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Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106
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-
1-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- 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-Ad molecules and class A
scavenger receptors), suggesting Ag presentation by cutaneous
macrophages in early fibrosing disease. Early elevated cutaneous mRNA
expression of TGF-1, but not TGF-2 or TGF-3, and
elevated C-C chemokines macrophage chemoattractant protein-1,
macrophage inflammatory protein-1
, and RANTES precede subsequent
skin and lung fibrosis. Therefore, TGF-1-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- prevent
Scl GVHD by effectively blocking the influx of monocyte/macrophages and
T cells into skin and by abrogating up-regulation of TGF-1, 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.
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