The long-term goal of this research is to improve survival for patients after allogeneic stem cell transplantation by limiting graft-versus-host disease (GvHD) while maintaining the graft-versus-leukemia effect of donor immune cells. Clinical data from the BMT CTN 0201 clinical trial, in which transplant recipients with leukemia or MDS were randomized to receive BM versus G-CSF-mobilized blood stem cell allografts, found identical overall survival comparing the two graft sources, with less chronic GvHD in BM recipients. Among recipients of BM allografts, better survival was seen among recipients of larger numbers of plasmacytoid dendritic cells (pDC) and naive T-cells compared with patients who received fewer of these donor cells. Surprisingly, lower rates of severe acute GvHD (but not relapse) were seen in recipients of BM allografts containing more naive donor T-cells. Our recent published data shows that 1) highly purified donor pDC limit severe GvHD in murine BMT by facilitating expansion of donor regulatory T-cells (Treg) through interferon-?- and IDO-dependent signaling with donor na?ve T-cells;2) plerixafor, a CXCR4 antagonist that mobilizes hematopoietic stem cells, also efficiently mobilizes pDC and na?ve T-cells. Our overall hypothesis is that donor pDC in the hematopoietic stem cell graft favorably regulate the site of donor T-cell activation and donor T-cell immune polarization. Clinical translation of this approach is limited by gaps in understanding how donor pDC and T-cells cells interact to regulate GvHD. First, what is the optimal graft source or mobilization strategy to enhance the ability of pDC to limit severe GvHD? Second, what is the nature of interaction between donor pDC and naive T-cells that leads to increased Treg activity? Third, how do pDC in the graft regulate post- transplant immunity, including graft-versus-leukemia GvL? Three aims will test our overall hypothesis: 1. To determine the method of collecting hematopoietic stem cells that optimizes the content and immunological activity of donor pDC and na?ve T-cells. 2. To test how pDC precursors in the donor stem cell graft and their progeny in vivo regulate homing and allo-reactivity of effector and regulatory T-cells in allo-HSCT recipients. 3. To define the relationship between the content of pDC and na?ve T-cells in grafts collected from healthy donors with post-transplant immune reconstitution, including GvL and GvHD activities. According to the overall hypothesis, GvHD can be reduced, GvL can be maintained, and transplant outcomes can be improved by increasing the content of immature donor pDC in allo-HSCT recipients at higher risk for graft rejection and/or GvHD. Mechanistic experiments with mice and an innovative clinical trial of plerixafor mobilization in humans will test this hypothesis by studying Treg induction and in vivo migration of donor T- cells and pDC. Knowledge gained from this project will improve outcomes for patients undergoing allogeneic stem cell transplants and will have applications in cancer immunotherapy and organ transplantation. !
The major problem in allogeneic hematopoietic stem cell transplantation is optimizing the balance between allo-reactive donor T-cells that cause graft versus host-disease and allo-reactive T-cells with anti-tumor activity. The proposed research can lead to improved survival for transplant recipients through increased understanding of the mechanisms by which donor plasmacytoid dendritic cells (pDC) regulate the allo-reactivity of donor T-cells, which will lead to novel strategies to optimize the content and function of critical immune cells in the stem cell graft.