Skin-Intrinsic Immunosuppressive Mesenchymal Stem Cells and aGVHD

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Project Summary/Abstract Acute graft-versus-host disease (aGVHD) is a major limiting complication of allogeneic stem cell transplantation for the treatment of leukemia/lymphoma and certain solid tumors. aGVHD occurs when T lymphocytes from donor bone marrow attack cells within the recipient that are critical to the function vital organs, namely skin, liver and gut. During the past three decades of research, Dr. Murphy’s laboratory has found that in skin and squamous mucosae, the first sites of effector-target cell interaction provoked by differences in minor histocompatibility antigens, involve T cells bearing Vb-specific markers that home selectively to epithelial rete ridges as well as the epithelial stem cell-rich bulge regions of murine hair follicles. This association results in death by apoptosis of adjacent epithelial cells that express the stem cell marker, cytokeratin 15. Systemic therapeutic inhibition of these effector limbs is riddled with problems that include collateral impact on immune reconstitution and blunting of graft-versus-tumor effects. However, we now know through discoveries made in collaboration with co-PIs of this proposal, Drs. Markus and Natasha Frank, that the skin and squamous mucosae harbor intrinsic cellular pathways capable of potent immunosuppression. Specifically, we have discovered a dermal dendritic cell that has stem cell characteristics, expresses the multidrug resistance transporter ABCB5, and also expresses PD-1. This cell has the ability to thwart T cell responses, including alloreactivity, and therefore holds significant but as yet unexplored promise as a skin- intrinsic pathway that may be leveraged to inhibit the tissue injury in aGVHD. In this proposal, Dr. Murphy and the Drs. Frank have combined forces to address the long-term objective of harnessing the skin’s intrinsic immunosuppressive capabilities to thwart aGVHD. The proposal’s specific objective is to determine the impact of PD-1-expressing immunosuppressive dermal mesenchymal stem cells on the earliest and most specific effector-target cell interactions responsible for aGVHD. To this end, we have proposed three specific aims: 1) to correlate spatiotemporal multiplex immune profiling with all aspects of disease morbidity and recovery in aGVHD; 2) to dissect ABCB5 dermal stem cell function in aGVHD and define PD-1/PD-L1-centered strategies for skin-intrinsic immunosuppression; and 3) to apply ABCB5+ dermal stem cell transplant strategies to influence aGVHD severity using spatiotemporal multiplex immune profiling as effector-target bioassay. The approaches involve state-of-the-art multiplex immunophenotyping of effector-target cell interactions that sensitively and specifically typify tissue injury in aGVHD, and leverage ABCB5 gene knockout and lineage tracing models in context of PD-L1 Ig administration and ABCB5+ stem cell engraftment. The rationale is that upon successful completion of this work, we will identify novel therapeutic approaches to the treatment and prevention of aGVHD skin and squamous mucosal pathology through manipulation of skin- intrinsic immunosuppressive pathways.