Acute and chronic graft-vs-host disease (GVHD) as seen in vivo involves much more than an allogeneic immune reaction. Most importantly, a profound and prolonged immune deficiency as well as loss of the regulatory networks governing tolerance contribute to the pathogenesis. In previous studies, we related an abnormal thymic microenvironment to the development of syngeneic GVHD and chronic GVHD. We have also explored methods for restoring the thymic microenvironment. Histopathological descriptions of GVHD emphasize injury to the epithelium, such as in skin, hepatic bile ducts, etc. We have demonstrated significant endothelial cell injury with GVHD as well. While this injury could lead to obvious complications such as hemorrhage, endothelial cell injury potentially could also contribute to prolonged immune deficiency and loss of immune regulation by interfering with lymphocyte homing. In this project, we will extend the previous studies to explore a possible causal relation between abnormal thymic microenvironment as well as endothelial cell injury and the complications of immune deficiency and deregulation seen with GVHD. The basic assumptions for this project are: Reprogramming the thymus through recruitment of appropriate dendritic cells can establish and restore immune regulation and help to prevent acute and chronic GVHD. Endothelial cell injury caused by GVHD can significantly delay immune reconstitution.
The specific aim for this project are to: 1. establish the causes of abnormal thymic microenvironment and contribution to chronic GVHD. 2. explore thymic re-education as an adjunct in the prevention and treatment of GVHD. 3. determine the relationship between GVHD associated endothelial cell injury and delayed immune reconstitution. The proposed studies will utilize basic bone marrow transplant procedures in rats, immuno-histochemistry, flow cytometry, and cell and tissue culture procedures. These studies will complement the goals of the other projects in the GVHD section, including those characterizing T cell rearrangements, cellular targets of GVHD, and new methods of treatment.
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