Prolonged survival of allografts induced by mycobacterial Hsp70 is dependent on CD4+CD25+ regulatory T cells.
Prolonged survival of allografts induced by mycobacterial Hsp70 is dependent on CD4+CD25+ regulatory T cells.
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DOI：
10.1371/journal.pone.0014264
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发表时间：
2010-12-08
期刊：
影响因子：
3.7
通讯作者：
Bonorino C
中科院分区：
文献类型：
--
作者：
Borges TJ;Porto BN;Teixeira CA;Rodrigues M;Machado FD;Ornaghi AP;de Souza AP;Maito F;Pavanelli WR;Silva JS;Bonorino C
热休克蛋白（Hsps）是一种具有免疫调节特性的应激诱导蛋白。结核分枝杆菌的Hsp70 （TBHsp70）已被证明对啮齿动物自身免疫性关节炎模型具有抗炎作用，并且证明其保护作用依赖于白细胞介素-10 （IL-10）。我们之前观察到，TBHsp70抑制树突状细胞（dc）的成熟，并诱导这些细胞和滑液细胞产生IL-10。我们研究了TBHsp70是否可以抑制同种异体移植系统（移植的同种异体黑色素瘤和正常的同种异体皮肤移植）中的同种异体移植排斥反应。在这两种系统中，用TBHsp70治疗可显著抑制移植物的排斥反应，并与调节性T细胞（Tregs）募集相关。这种作用不是肿瘤介导的，因为在无肿瘤小鼠中注射TBHsp70诱导引流淋巴结中Tregs的增加，抑制淋巴结T细胞的增殖和增加IL-10的产生。最后，TBHsp70抑制同种异体皮肤移植急性排斥反应，使用单克隆抗体消耗Tregs完全消除这种作用。我们提出了该蛋白在移植排斥系统中免疫抑制作用的第一个证据，使用一种创新的方法-将移植物组织浸泡在TBHsp70溶液中而不是注射蛋白质。此外，这是第一个证明TBHsp70免疫抑制作用依赖Treg细胞的研究。这一发现与阐明TBHsp70的免疫调节机制有关。我们认为该蛋白不仅可用于慢性炎症性疾病，也可用于器官移植管理。
Heat shock proteins (Hsps) are stress induced proteins with immunomodulatory properties. The Hsp70 of Mycobacterium tuberculosis (TBHsp70) has been shown to have an anti-inflammatory role on rodent autoimmune arthritis models, and the protective effects were demonstrated to be dependent on interleukin-10 (IL-10). We have previously observed that TBHsp70 inhibited maturation of dendritic cells (DCs) and induced IL-10 production by these cells, as well as in synovial fluid cells. We investigated if TBHsp70 could inhibit allograft rejection in two murine allograft systems, a transplanted allogeneic melanoma and a regular skin allograft. In both systems, treatment with TBHsp70 significantly inhibited rejection of the graft, and correlated with regulatory T cells (Tregs) recruitment. This effect was not tumor mediated because injection of TBHsp70 in tumor-free mice induced an increase of Tregs in the draining lymph nodes as well as inhibition of proliferation of lymph node T cells and an increase in IL-10 production. Finally, TBHsp70 inhibited skin allograft acute rejection, and depletion of Tregs using a monoclonal antibody completely abolished this effect. We present the first evidence for an immunosuppressive role for this protein in a graft rejection system, using an innovative approach – immersion of the graft tissue in TBHsp70 solution instead of protein injection. Also, this is the first study that demonstrates dependence on Treg cells for the immunosuppressive role of TBHsp70. This finding is relevant for the elucidation of the immunomodulatory mechanism of TBHsp70. We propose that this protein can be used not only for chronic inflammatory diseases, but is also useful for organ transplantation management.
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