Wang Shuang, Jiang Jifu, Guan Qiunong, Lan Zhu, Wang Hao, Nguan Christopher Y C, Jevnikar Anthony M, Du Caigan
Department of Medicine, The University of Western Ontario, London, ON, Canada.
Transpl Immunol. 2008 May;19(2):93-102. doi: 10.1016/j.trim.2008.03.004. Epub 2008 Apr 28.
Regulatory T (Treg) cells are the immune suppressors in the maintenance of immune homeostasis and tolerance to self and non-self antigens, and may have therapeutic potential in the treatment of transplant rejection in patients. However, Treg cell development and action are poorly understood in transplantation. In this study, the association of CD4(+)Foxp3(+) infiltrates within renal allograft tissue with graft survival was investigated in a mouse model.
Kidney donors from C57BL/6J mice (H-2(b)) were transplanted to bilaterally nephrectomized Balb/c recipient mice (H-2(d)). Treg cells were examined with FACS and immunohistochemical staining.
Here we showed that without any immunosuppressive regimen, kidney allografts were mostly rejected from 20 to 60 days after transplantation. During the progression of allograft rejection Foxp3(+) Treg phenotype infiltrates were significantly diminished, while intragraft expression of TGF-beta1, IL-6, IL-17 and IL-23 was up-regulated. The regulatory function of CD4(+)CD25(+) infiltrates was confirmed by their suppressive activity in mixed lymphocyte reaction. Further in vitro studies indicated that primary renal tubular epithelial cell (TEC) cultures produced high levels of IL-6 in response to allogeneic lymphocyte or IL-17 stimulation, and neutralization of IL-6 increased CD4(+)CD25(+)Foxp3(+) cells in co-cultures with TEC.
Diminution of Foxp3(+) Treg infiltrates associates with renal allograft rejection, and neutralization of IL-6 activity enhances Foxp3(+) Treg cell differentiation. Our findings suggest that increase in intragraft IL-6 may down-regulate infiltrating Foxp3(+) Treg cells.
调节性T（Treg）细胞是维持免疫稳态以及对自身和非自身抗原产生耐受性的免疫抑制细胞，在治疗患者移植排斥反应方面可能具有治疗潜力。然而，在移植过程中，Treg细胞的发育和作用尚不清楚。在本研究中，我们在小鼠模型中研究了肾移植组织中CD4(+)Foxp3(+)浸润细胞与移植物存活之间的关系。
将C57BL/6J小鼠（H-2(b)）的肾脏供体移植到双侧肾切除的Balb/c受体小鼠（H-2(d)）体内。通过流式细胞术（FACS）和免疫组织化学染色检测Treg细胞。
我们发现，在没有任何免疫抑制方案的情况下，肾移植在移植后20至60天大多被排斥。在移植排斥反应过程中，Foxp3(+) Treg表型浸润细胞显著减少，而移植组织内转化生长因子-β1（TGF-β1）、白细胞介素-6（IL-6）、白细胞介素-17（IL-17）和白细胞介素-23（IL-23）的表达上调。CD4(+)CD25(+)浸润细胞的调节功能通过其在混合淋巴细胞反应中的抑制活性得到证实。进一步的体外研究表明，原代肾小管上皮细胞（TEC）培养物在同种异体淋巴细胞或IL-17刺激下产生高水平的IL-6，并且在与TEC共培养时，中和IL-6可增加CD4(+)CD25(+)Foxp3(+)细胞。
Foxp3(+) Treg浸润细胞减少与肾移植排斥反应相关，中和IL-6活性可增强Foxp3(+) Treg细胞分化。我们的研究结果表明，移植组织内IL-6的增加可能下调浸润的Foxp3(+) Treg细胞。
