Control of GVHD with Retained GVT

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The goals of this Project are to enhance our understanding of graft vs host disease (GVHD) and graft vs tumor (GVT) reactions to gain greater insight into these complex biological reactions and to develop strategies which may be translated to the clinic. We will utilize a novel bioluminescent imaging strategy whereby cell populations of interest are labeled with the luciferase (luc) gene and emit light. Towards this end we have generated a unique gfp/luc transgenic mouse line to ensure uniform gene expression and availability of labeled cell populations. Trafficking and survival of luc* cells can be followed in real time with high precision and sensitivity. We will evaluate the GVHD inducing capacity of primary CD4+ and CDS* T cells with respect to the location of key events in GVHD induction. We hypothesize that GVHD develops through the spatial and temporal migration of lymphocytes to key sites whereby alloreactive cells proliferate and upregulate other cell surface molecules required for entry into GVHD target organs such as the gastrointestinal tract, skin and liver. Bioluminescent based imaging will be utilized to identify the major sites of GVHD induction to direct tissue sampling and characterization of the infiltrating cell populations by FACS and immunofluorescence. We will further explore cell populations known to have GVT reactivity yet with limited GVHD potential to compare and contrast the trafficking and survival characteristics of these cells to primary T cells. We will focus on the use of cytokine induced killer (CIK) and natural killer (NK) cells since both cell populations have been shown to not result in clinically significant GVHD in clinical trials and may promote GVT effects. This basic and translational project will provide insights into GVHD pathophysiology and characterize cell populations capable of GVHD and GVT effects that could be translated to the clinic where CIK cells are being explored in Project 1, This Project interacts with Projects 1,2,4,5,7 and 8 and utilizes all of the Cores.