The overarching goal is to identify and enrich donor dendritic cell (DC) populations that reduce graft-versus-host disease (GvHD) and improve survival after allogeneic bone marrow transplantation (allo-BMT). Our proposal is grounded on published findings that the content of donor DC in the bone marrow graft and in the blood of transplant recipients have significant impact on clinical outcomes, improving survival by decreasing GvHD-mortality without increasing relapse. Preclinical data from murine BMT model systems also show that donor plasmacytoid dendritic cells (pDC) from bone marrow but not G-CSF mobilized grafts improve survival by decreasing the severity of GvHD. The ability of donor pDC to limit GvHD is dependent upon their expression of chemokine receptors, cytokines, neuropeptides and catabolic enzymes, but it is not known whether the same DC subset produces all these factors, or whether there are multiple sub-populations of DC, each with different functions. Another key question is how homing of donor DC to lymphoid and GvHD-target organs regulates T cell immunity including GvHD and graft-versus-leukemia (GvL). Answering these questions and identifying cost- effective procedures for collecting grafts containing immune-regulatory DC will facilitate application of these exciting observations to clinical practice. To progress towards our overall goal, we propose three specific aims:
Aim 1. To identify the phenotype and gene expression profile of the most potent immuno-regulatory subset of donor DC present in bone marrow and other graft sources. Hypothesis: bone marrow contains subsets of DC progenitors that secrete immune-regulatory interleukins and chemokines that limit GvHD by facilitating the generation of donor-derived induced-Treg (iTreg).
Aim 2. To define the mechanism by which donor bone marrow DC progenitors limit GvHD without affecting the GvL activity of donor T cells. Hypothesis: bone marrow contains a subset of DC progenitors that limit GvHD by generating iT-reg from nave donor T cells in GVHD target tissues while GvL is mediated by donor T cells activated in secondary lymphoid organs.
Aim 3. To define a stem cell mobilization approach that yields an engrafting number of stem cells and increased numbers of immuno-regulatory DC progenitors Hypothesis: treatment of donors with a short- course of Flt3-L will increase the numbers of immune-regulatory donor DC and a single injection of plerixafor will mobilize these DC and hematopoietic stem cells into the blood where they can be collected by apheresis. Our work to define mechanisms by which DC regulate immunity in allo-BMT will inform broad fields of medicine.
Over the past 30 years techniques of obtaining allografts for stem cell transplantation has shifted to increasing use of blood stem cell grafts collected by apheresis, in spite of higher rates of chronic graft-versus-host disease seen among recipients of G-CSF-mobilized grafts compared with marrow grafts. Our research has shown that rare antigen presenting cells in the graft, called dendritic cells, have a significant influence on the incidence and severity of graft-versus-host disease. Our work will define the type of donor dendritic cell that most effectively limits graft-versus-host disease without compromising the graft-versus-leukemia activity of the transplant, and will optimize novel ways of obtaining donor grafts that are enriched for this cell population.