Subset characterization of myeloid-derived suppressor cells arising during induction of BM chimerism in mice

Abstract

To date, myeloid-derived suppressor cells (MDSC) have been best studied in cancer, where they represent an escape mechanism for immune surveillance. MDSC are now also gaining interest in the context of transplantation. Suppressive CD11b þ myeloid progenitor cells have been reported to expand endogenously during BM chimerism induction in mice; in particular, in irradiated MHC-matched BM chimeras and in parent-in-F1 BM chimeras. Myeloid cell expansion coincided with a time frame where donor lymphocyte infusion (DLI) therapy-mediated GVL effects without GVHD. Hypothesizing that regulatory myeloid cells may have a role in regulating post-transplant T-cell alloreactivity, we performed a detailed phenotypic and functional characterization of these cells in the parent-in-F1 C57BL/6-[C57BL/6xDBA2] model. We found that transiently expanding CD11b þ myeloid progenitor cells comprise the two phenotypically and functionally distinct mononuclear and polymorphonuclear MDSC subsets that were recently described in tumor-bearing mice. Both MDSC subsets suppressed in vitro and in vivo alloreactive T-cell proliferation. Also, both the subsets mediated enhanced in vitro suppression when harvested from chimeras, given a prior in vivo challenge with non-tolerant donor T cells, indicating that allo-activated T cells can activate MDSC in vivo. This study provides the basis to investigate the---potentially beneficial---role of expanding MDSC in influencing the risk of GVHD during chimerism induction.

Dynamic Change and Impact of Myeloid-Derived Suppressor Cells in Allogeneic Bone Marrow Transplantation in Mice

“…Previous work by others suggests that MDSCs accumulate in murine models of allogeneic BMT (17, 34), but the relationships between MDSC accumulation, GVHD severity and tumor relapse was not clear. In our current work, we systemically studied the accumulation of MDSCs in allogeneic and syngeneic BMT recipients.…”

The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects

“…Furthermore, we analyzed subpopulations of myeloid-derived suppressor cells (MDSCs) that were positive for Gr-1 and CD11b. These cells inhibit alloreactions and expand to achieve hematopoietic chimerism after BMT (24,25); this suggests that they contribute to smooth engraftment. In particular, the population of granulocytic MDSCs with a CD11b lo population ( Figure 3D).…”

Granulocytic Myeloid-Derived Suppressor Cells Accumulate in Human Placenta and Polarize toward a Th2 Phenotype

“…They are part of normal hematopoiesis but are dramatically expanded and activated in many types of cancer in humans and mice (11)(12)(13)(14) as well as under other pathological conditions such as infection (15,16), trauma (17), or transplant rejection (18,19). GR-MDSCs express the common myeloid marker CD33 and the granulocytic lineage markers CD66b or CD15 whereas they do not exhibit monocytic Ags such as CD14 and HLA-DR (10,20,21).…”