Murine Sclerodermatous Graft-Versus-Host Disease, a Model for Human Scleroderma: Cutaneous Cytokines, Chemokines, and Immune Cell Activation

• Published in: The Journal of immunology (1950) 2002-03, Vol.168 (6), p.3088-3098
• Main Authors: Zhang, Yan, McCormick, Laura L, Desai, Snehal R, Wu, Caiyun, Gilliam, Anita C
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow Transplantation - immunology; Cell Migration Inhibition; Cell Movement - immunology; Chemokine CCL2 - biosynthesis; Chemokine CCL2 - genetics; Chemokine CCL4; Chemokine CCL5 - biosynthesis; Chemokine CCL5 - genetics; Chemokines - biosynthesis; Collagen Type I - antagonists & inhibitors; Collagen Type I - biosynthesis; Cytokines - biosynthesis; Disease Models, Animal; Female; Graft vs Host Disease - immunology; Graft vs Host Disease - metabolism; Graft vs Host Disease - pathology; Graft vs Host Disease - prevention & control; Histocompatibility Antigens Class II - biosynthesis; Humans; Immune Sera - administration & dosage; Leukocyte Common Antigens - biosynthesis; Lymphocyte Activation; Macrophage Activation; Macrophage Inflammatory Proteins - biosynthesis; Macrophage Inflammatory Proteins - genetics; Macrophage-1 Antigen - biosynthesis; Macrophages - immunology; Macrophages - metabolism; Macrophages - pathology; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Monocytes - immunology; Monocytes - metabolism; Monocytes - pathology; Receptors, Immunologic - biosynthesis; Receptors, Lipoprotein; Receptors, Scavenger; RNA, Messenger - antagonists & inhibitors; RNA, Messenger - biosynthesis; Scavenger Receptors, Class A; Scavenger Receptors, Class B; Scleroderma, Systemic - immunology; Scleroderma, Systemic - metabolism; Scleroderma, Systemic - pathology; Scleroderma, Systemic - prevention & control; Skin - immunology; Skin - metabolism; Skin - pathology; Spleen - cytology; Spleen - transplantation; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - biosynthesis; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - immunology; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Transforming Growth Factor beta3; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.168.6.3088

Murine sclerodermatous graft-vs-host disease (Scl GVHD) models human scleroderma, with prominent skin thickening, lung fibrosis, and up-regulation of cutaneous collagen mRNA. Fibrosis in Scl GVHD may be driven by infiltrating TGF-beta1-producing mononuclear cells. Here we characterize the origin and types of those cutaneous effector cells, the cytokine and chemokine environments, and the effects of anti-TGF-beta Ab on skin fibrosis, immune cell activation markers, and collagen and cytokine synthesis. Donor cells infiltrating skin in Scl GVHD increase significantly at early time points post-transplantation and are detectable by PCR analysis of Y-chromosome sequences when female mice are transplanted with male cells. Cutaneous monocyte/macrophages and T cells are the most numerous cells in Scl GVHD compared with syngeneic controls. These immune cells up-regulate activation markers (MHC class II I-A(d) molecules and class A scavenger receptors), suggesting Ag presentation by cutaneous macrophages in early fibrosing disease. Early elevated cutaneous mRNA expression of TGF-beta1, but not TGF-beta2 or TGF-beta3, and elevated C-C chemokines macrophage chemoattractant protein-1, macrophage inflammatory protein-1alpha, and RANTES precede subsequent skin and lung fibrosis. Therefore, TGF-beta1-producing donor mononuclear cells may be critical effector cells, and C-C chemokines may play important roles in the initiation of Scl GVHD. Abs to TGF-beta prevent Scl GVHD by effectively blocking the influx of monocyte/macrophages and T cells into skin and by abrogating up-regulation of TGF-beta1, thereby preventing new collagen synthesis. The Scl GVHD model is valuable for testing new interventions in early fibrosing diseases, and chemokines may be new potential targets in scleroderma.