Allogeneic hematopoietic stem cell transplantation (HSCT) is curative therapy for hematologic malignancies, aplastic anemia and a variety of genetic conditions; however, significant treatment-related morbidity and mortality results from the development of acute graft-versus-host disease (GVHD). Acute GVHD is caused by an immunological attack by donor effector cells against recipient tissues, particularly the skin, liver and intestines. In all cell-mediated inflammatory conditions, the migration of blood-borne effector cells into the involved sites is a highly specific and dynamic process, the first step of which is regulated by discrete adhesive interactions between circulating cells and target tissue endothelium. Utilizing an in vitro lymphocyte-skin adherence assay that is performed under shear conditions to mimic blood flow, the applicant has observed a highly specific adhesive interaction between human peripheral blood mononuclear cells (PBMC) and endothelium of papillary dermis in acute cutaneous GVHD. He hypothesizes that this adhesive interaction regulates in part the migration/recruitment of effector cells to skin in acute GVHD. The objective of this application is to elucidate, using human cells and skin specimens, the molecular basis of this PBMC-endothelial interaction, the cellular components of PBMC which bear the capacity to adhere to endothelium in acute GVHD, and the role of these adhesive interactions in the pathogenesis of acute GVHD. Specifically, he will: (1) Investigate the role of adhesion molecules known to mediate leukocyte-endothelial interactions and the structure of binding determinants which direct PBMC attachment to the dermal endothelium; (2) Test the binding capability of discrete subsets of PBMC and whether such subsets utilize similar adhesion molecules to bind to the endothelium cutaneous GVHD; (3) Examine the adherence of PBMC to dermal microvascular endothelial cells and determine the effects of inflammatory cytokines on the adherence capacity of the cultured cells; and (4) Establish a SCID Hu model of cutaneous GVHD to directly examine the role of adhesion molecules in the effector phase of cutaneous GVHD and the prevention of GVHD by use of reagents to block PBMC-endothelial adhesive interactions. The results of these studies should provide fundamental insights into the pathobiology of acute GVHD in humans. The identification of adhesion molecules mediating effector cell migration to target tissues may allow for therapeutic approaches to selectively interfere with the development of acute GVHD, thereby providing specific and efficient treatment for acute GVHD and preservation of beneficial alloreactivity, such as the graft-versus-leukemia effect, in patients undergoing allogeneic HSCT for hematologic malignancy.
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