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.
Askew
David
D
Department of Dermatology, Case Western Reserve University, Cleveland, Ohio 44106-0528, USA. david.askew@case.edu
Zhou
Lixin
L
Wu
Cayun
C
Chen
Guofen
G
Gilliam
Anita C
AC
D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002450:Cell Communication; D016207:Cytokines / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D005355:Fibrosis; D006086:Graft vs Host Disease / Q000209:etiology*; D006801:Humans; D015603:Keratinocytes / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D012595:Scleroderma, Systemic / Q000209:etiology* / Q000628:therapy; D012867:Skin / Q000473:pathology; D013154:Spleen / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
D016207:Cytokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha