The Role of IL-12 Producing Antigen Presenting Cells in Bone Marrow Transplant Outcomes 公开
Kaufman, Katarzyna Darlak (2013)
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a treatment used to cure patients with high risk and relapsed cancers of the blood and bone marrow, such as acute leukemia or multiple myeloma, via a graft-versus-leukemia (GvL) effect. The GvL effect of the graft is mediated primarily by donor T cells that are activated by a combination of both donor and host antigen presenting cells (APCs). However, a strong GvL effect is often is accompanied by a phenomenon called graft-versus-host-disease (GvHD). A fundamental question in the field is that of how to separate the phenomenon of GvL activity from that of GvHD. Dendritic cells (DCs) are APCs that stand at the forefront of GvHD initiation and are a likely target in tipping the balance from GvHD towards GvL. Clinical studies have indicated that higher numbers of donor plasmacytoid DCs (pDCs) are correlated with improved survival and lower GvHD in patients undergoing unrelated donor allo-HSCT. Upon conducting murine studies, it was also found that mice receiving purified populations of HSCs, T cells, and pDCs had improved donor T cell expansion, enhanced T-helper-type-I (TH1) polarization of donor T cells, enhanced GvL activity and survival, without an increase in GvHD. While sorting of purified populations enhanced survival in murine systems, the sorting of purified populations is not translatable to clinical practice. We aimed to develop a feasible method for enriching pDCs in BMT, while elucidating the mechanism by which donor pDCs separated GvL from GvHD. We found that by depleting myeloid DCs (mDCs) and in turn enriching for pDCs in total BM in a murine allogeneic model of BMT, we mirrored the results seen in transplants with purified populations. Mice receiving mDC depleted BM had enhanced GvL, donor T cell expansion, as well as an increase in serum IFN-γ compared with mice receiving unmanipulated BMT. We also found that the trends were dependent upon the ability of cells in donor BM to produce IL-12. The primary IL-12 producers were presumably pDCs. To confirm this, we transplanted mice with purified population of HSCs, T cells, and pDCs from either WT or IL-12 KO mice and found an increase in survival when mice received WT pDCs as compared with IL-12 KO pDCs. In addition to minimizing GvHD in transplant, graft failure is also of concern in certain transplant conditions. We aimed to elucidate the role of IL-12 producing host-APCs in engraftment in a murine model of allogeneic transplant. By creating radiation chimeras where host hematopoietic cells were incapable of producing IL-12, we found that IL-12 production played an important role in facilitating donor T cell engraftment. Taken together, the data shed light on fundamental questions in the field of allo-HSCT and support local production of IL-12 as a critical event necessary to improve GvL, minimize GvHD, and improve engraftment.
Table of Contents
Chapter 1 - Introduction ...1
A brief history of bone marrow transplantation...4
Early days of transplantation...4
BMT for leukemia...7
Separating GvL from GvHD...9
GvHD...9
GvL...12
Preventing GvHD while preserving GvL...13
DCs and their subsets...15
The role of DCs in GvHD and GvL...19
Interleukin-12...23
IL-12 production and other forms...25
IL-12 activity on T cells and the immune response...27
Other IL-12 family members...28
Anti-tumor activity of IL-12...30
IL-12 and GvHD...31
References...32
Chapter 2 - Enrichment of IL-12 Producing Plasmacytoid Dendritic Cells in
Donor Bone Marrow Enhances Graft-Versus-Leukemia Activity in Allogeneic Hematopoietic Stem Cell Transplantation...49
Abstract...50
Introduction...51
Materials and Methods...53
Results...58
Discussion...64
References...69
Figure Legends...73
Figures...77
Chapter 3 - Host Bone Marrow-derived IL-12 Enhances Donor T cell Engraftment
in a Mouse Model of Bone Marrow Transplantation...81
Abstract...82
Introduction...83
Materials and Methods...85
Results...89
Discussion...94
References...99
Figure Legends...102
Figures...106
Chapter 4 - Discussion...111
Discussion...111
References...124
Figure legends...126
Figures...127
List of Figures
Chapter 2
Figure 1...77
Figure 2...78
Figure 3...79
Figure 4...80
Chapter 3
Figure 1...106
Figure 2...107
Figure 3...108
Figure 4...109
Figure 5...110
Chapter 4
Figure 1...127
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