Murine sclerodermatous graft-versus-host disease, a model for human scleroderma: cutaneous cytokines, chemokines, and immune cell activation.
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.
Zhang
Yan
Y
Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106, USA.
McCormick
Laura L
LL
Desai
Snehal R
SR
Wu
Caiyun
C
Gilliam
Anita C
AC
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000276:immunology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics; D018925:Chemokines / Q000096:biosynthesis*; D024042:Collagen Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis*; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D006801:Humans; D007106:Immune Sera / Q000008:administration & dosage; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008262:Macrophage Activation; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000235:genetics; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000096:biosynthesis; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; D012595:Scleroderma, Systemic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D012867:Skin / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; D015854:Up-Regulation / Q000276:immunology
D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D018925:Chemokines; D024042:Collagen Type I; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D007106:Immune Sera; D019402:Macrophage Inflammatory Proteins; D016177:Macrophage-1 Antigen; D008565:Membrane Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; C508960:TGFB1 protein, human; C509041:TGFB2 protein, human; C508961:Tgfb1 protein, mouse; C509045:Tgfb3 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; D017493:Leukocyte Common Antigens