Regulation of Premature Keratinocyte Apoptosis in GVHD

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The epidermis is a key component of human skin strategically located at the interface with the environment shielding the body from harmful physical, chemical, and infectious agents that could perturb homeostasis. The epidermis creates this protective shield by production of a biological barrier, the stratum comeum formed by keratinocytes (KCs) that have undergone terminal differentiation followed by cell death. Not only must there be proper regulation of a balance between cell death and cell proliferation, but molecular events that regulate KC cell death must be timed to occur in both a spatially and temporarily coordinated fashion to produce an effective barrier. Our hypothesis is that acute GVHD involves a three-step process. In the first step, which occurs due to the conditioning regimen, susceptible epidermal KCs are triggered to undergo premature apoptosis accompanied by release of cytokines, chemotactic polypeptides, and adhesion molecules, in the second and third steps, the cutaneous microenvironment responds to this "danger" signal by activation of resident dendritic antigen presenting cells which stimulate donor T cells to proliferate and release additional cytokines that further damage epidermal KCs. The specific aims are: Aim 1: To examine human skin to define: KC apoptotic susceptibility and immunomodulatory effects of BMT conditioning. Aim 2: To examine skin obtained from acute GVHD lesions, as well as SCID-Hu grafts from experimentally produced GVHD lesions, characterize infiltrating immunocytes, and identify/localize relevant cytokines, death receptors, and caspases. Aim 3: To determine key biochemical components of death effector pathways responsible for premature KC apoptosis in GVHD using ex vivo models (EEs and LRCs). Aim 4: To determine methods to minimize/prevent KC apoptosis of histone deacetylase inhibitors, TNFalpha and cells genetically engineered to express several proteins.