Year 2

The scientific progress on this award has been extensive. The purpose of this project was to determine whether we could improve the efficiency of hematopoietic stem cell (HSC) engraftment in order to downregulate the host response to transplanted organs, by essentially tricking the host into accepting a foreign organ as it’s own. There were two aims of the project. The first aim was to essentially optimize the engraftment of HSC and the second aim was to test how improved engraftment yielded improvements in transplantation efficiency and understand the immunologic mechanisms by which the transplant was accepted.

In Aim 1 we developed a murine model of hematopoietic stem cell-induced mixed chimerism and discovered that the deletion of specific receptors that resided on the cells, but not others, directly influenced HSCs engraftment in allogeneic hosts. During the first funding period we focused on defining which specific receptors contributed to HSC engraftment. During the second funding period we defined whether engraftment was specific to the specific receptors and determined the fate of the engrafted cells.

In Aim 2, we studied whether the receptor deficiency resulted in host unresponsiveness to donor antigens and we conducted extensive experiments to analyze the role of the specific receptors in host T cell activation and T cell unresponsiveness, using mixed lymphocyte experiments, cytokine analyses, flow cytometric and molecular biology experiments. There were two foci to this aim. The first was to determine whether HSC engraftment resulted in host unresponsiveness to donor antigens and the second was to define those mechanisms that caused downregulation of host responses. In this aim we were able to define the mechanisms by which the host unresponsiveness occurred, which set the stage for future manuscript submissions and future grant proposals directed at how to manipulate these receptors on human hematopoietic stem cells.