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.
"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. "
[Show abstract][Hide abstract] ABSTRACT: The study of human-specific infectious agents has been hindered by the lack of optimal small animal models. More recently development of novel strains of immunodeficient mice has began to provide the opportunity to utilize small animal models for the study of many human-specific infectious agents. The introduction of a targeted mutation in the IL2 receptor common gamma chain gene (IL2rgnull) in mice already deficient in T and B cells led to a breakthrough in the ability to engraft hematopoietic stem cells, as well as functional human lymphoid cells and tissues, effectively creating human immune systems in immunodeficient mice. These humanized mice are becoming increasingly important as pre-clinical models for the study of human immunodeficiency virus-1 (HIV) and other human-specific infectious agents. However, there remain a number of opportunities to further improve humanized mouse models for the study of human-specific infectious agents. This is being done by the implementatation of innovative technologies, which collectively will accelerate the development of new models of genetically modified mice, including; i) modifications of the host to reduce innate immunity, which impedes human cell engraftment; ii) genetic modification to provide human-specific growth factors and cytokines required for optimal human cell growth and function; iii) new cell and tissue engraftment protocols. The development of “next generation” humanized mouse models continue to provide exciting opportunities for the establishment of robust small animal models to study the pathogenesis of human-specific infectious agents, as well as for testing the efficacy of therapeutic agents and experimental vaccines.
[Show abstract][Hide abstract] ABSTRACT: Prevention of Graft-versus-Host-Disease (GvHD) by preserved Graft-versus-Leukaemia (GvL) effect is one of the major obstacles following allogeneic haematopoietic stem cell transplantation. Currently used drugs are associated with side effects and were not able to separate GvHD from the GvL-effect because of general T-cell suppression. This review focuses on murine models for GvHD and currently available treatment options involving antibodies and applications for the therapeutic use of aptamers as well as strategies for targeting immune responses by allogenic antigens.
Journal of Cellular and Molecular Medicine 10/2014; 19(1). DOI:10.1111/jcmm.12416 · 4.01 Impact Factor
Franziska S. Hoffmann, Johann Hofereiter, Heike Rübsamen, Johannes Melms, Sigrid Schwarz, Hans Faber, Peter Weber, Benno Pütz, Verena Loleit, Frank Weber, Reinhard Hohlfeld, Edgar Meinl, Markus Krumbholz
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