Faust Susan M, Lu Guanyi, Marini Bernard L, Zou Weiping, Gordon David, Iwakura Yoichiro, Laouar Yasmina, Bishop D Keith
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
J Immunol. 2009 Dec 1;183(11):7297-306. doi: 10.4049/jimmunol.0902446. Epub 2009 Nov 16.
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.
慢性同种异体移植排斥反应（CR）是长期移植存活的主要障碍。CR是一种以间质纤维化、血管内膜增生和移植物功能障碍为特征的进行性疾病。导致CR的潜在机制仍不清楚。转化生长因子β（TGFβ）被认为与包括CR在内的纤维化疾病的发生有关，但由于其免疫抑制活性，在移植环境中具有有益作用。为了评估T细胞TGFβ信号在同种异体移植接受和CR进展中的需求，我们将T细胞TGFβ信号缺失的小鼠作为同种异体移植受体。我们比较了短暂清除CD4(+)细胞（会发生CR并表达移植物内TGFβ）的受体的反应与接受抗CD40L单克隆抗体治疗（不会发生CR且不表达移植物内TGFβ）的小鼠的反应。在接受抗CD40L单克隆抗体治疗的小鼠中，同种异体移植的接受以及对移植物反应性T和B细胞的抑制与T细胞TGFβ信号无关。在短暂清除CD4(+) T细胞的受体中，T细胞TGFβ信号对于与CR相关的纤维化发展、长期移植物接受以及对移植物反应性T和B细胞反应的抑制是必需的。此外，白细胞介素-17（IL-17）被确定为TGFβ驱动的同种异体移植纤维化的关键因素。因此，IL-17可能为预防移植物纤维化（CR的一种表现）提供一个治疗靶点，同时保留TGFβ的免疫抑制活性。
