Absence of cutaneous TNFalpha-producing CD4+ T cells and TNFalpha may allow for fibrosis rather than epithelial cytotoxicity in murine sclerodermatous graft-versus-host disease, a model for human scleroderma.

Graft-versus-host disease (GVHD) is a complication of hematopoietic cell transplantation and is a major source of morbidity and mortality. Two main forms of GVHD occur: cytotoxic GVHD (Cyt GVHD), in which TNFalpha is a critical cytokine in epithelial injury, and sclerodermatous GVHD (Scl GVHD), in which TGFbeta plays a major role in fibrosis. To understand the critical early events in GVHD and scleroderma, we are studying a murine model that uses differences in minor histocompatibility antigens to generate Scl GVHD. We asked the question: what is the immune environment in this model that promotes fibrosis rather than the epithelial injury of Cyt GVHD? We found that in Scl GVHD, cutaneous CD4+ T cells produced IFNgamma and IL-2 but not TNFalpha, also absent by gene array analysis. The role of cutaneous CD4+ T cells in Scl GVHD may not be an active process through production of TGFbeta, but may rather be a passive one due to lack of antigen-presenting cell (APC) support for CD4+ T cells and failure to produce TNFalpha, a potent inhibitor of TGFbeta-induced fibrosis as well as inducer of keratinocyte apoptosis. These APC-T cell interactions and the cytokine environment promote fibrosis rather than cytotoxic epithelial injury in skin in Scl GVHD.