Chronic graft-versus-host-disease in CD34+-humanized NSG mice is associated with human susceptibility HLA haplotypes for autoimmune disease. (August 2015)

• Record Type: Journal Article
• Authors: Sonntag, Katja; Eckert, Franziska; Welker, Christian; Müller, Hartmut; Müller, Friederike; Zips, Daniel; Sipos, Bence; Klein, Reinhild; Blank, Gregor; Feuchtinger, Tobias; Schumm, Michael; Handgretinger, Rupert; Schilbach, Karin
• Is Part Of: Journal of autoimmunity. Volume 62(2015)
• Page Start: 55
• Page End: 66
• Publication Date: 2015-08
• Subjects: Chronic graft-versus-host disease -- Autoimmunity -- cGVHD model -- cGVHD pathology -- Extended HLA haplotypes -- T-cell-receptor repertoire -- Humanized mouse; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2015.06.006
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: Chronic graft-versus-host disease (cGVHD) is a significant hurdle to long-term hematopoietic stem-cell transplantation success. Insights into the pathogenesis and mechanistical investigations of novel therapeutic strategies are limited as appropriate animal models are missing. The immunodeficient NSG mouse – when humanized with human bone marrow, fetal liver and thymus (BLT NSG) – is prone for cGVHD, yet mainly affects the skin. In contrast, the NSG mouse humanized exclusively with CD34 + -selected, CD3 + -depleted stem cells (CD34 + NSG) has neither been described for acute nor chronic GVHD so far. This is the first report about the development of systemic autoimmune cGVHD ≥24 weeks post stem cell receipt involving lung, liver, skin, gingiva and intestine in two NSG cohorts humanized with CD34 + grafts from different donors. Affected mice presented with sclerodermatous skin, fibrotic lung, severe hepatitis, and massive dental malformation/loss. CD4 + -dominated, TH 2-biased, bulky T-cell infiltrates featured highly skewed T cell receptor (TCR) repertoires, clonal expansions, and autoreactive TCRs. In affected tissues profibrotic IL-13 and -4 dominated over TH 1 cytokines IFN-γ and TNF-α. Thus, the time point of manifestation and the phenotype match human systemic pleiotropic sclerodermatous GVHD. The CD34 + NSG-model's intrinsic deficiency of thymus, thymus-derived regulatory T cells (nTreg) and B cells emphasizes the role of the genetic polymorphism and the cytokines in the pathogenesis of cGVHD. Importantly, the only factor discriminating diseased versus non-diseased CD34 + NSG cohorts were two risk HLA haplotypes that in human mediate susceptibility for autoimmune disease (psoriasis). Thus, the CD34 + NSG model may serve as a platform for addressing issues related to the pathophysiology and treatment of human autoimmunity and chronic GVHD. Highlights: First report on autoimmune, cGVHD in CD34 + -stem-cell-humanized NSG mice. cGVHD occurs late after transplantation and in the absence of prior aGVHD. cGVHD-NSG mice reproduce the full spectrum of pleiotropism of human cGVHD. cGVHD-inducing grafts carry human autoimmunity susceptibility extended HLA-haplotypes. The Risk HLA-haplotype NSG model allows to study human cGVHD and autoimmune disease.