The objective of this five-year proposal is to allow the principal investigator to acquire new skills and experience in a clinically relevant large animal model of tolerance induction through the use of in utero hematopoietic cell transplantation. This will build on prior experience in the murine model obtained in the laboratory of Dr. Alan Flake and complement clinical training in pediatric surgery, solid organ transplantation, and fetal therapy. This unique combination of expertise will hopefully translate into a clinically relevant approach to the treatment of prenatally diagnosed conditions that can be treated with either hematopoietic or solid organ transplantation after birth, once donor specific tolerance has been established in utero. Dr. David Sachs will mentor the principal investigator throughout the research program. Dr. Sachs is Director of the Transplantation Biology Research Center (TBRC) at the Massachusetts General Hospital and is a well-respected leader in tolerance and hematopoietic chimerism research. He as a strong track record of mentorship, which now includes several well-established independent surgical investigators. Along with an advisory panel that will include Dr. Alan Flake and Dr. Megan Sykes, Dr. Sachs will provide a rich environment in which the principal investigator can develop into an independent researcher. The research plan will build on the well-established miniature swine model of chimerism and kidney allograft tolerance that has been developed in the laboratory of Dr. Sachs over the past two decades. The goal will be to determine and optimize the parameters required to achieve chimerism and kidney allograft tolerance after in utero hematopoietic cell transplantation in miniature swine.
The specific aims are: 1) To compare bone marrow and cytokine mobilized peripheral blood mononuclear cells (CM-PBMC) as a donor cell source for achieving stable multilineage engraftment, 2) Determine if a difference exists between maternal and paternal sources of hematopoietic cells for use as a donor cell source, and 3) Determine the relationship between chimerism and tolerance to donor specific kidney transplantation after birth. This will be the first attempt to systematically analyze factors, in a genetically well-defined large animal model, that might be important to the ultimate clinical success of in utero hematopoietic cell transplantation.
