Role of T cell TGFbeta signaling and IL-17 in allograft acceptance and fibrosis associated with chronic rejection.
Chronic allograft rejection (CR) is the main barrier to long-term transplant survival. CR is a progressive disease defined by interstitial fibrosis, vascular neointimal development, and graft dysfunction. The underlying mechanisms responsible for CR remain poorly defined. TGFbeta has been implicated in promoting fibrotic diseases including CR, but is beneficial in the transplant setting due to its immunosuppressive activity. To assess the requirement for T cell TGFbeta signaling in allograft acceptance and the progression of CR, we used mice with abrogated T cell TGFbeta signaling as allograft recipients. We compared responses from recipients that were transiently depleted of CD4(+) cells (that develop CR and express intragraft TGFbeta) with responses from mice that received anti-CD40L mAb therapy (that do not develop CR and do not express intragraft TGFbeta). Allograft acceptance and suppression of graft-reactive T and B cells were independent of T cell TGFbeta signaling in mice treated with anti-CD40L mAb. In recipients transiently depleted of CD4(+) T cells, T cell TGFbeta signaling was required for the development of fibrosis associated with CR, long-term graft acceptance, and suppression of graft-reactive T and B cell responses. Furthermore, IL-17 was identified as a critical element in TGFbeta-driven allograft fibrosis. Thus, IL-17 may provide a therapeutic target for preventing graft fibrosis, a measure of CR, while sparing the immunosuppressive activity of TGFbeta.
Faust
Susan M
SM
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
Lu
Guanyi
G
Marini
Bernard L
BL
Zou
Weiping
W
Gordon
David
D
Iwakura
Yoichiro
Y
Laouar
Yasmina
Y
Bishop
D Keith
DK
D000818:Animals; D002908:Chronic Disease; D005355:Fibrosis; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014184:Transplantation, Homologous
D020381:Interleukin-17; D016212:Transforming Growth Factor beta