with Chronic Rejection Allograft Acceptance and Fibrosis Associated Signaling and IL-17 in b Role of T Cell TGF

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. TGF (cid:1) 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 TGF (cid:1) signaling in allograft acceptance and the progression of CR, we used mice with abrogated T cell TGF (cid:1) signaling as allograft recipients. We compared responses from recipients that were transiently depleted of CD4 (cid:2) cells (that develop CR and express intragraft TGF (cid:1) ) with responses from mice that received anti-CD40L mAb therapy (that do not develop CR and do not express intragraft TGF (cid:1) ). Allograft acceptance and suppression of graft-reactive T and B cells were independent of T cell TGF (cid:1) signaling in mice treated with anti-CD40L mAb. In recipients transiently depleted of CD4 (cid:2) T cells, T cell TGF (cid:1) 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 TGF (cid:1) -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 TGF (cid:1) . The Journal of Immunology, 2009, the internal control, IL-2 (324 bp). Primers transgene forward and reverse were used to detect the transgenic allele (100 bp). CD4-DNR mice exhibit an autoimmune phenotype and immunopathology with age, result- ing in the development of multifocal inflammation best characterized by inflammatory bowel disease between 3 and 5 mo of age (10). To avoid potential complications of age-related autoimmunity, mice were transplanted at 6 wk of age and at the termination of each experiment the colons were examined macroscopically and histologically for autoimmune mani-festations. None of the mice used in this study exhibited an autoimmune phenotype. IL-17 (cid:2) / (cid:2) mice (46) were generated by Dr. Y. Iwakura (Uni-versity of Tokyo, Tokyo, Japan) and provided by Dr. W. Zou (University of Michigan, Ann Arbor, MI) in collaboration. All mice were housed under specific pathogen-free conditions in the Unit for Laboratory Animal Med- icine at the University of Michigan. These experiments were approved by the University Committee on Use and Care of Animals at the University of Michigan.