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 microvesselscontrol 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 antigenpresentingcells that can foster the induction of antigen-specific cellular immune responses. We have shownrecently 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 potentialmechanism 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 immuneresponses in the BM differ from those in secondary lymphoid tissues.
Sub aim 1. 1 will determine how differentDC subsets are recruited to the BM and characterize the migratory behavior of homed DCs within the BM. Thiswill include an analysis of plasmacytoid DCs (PDCs), which will be studied in a new transgenic mouse strain inwhich PDCs express GFP. In collaboration with Denisa Wagner, we will pursue preliminary observations thattissue-resident PDCs activate TNF-alpha converting enzyme (TACE).
Sub aim 1. 2 will generate an in-depthanalysis of naive T cell interactions with different DC subsets in the BM and subaim 1.3 will extend thisanalysis to explore DC-mediated recall responses by BM-resident Tcm. In collaboration with Leslie Silbersteinwe will investigate whether differential CXCR4 signaling is responsible for preliminary findings that differentleukocyte subsets have distinct retention kinetics after homing to the BM.
Sub aim 1. 4 will explore if T cellactivation in BM induces cytotoxic effector cells (CTLs) and how CTLs function in this organ. Together, theexperiments in aim 1 will clarify how blood cell transfusions containing T cells and/or DCs influence cellularimmunity in the BM.
Aim 2 will continue to study the mechanisms of multiple myeloma (MM) dissemination in the BM.
This aim willalso investigate the potential for CTL-mediated immunotherapy of MM, a highly aggressive plasma cell-derivedtumor with pronounced BM tropism. The tumor cells are thought to arise during germinal center reactions insecondary lymphoid organs and must home via the blood to the BM to establish disease. Preliminary work forthis aim has established an in vivo model to study MM migration and growth in murine BM.
Sub aim 2. 1 willexplore the molecular and cellular mechanisms of MM cell dissemination in the BM.
Sub aim 2. 2 will pursuepreliminary observations indicating that the CXCR4-CXCL12 pathway is critical for the survival and/orproliferation 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 andtechniques previously generated in this project.
This aim will produce novel information that may improveclinical approaches in transfusion medicine and hematology/oncology to the treatment of MM.
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