance toward transplanted allogeneic tissue and cells. While systemic immunosuppression regimens have saved lives by enabling long-term allogeneic graft survival, they come with a host of potentially severe side effects, including infections and malignancies. The development of a method to induce donor-specific, localized tolerance toward allogeneic grafts, and thereby eliminate the need for chronic systemic immunosuppression, would dramatically reduce the risks associated with cell and tissue transplantation. Typical tolerogenic immunomodulatory approaches are systemic, potentially resulting in off-target and detrimental effects. Many groups have turned toward local delivery or presentation of immunomodulatory factors, which can eliminate systemic and off-target effects, but have limited opportunity for renewal when exhausted, resulting in a transient treatment. One approach to achieve more persistent localized immunomodulation includes the use of tolerogenic cells, such as T regulatory cells, tolerized mesenchymal stem cells or tolerized antigen presenting cells. However, while these cells can be influenced to take on a tolerogenic phenotype in vitro, it is unclear whether, or for how long, these manipulated cells maintain this phenotype in vivo. An alternative strategy would be the use of professional tolerogenic cells, such as placenta-derived trophoblasts, wherein their primary physiological role is sustained and persistent maintenance of tolerance toward allogeneic tissue. Our research approaches immunological tolerance from the perspective of the only physiologically natural scenario of allogeneic tissue tolerance, placental pregnancy. In placental pregnancy, semi-allogeneic and fully allogeneic conceptus are protected from immune response by the placenta, a fetus-derived organ consisting of various types of trophoblasts which physically isolate the fetus from the mother. We aim to probe and exploit the tolerogenic immunomodulatory mechanisms of trophoblasts and their capacity to induce tolerance in allogeneic graft transplantation through three main projects: (1) develop artificial placenta organoids using tunable hydrogel matrices to direct trophoblast differentiation and explore their immunomodulatory mechanisms in vitro; (2) engineer a safe and translatable method of artificial placenta organoid transplantation for tolerogenic cell therapy; (3) develop a tolerance-inducing vaccine via implantation of artificial placenta organoids for antigen-specific tolerance against allogeneic grafts. The use of placenta-based mechanisms to induce tolerance toward allogeneic grafts is a drastically understudied area of immunology, and presents an opportunity to widen and enrich the broader research areas of transplantation and transplantation immunology.

Project Narrative The proposed research is relevant to public health because it aims to develop a method to transplant cells and tissue in the absence of chronic systemic immunosuppression, which could lead to improved outcomes in the general population of transplant recipients. This project is relevant to NIH’s mission, as the development of methods to transplant cells and tissue in the absence of immunosuppression would impact tens of thousands of transplant recipients per year.