) The capacity of memory T-cells to traffic preferentially to distinct epithelial tissues has only recently been appreciated. Evidence is accumulating that a skin homing memory T-cell population, identified by E/P selectin ligand expression (e.g., CLA/PSGL-1) and absence of integrin alpha 4 beta 7, mediates antigen specific effector responses in skin, while a reciprocal memory T-cell subset (integrin alpha 4 beta 7 positive, E/P selecting ligand negative) mediates effector responses in the gastrointestinal tract (gut). Importantly, these memory T-cells use these cell surface molecules to initiate the tethering and rolling (under physiologic flow conditions) on endothelial cells in post capillary venules that are required for their ultimate extravasation in both normal and inflamed skin or gut. Such polarized populations of memory cells are thought to emerge during the naive to memory T-cell transition in the specialized lymphoid micro-environment of lymph nodes draining each epithelial surface, respectively. GVHD is a nearly inevitable complication of allogeneic bone marrow transplantation. Much of the morbidity from GVHD derives from the involvement of the two major epithelial interfaces with the environment: the skin and the gut. The present proposal tests the hypothesis that distinct subsets of effector T-cells with similar antigenic specificities mediate skin and gut GVHC. A second testable hypothesis is that these polarized subsets of memory T-cell s emerge in part from transferred graft naive T-cells that are activated by alloantigen in lymph node draining either gut or skin, respectively. A final hypothesis is that the strength of the conditioning regimen influences this process in two ways. First, tissue injury and attendant inflammation from primary cytokine release leads to enhanced egress of dendritic cells form blood, which in to carry damaged tissue antigen via afferent lymphatics to draining lymph nodes. Second, the increased expression of adhesion molecules on endothelial cells in inflamed skin and gut enhance the efficiency of memory T-cell extravasation. Each of these hypotheses will be directly testing using a well-characterized murine model allogeneic BMT (MHC identical). The lethal GVHD that results is dependent on T-cells in the allografted population. Both antibodies and blocking molecules specific for memory and naive is dependent on T-cell homing ligand/receptor pairs, as well as transgenic mice deficient in one or more genes critical to these adhesive interactions (e.g., E/P selectin), FucTVll, beta 7 integrin), will be used to ask precise and directed questions about the cellular and molecular requirements for the evolution of skin and gut specific GVHD, respectively. The capacity to selectively modify GVHD involving one or both of these tissues, while not suppressing ostensibly beneficial alloimmune responses (e.g., graft versus leukemia or global immunocompetence is the longterm therapeutic goal underlying this study.
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| Major-Monfried, Hannah; Renteria, Anne S; Pawarode, Attaphol et al. (2018) MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD. Blood 131:2846-2855 |
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| Stickel, N; Hanke, K; Marschner, D et al. (2017) MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation. Leukemia 31:2732-2741 |
| Ferrara, James Lm; Smith, Christopher M; Sheets, Julia et al. (2017) Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis. J Clin Invest 127:2441-2451 |
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