Mice Engrafted With Human Fetal Thymic Tissue And Hematopoietic Stem Cells Develop Pathology Resembling Chronic GVHD.

Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation (Impact Factor: 3.4). 06/2013; 19(9). DOI: 10.1016/j.bbmt.2013.06.007
Source: PubMed


Chronic Graft versus Host Disease (cGVHD) is a significant roadblock to long-term hematopoeitic stem cell (HSC) transplantation success. Effective treatments for cGVHD have been difficult to develop, in part because of a paucity of animal models that recapitulate the multi-organ pathologies observed in clinical cGVHD. Here we present an analysis of the pathology that occurs in immunodeficient mice engrafted with human fetal HSCs and implanted with fragments of human fetal thymus and liver. Starting at timepoints generally later than 100 days post-transplantation, the mice developed signs of illness, including multi-organ cellular infiltrates containing human T cells, B cells and macrophages, fibrosis in sites such as lungs and liver, and thickened skin with alopecia. Experimental manipulations that delayed or reduced the efficiency of the HSC engraftment did not affect the timing or progression of disease manifestations, suggesting that pathology in this model is driven more by factors associated with the engrafted human thymic organoid. Disease progression was typically accompanied by extensive fibrosis and degradation of the thymic organoid, and there was an inverse correlation of disease severity with the frequency of Foxp3(+) thymocytes. Hence, the human thymic tissue may contribute T cells with pathogenic potential, but the generation of Tregs in the thymic organoid may help to control these cells before pathology resembling cGVHD eventually develops. This model thus provides a new system to investigate disease pathophysiology relating to human thymic events, as well as to evaluate treatment strategies to combat multi-organ fibrotic pathology produced by human immune cells.

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    • "The obvious challenges associated with this model include obtaining a quality source of the required tissues and mastering the surgical procedures . In addition, several reports indicate that this model suffers from a wasting syndrome resembling GVHD (Ali et al., 2012; Covassin et al., 2013; Greenblatt et al., 2012; Lockridge et al., 2013). This is thought to be partially due to implantation of preexisting mature T cells that may have contaminated CD34 þ HSC and/or fetal liver and thymus fragments. "
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