Interspecies Comparison of Human and Murine Scleroderma Reveals IL-13 and CCL2 as Disease Subset-Specific Targets

• Published in: The American journal of pathology Vol. 180; no. 3; pp. 1080 - 1094
• Main Authors: Greenblatt, Matthew B., Sargent, Jennifer L., Farina, Giuseppina, Tsang, Kelly, Lafyatis, Robert, Glimcher, Laurie H., Whitfield, Michael L., Aliprantis, Antonios O.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.03.2012; American Society for Investigative Pathology
• Subjects: Animals; Biological and medical sciences; Chemokine CCL2 - antagonists & inhibitors; Chemokine CCL2 - genetics; Disease Models, Animal; Fibroblasts - metabolism; Gene Expression; Gene Expression Profiling; Graft vs Host Disease - genetics; Humans; Interleukin-13 - genetics; Investigative techniques, diagnostic techniques (general aspects); Macrophages - metabolism; Medical sciences; Mice; Mice, Inbred BALB C; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Receptors, Interleukin-13 - metabolism; Receptors, Interleukin-4 - metabolism; Regular; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Scleroderma, Systemic - genetics; Signal Transduction; T-Lymphocytes - metabolism; Up-Regulation; Human; Immunopathology; Connective tissue disease; Skin disease; Targeting; Cytokine; Rodentia; Autoimmune disease; Interleukin 13; Vertebrata; Anatomic pathology; Mammalia; Mouse; Animal; Systemic disease; Scleroderma; Comparative study; Monocyte chemoattractant protein 1
• ISSN: 0002-9440; 1525-2191; 1525-2191
• DOI: 10.1016/j.ajpath.2011.11.024

Development of personalized treatment regimens is hampered by lack of insight into how individual animal models reflect subsets of human disease, and autoimmune and inflammatory conditions have proven resistant to such efforts. Scleroderma is a lethal autoimmune disease characterized by fibrosis, with no effective therapy. Comparative gene expression profiling showed that murine sclerodermatous graft-versus-host disease (sclGVHD) approximates an inflammatory subset of scleroderma estimated at 17% to 36% of patients analyzed with diffuse, 28% with limited, and 100% with localized scleroderma. Both sclGVHD and the inflammatory subset demonstrated IL-13 cytokine pathway activation. Host dermal myeloid cells and graft T cells were identified as sources of IL-13 in the model, and genetic deficiency of either IL-13 or IL-4Rα, an IL-13 signal transducer, protected the host from disease. To identify therapeutic targets, we explored the intersection of genes coordinately up-regulated in sclGVHD, the human inflammatory subset, and IL-13–treated fibroblasts; we identified chemokine CCL2 as a potential target. Treatment with anti-CCL2 antibodies prevented sclGVHD. Last, we showed that IL-13 pathway activation in scleroderma patients correlated with clinical skin scores, a marker of disease severity. Thus, an inflammatory subset of scleroderma is driven by IL-13 and may benefit from IL-13 or CCL2 blockade. This approach serves as a model for personalized translational medicine, in which well-characterized animal models are matched to molecularly stratified patient subsets.