Project 3 will continue investigations of the cellular traffic in the bone marrow (BM). Using intravital microscopy (IVM), previous work in this project has shown how specialized endothelial cells (EC) in BM microvessels control the selective transit of blood cells into and out of the extravascular space.
Aim 1 will characterize the nature and consequences of T cell interactions with dendritic cells (DCs) in the BM.
This aim i s based on the hypothesis that the BM is a gathering place for T cells and professional antigenpresenting cells that can foster the induction of antigen-specific cellular immune responses. We have shown recently that the BM is a reservoir and site of recruitment for CDS T cells, particularly central memory cells (Tcm). Preliminary data indicate that DCs can migrate from peripheral tissues to the BM, suggesting a potential mechanism for the induction of primary and secondary immune responses to peripheral antigens in the BM. However, it is not known how such immune responses are induced at the single-cell level and how immune responses in the BM differ from those in secondary lymphoid tissues.
Sub aim 1. 1 will determine how different DC subsets are recruited to the BM and characterize the migratory behavior of homed DCs within the BM. This will include an analysis of plasmacytoid DCs (PDCs), which will be studied in a new transgenic mouse strain in which PDCs express GFP. In collaboration with Denisa Wagner, we will pursue preliminary observations that tissue-resident PDCs activate TNF-alpha converting enzyme (TACE).
Sub aim 1. 2 will generate an in-depth analysis of naive T cell interactions with different DC subsets in the BM and subaim 1.3 will extend this analysis to explore DC-mediated recall responses by BM-resident Tcm. In collaboration with Leslie Silberstein we will investigate whether differential CXCR4 signaling is responsible for preliminary findings that different leukocyte subsets have distinct retention kinetics after homing to the BM.
Sub aim 1. 4 will explore if T cell activation in BM induces cytotoxic effector cells (CTLs) and how CTLs function in this organ. Together, the experiments in aim 1 will clarify how blood cell transfusions containing T cells and/or DCs influence cellular immunity in the BM.
Aim 2 will continue to study the mechanisms of multiple myeloma (MM) dissemination in the BM.
This aim will also investigate the potential for CTL-mediated immunotherapy of MM, a highly aggressive plasma cell-derived tumor with pronounced BM tropism. The tumor cells are thought to arise during germinal center reactions in secondary lymphoid organs and must home via the blood to the BM to establish disease. Preliminary work for this aim has established an in vivo model to study MM migration and growth in murine BM.
Sub aim 2. 1 will explore the molecular and cellular mechanisms of MM cell dissemination in the BM.
Sub aim 2. 2 will pursue preliminary observations indicating that the CXCR4-CXCL12 pathway is critical for the survival and/or proliferation of MM cells in the BM. This work will be done in collaboration with Leslie Silberstein. Finally, subaim 2.3 will explore the feasibility of T cell-based anti-MM immunotherapy building on knowledge and techniques previously generated in this project.
This aim will produce novel information that may improve clinical approaches in transfusion medicine and hematology/oncology to the treatment of MM.
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