We are using murine sclerodermatous graft versus host disease (Scl GVHD) to model human scleroderma, an autoimmune disease of unknown etiology. In our animal model, BALB/c mice (H-2d) develop skin thickening rather than classic GVHD when transplanted across minor histocompatibility loci with bone marrow and spleen cells from B10.D2 (H-2d) mice. Based on data from the literature and our published studies, we hypothesize that TGF-beta1 producing monocyte/macrophages are the crucial effector cells in Scl GVHD, where increased TGF-beta1 leads to upregulation of proalpha1(I)collagen by fibroblasts in early disease. To test this hypothesis, we propose in Aim I to characterize cells infiltrating skin of animals with Scl GVHD in several ways: (1) by FISH analysis to determine if they are male donor or female recipient cells, (2) by immunostaining and multiparameter flow cytometry analysis with specific antibodies to monocyte/macrophages and NK cell markers to determine the predominant cell in skin, and (3) by RT/PCR analysis of sorted cells to determine which cell type is making TGF-beta, and which isoform of TGF-beta predominates (beta1, beta2, beta3).
In Aim II, we will test the hypothesis by depleting or inhibiting homing to skin of monocytes and other immune cells using several strategies. The final readout is ability to prevent and reverse skin thickening. This animal model provides the unique opportunity to study monocyte/macrophage biology, basic immunology in an autoimmune fibrosing disorder, and to develop novel therapies for scleroderma and Scl GVHD.
| Zhang, Alexandra Y; Wu, Caiyun; Zhou, Lixin et al. (2006) Transduced monocyte/macrophages targeted to murine skin by UV light. Exp Dermatol 15:51-7 |
| Zhang, Yan; McCormick, Laura L; Gilliam, Anita C (2003) Latency-associated peptide prevents skin fibrosis in murine sclerodermatous graft-versus-host disease, a model for human scleroderma. J Invest Dermatol 121:713-9 |
| Zhang, Yan; Gilliam, Anita C (2002) Animal models for scleroderma: an update. Curr Rheumatol Rep 4:150-62 |
| Zhang, Yan; McCormick, Laura L; Desai, Snehal R et al. (2002) Murine sclerodermatous graft-versus-host disease, a model for human scleroderma: cutaneous cytokines, chemokines, and immune cell activation. J Immunol 168:3088-98 |
