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

J Invest Dermatol. 2007 Aug;127(8):1905-14. doi: 10.1038/sj.jid.5700813. Epub 2007 Apr 12.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / physiology
  • Apoptosis
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Communication
  • Cytokines / genetics
  • Cytokines / physiology
  • Disease Models, Animal*
  • Fibrosis
  • Graft vs Host Disease / etiology*
  • Humans
  • Keratinocytes / pathology
  • Lymphocyte Activation
  • Mice
  • RNA, Messenger / analysis
  • Scleroderma, Systemic / etiology*
  • Scleroderma, Systemic / therapy
  • Skin / pathology
  • Spleen / immunology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / physiology*


  • Cytokines
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha