Latency-associated peptide prevents skin fibrosis in murine sclerodermatous graft-versus-host disease, a model for human scleroderma.
Murine sclerodermatous graft-versus-host disease (Scl GVHD), produced by transplanting B10.D2 bone marrow and spleen cells to lethally irradiated BALB/cJ mice, is a model for human scleroderma. Mice with Scl GVHD have skin thickening, lung fibrosis, cutaneous mononuclear cell infiltration, and upregulation of cutaneous transforming growth factor beta1 (TGF-beta1) and type I collagen mRNAs by day 21 after bone marrow transplantation. Elevated TGF-beta1 appears to be the critical cytokine driving fibrosis in Scl GVHD, which can be prevented with antibodies to TGF-beta administered early in disease. Here we demonstrate that we can also prevent skin thickening in mice with Scl GVHD with a naturally occurring antagonist to TGF-beta1, human latency-associated peptide (LAP). By quantitative real-time PCR analysis and immunostaining, LAP treatment also abrogates the upregulation of cutaneous TGF-beta1 and connective tissue growth factor mRNAs and type I collagen synthesis in Scl GVHD. In contrast to anti-TGF-beta antibodies, LAP at 4 ng total per mouse has no significant suppressive effect on cutaneous influx of T cells and monocytes or immune cell activation. LAP may be a potential new therapy in scleroderma and other TGF-beta-driven fibrosing disease that targets TGF-beta more specifically, without affecting systemic critical roles of TGF-beta on immune cell function.
Zhang
Yan
Y
Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, Ohio 44106-5028, USA.
McCormick
Laura L
LL
Gilliam
Anita C
AC
D000818:Animals; D015415:Biomarkers; D024042:Collagen Type I / Q000096:biosynthesis; D055513:Connective Tissue Growth Factor; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D017874:Immediate-Early Proteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000494:pharmacology*; D011498:Protein Precursors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D012867:Skin / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000187:drug effects
D015415:Biomarkers; C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D024042:Collagen Type I; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D011498:Protein Precursors; D012333:RNA, Messenger; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor