Plasmacytoid dendritic cell enrichment of bone marrow allografts enhances GvL activity by facilitating donor T cell engraftment and Th1 polarization (126.25)

Abstract

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) can cure patients with relapsed acute leukemia via a graft vs. leukemia (GvL) effect, but is complicated by graft vs. host disease (GvHD). Host dendritic cells (DC) following chemotherapy initiate GvHD in mouse models of allo-HSCT, but the role of donor DC is unclear. We have previously shown that transplanting purified plasmacytoid DC (pDC) along with HSC and T cells leads to Th1 donor T cell polarization and improved GvL activity. The goals of this study were: 1) To determine whether passive enrichment of pDC by depleting myeloid DC (mDC) from a bone marrow (BM) graft along with a fixed number of donor T cells would increase Th1 polarization and improve survival in leukemia-bearing mice, and 2) determine the role of IL-12 produced by donor pDC. Lethally irradiated B10.BR or FVB mice received BM and T cells from B6 or IL-12 KO B6 donors. Depletion of mDC from BM was achieved by FACS. Recipients of mDC-depleted BM had increased serum IFN-γ and increased donor T-cell proliferation and engraftment. Transplanting mDC-depleted BM enhanced survival without increasing GvHD in leukemia-bearing mice compared with undepleted BM. Enhanced proliferation and engraftment of donor T cells was not seen with mDC-depleted BM from IL-12 KO donors. These data show that pDC enrichment of BM allografts enhances donor T-cell Th1 polarization, engraftment, and GvL activity. The immune effects of mDC-depletion appear to be IL-12 dependent.