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首页> 外文OA文献 >Mecanismos da modulação da expressão de MHC II e CD86 em células dendríticas pela DNAK e a diminuição da rejeição em transplantes de pele
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Mecanismos da modulação da expressão de MHC II e CD86 em células dendríticas pela DNAK e a diminuição da rejeição em transplantes de pele

机译：DNAK调节树突状细胞MHC II和CD86表达的机制及皮肤移植排斥反应的减少

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摘要

Dendritic cells (DCs) are the major antigen-presenting cells. They provide three main signals to fully activate T cells. Signal one is when the complex peptide:MHC (p:MHC) expressed by DC is recognized by T cell receptor; signal two is the expression of co-stimulatory molecules from the B7 family (CD80 and CD86). The third signal consists in the cytokines produced by DCs, which will bias the quality of T cell response. Once one of this signal is blocked/interrupted, T cells are not fully activated. T cells are involved in the eradication of pathogens, but also in the pathogenesis of several disorders and, strategies that modulate signal two are being used to treat these disorders. Novel therapies that inhibit the second signal (checkpoint blockade) or T cell modulation by these molecules have being used/tested to manage tumors, autoimmune disorders and transplant rejection. Our group demonstrated that the M. tuberculosis protein DnaK (prokaryote Hsp70) has an immunosuppressive role on DCs, and can suppress rejection in a murine skin allograft model. Nevertheless, the molecular mechanism involved in this response need to be further elucidated. In the present work, we demonstrated that the treatment of murine DC with DnaK could decrease the basal levels TNF-α, IFN-γ and MCP-1 produced by these cells. This modulation was concomitant with a downregulation of the transcription factors C/EBPβ and C/EBPδ in a TLR2-ERK-STAT3-IL-10-dependent way. Beyond the signal three, DnaK could also downregulate the expression of MHC II (signal one) and CD86 (signal theree) on DCs, through the induction of a molecule called MARCH1. We developed an-situ treatment of skin grafts with DnaK prior the transplant. We observed that this treatment prolongs allograft survival with a decreased alloimmunity, and this dependent on MARCH1.The molecular pathway TLR2-ERK-STAT3-IL-10 was required for MARCH1 induction by DnaK. Moreover, we found that DnaK modulates a specific skin migratory DC – the CD103+ DCs. This is the major subset involved in skin allograft rejection. We tested in which innate receptors DnaK could bind and found that DnaK could not bind directly on TLR2, but in the LOX-1 and Siglec-E receptor, in a LOX-1/Siglec-E/TLR2 complex. Finally, from the data obtained we patented a new formulation and method to treat allografts prior the transplantation. Thus, DnaK tolerizes dendritic cells through the modulation of the three signals required to activate T cells. We believe that consists an innovative strategy to treat inflammatory disorders, rejection, asthma and sepsis.
机译：树突状细胞（DC）是主要的抗原呈递细胞。它们提供了三个主要信号来完全激活T细胞。信号一是当DC表达的复合肽：MHC（p：MHC）被T细胞受体识别时;信号二是来自B7家族的共刺激分子（CD80和CD86）的表达。第三个信号由DC产生的细胞因子组成，这将使T细胞反应的质量发生偏差。一旦该信号之一被阻止/中断，T细胞就不会完全激活。 T细胞不仅可以消灭病原体，还可以参与多种疾病的发病机制，并且通过调节信号二的策略来治疗这些疾病。通过这些分子抑制第二信号（检查点封锁）或T细胞调节的新疗法已被使用/测试用于治疗肿瘤，自身免疫性疾病和移植排斥。我们的小组证明了结核分枝杆菌蛋白DnaK（原核生物Hsp70）对DC具有免疫抑制作用，并且可以抑制小鼠皮肤同种异体移植模型的排斥反应。尽管如此，涉及此反应的分子机制仍需进一步阐明。在目前的工作中，我们证明了用DnaK处理鼠DC可以降低这些细胞产生的基础水平TNF-α，IFN-γ和MCP-1。这种调节伴随着以TLR2-ERK-STAT3-IL-10-依赖性方式下调转录因子C /EBPβ和C /EBPδ。除了信号三之外，DnaK还可以通过诱导一种名为MARCH1的分子来下调DC上MHC II（信号一）和CD86（信号theree）的表达。我们在移植前开发了用DnaK进行皮肤移植的原位治疗。我们观察到这种治疗延长了同种异体移植物的存活，同种异体免疫力降低，这取决于MARCH1.DnaK诱导MARCH1需要分子途径TLR2-ERK-STAT3-IL-10。此外，我们发现DnaK可以调节特定的皮肤迁移DC – CD103 + DC。这是同种异体皮肤排斥反应的主要子集。我们测试了DnaK可以结合哪些先天受体，发现DnaK不能直接结合TLR2，而是结合在LOX-1 / Siglec-E / TLR2复合体的LOX-1和Siglec-E受体中。最后，从获得的数据中，我们获得了在移植前治疗同种异体移植物的新配方和方法的专利。因此，DnaK通过激活T细胞所需的三个信号的调节来耐受树突状细胞。我们认为，这是治疗炎性疾病，排斥反应，哮喘和败血症的创新策略。

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    Borges Thiago de Jesus;

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  • 年度 2015
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