Scleroderma is a chronic autoimmune disease characterized by fibrosis of organs and skin, due to upregulated synthesis of collagen by fibroblasts. There is no effective treatment for scleroderma to date. We are using murine sclerodermatous graft versus host disease (Scl GVHD) to model early scleroderma, which may be more amenable to therapy. In this model, we can generate measurable (up to 40% thicker) skin thickening within 21-28 days post bone marrow transplantation in mice with Scl GVHD. We and others have shown that in scleroderma and in early inflammatory Scl GVHD, the chemokine macrophage chemotactic protein-1 (MCP-1), an infiltrating monocyte/macrophage cell population and the cytokine transforming growth factor-beta TGF-beta are major players. We have also prevented murine Scl GVHD with early administration of a specific inhibitor of TGF-beta, latency-associated peptide (LAP) in vivo. In later fibrosing disease, inflammation subsides, and the fibroblasts are thought to have a permanently altered phenotype of unregulated collagen synthesis. The triggers for the switch from early reversible inflammatory disease and later noninflammatory fibrotic disease are not known. We hypothesize that the unique cutaneous environment in early inflammatory fibrosis involves cross talk between immune cells and fibroblasts. Critical fibroblast signals are required for immune cells to home to skin and become activated, and critical immune signals are required to produce an irreversible fibroblast phenotype. We plan to examine the cross talk between immune cells and fibroblasts in the following studies that are focused on cutaneous dendritic cells as initiators of the immune response, monocyte/macrophages and MCP-1.
Aim 1 : Immune cell studies. A. When can LAP no longer prevent or reverse skin fibrosis? This will establish """"""""reversible"""""""" versus """""""" irreversible"""""""" disease clinically. B. What are the effects of interventions stimulating (Fit3 ligand) or inhibiting (CTLA41g) dendritic cells, which are essential to initiate an immune response? C. What are the effects of monocyte/ macrophage interventions? Can we still generate Scl GVHD with macrophage-depleted bone marrow or by depleting macrophages in vivo after BMT? Can we generate Scl GVHD in MCP-1 knockout mice? Aim II. Fibroblast studies. A. Do cutaneous fibroblasts secrete immunomodulatory molecules (particularly MCP-1) in early inflammatory Scl GVHD? Can we inhibit fibroblast MCP-1 with interference RNA (RNAi) and block activation of immune cells and an altered fibroblast phenotype in vitro? B. What immunologic triggers are related to the excessive and persistent secretion of collagen by fibroblasts? Is SMAD dysregulation a critical event? Do clones of cells resistant to apoptosis explain the irreversible fibroblast phenotype? Are increased numbers of myofibroblasts generated in Scl GVHD that signal the onset of irreversible fibrosis? We are one of the few laboratories using this valuable model for scleroderma. We have the expertise in cutaneous immunobiology, and in dendritic cell and monocyte/macrophage biology. We are ideally suited to carry out this project to examine the cross talk between immune cells and fibroblasts in fibrosing disease, an entirely new and exciting area of research in scleroderma research. Developing more effective diagnostic tools and immunomodulatory therapies for early scleroderma is the ultimate goal of this research.
| Sung, Joanne J; Chen, Tina S; Gilliam, Anita C et al. (2011) Clinicohistopathological correlations in juvenile localized scleroderma: studies on a subset of children with hypopigmented juvenile localized scleroderma due to loss of epidermal melanocytes. J Am Acad Dermatol 65:364-373 |
| Gilliam, Anita C; Mullen, Renata H; Oviedo, Gina et al. (2009) Isolated benign primary cutaneous plasmacytosis in children: two illustrative cases. Arch Dermatol 145:299-302 |
| Lucas, Chere R; Korman, Neil J; Gilliam, Anita C (2009) Granulomatous periorificial dermatitis: a variant of granulomatous rosacea in children? J Cutan Med Surg 13:115-8 |
| Ali, Saba M; Gilliam, Anita C; Brodell, Robert T (2008) Sarcoidosis appearing in a tattoo. J Cutan Med Surg 12:43-8 |
| Miedler, John D; Kristjansson, Arni K; Gould, Jennifer et al. (2008) Pagetoid reticulosis in a 5-year-old boy. J Am Acad Dermatol 58:679-81 |
| Patel, Rishi R; Kirkland, Eugene B; Nguyen, Dennis H et al. (2008) Erythema nodosum in association with newly diagnosed hairy cell leukemia and group C streptococcus infection. Am J Dermatopathol 30:160-2 |
| Torres, Gisela; Behshad, Ramona; Han, Amy et al. (2008) ""I forgot to shave my hands"": A case of spiny keratoderma. J Am Acad Dermatol 58:344-8 |
| Chang, Timothy T; Behshad, Ramona; Brodell, Robert T et al. (2008) A male infant with anhidrotic ectodermal dysplasia/immunodeficiency accompanied by incontinentia pigmenti and a mutation in the NEMO pathway. J Am Acad Dermatol 58:316-20 |
| Han, Amy; Kristjansson, Arni K; Gilliam, Anita C et al. (2008) Pigmented olfactory neuroblastoma: a CD56-positive mimic of melanoma. Arch Dermatol 144:270-2 |
| Kristjansson, Arni K; Poulos, Georgann A; Chang, Timothy et al. (2008) Unusual flexural drug reaction with epidermal pustules associated with adalimumab treatment. J Am Acad Dermatol 58:S108-9 |
Showing the most recent 10 out of 21 publications
