The role of beta-defensins in allogeneic transplantation

β-防御素是由宿主编码的小分子抗菌肽，在天然免疫中起重要作用。除了这些多肽的直接杀微生物作用之外，很明显β-防御素家族的成员具有促进局部先天性炎症和全身适应性免疫应答的能力。这些功能似乎是由它们作为单核细胞、肥大细胞、APC和淋巴细胞的趋化因子和激活剂的能力介导的。有趣的是，几种β防御素的表达是由细胞内模式识别受体（NOD）诱导的，而同时NOD基因中的单核苷酸多态性（SNP）与同种异体移植后患者的严重移植物抗宿主病（GvHD）和较高的移植相关死亡率相关。我们假设β-防御素表达通过与特异性趋化因子受体（例如CCR 6和/或CCR 2）相互作用在骨髓移植（BMT）中起重要作用。本研究的目的是确定和功能特性的β-防御素和β-防御素受体在同种异体移植中的作用。将使用小鼠中的同种异体骨髓移植模型来测试同种异体移植后在患者中观察到的NOD的β-防御素诱导的表达与NOD基因中SNP的负相关性的相关性。此外，将评估β-防御素促进同种异体移植后局部先天性炎症和全身适应性免疫应答的能力。将详细分析β-防御素表达的转基因小鼠，以表征β-防御素诱导的细胞和分子机制。作为转化方法，将分析1）在BMT患者的GvHD靶组织和细支气管肺泡液中，和2）在肝移植受体的血清中的人β-防御素表达。

Beta-defensins are small antimicrobial peptides encoded by the host playing an important role in antimicrobial innate immunity. In addition to the direct microbicidal effects of these polypeptides it became evident that members of the beta-defensin family have the capacity to promote local innate inflammatory and systemic adaptive immune responses. These functions seem to be mediated by their ability to act as chemokines and activators of monocytes, mast cells, APCs, and lymphocytes. Interestingly, the expression of several betadefensins is induced by intracellular pattern recognition receptors (NODs), while at the same time single nucleotide polymorphisms (SNPs) in NOD genes are associated with severe graft versus host disease (GvHD) and higher transplantation-related mortality in patients after allogeneic transplantation. We assume that beta-defensin expression plays an important role in bone marrow transplantation (BMT) by interacting with specific chemokine receptors (e.g. CCR6 and/or CCR2). The aim of this study is to identify and functionally characterize the role of beta-defensins and beta-defensin receptors in allogeneic transplantation. The correlation of beta-defensininduced expression by NODs and the negative association of SNPs in NOD genes observed in patients after allogeneic transplantation will be tested using allogeneic bone marrow transplantation models in mice. Furthermore, the ability of beta–defensins to promote local innate inflammatory and systemic adaptive immune responses after allogeneic transplantation will be evaluated. Mice transgenic for beta-defensin expression will be analyzed in detail in order to characterize the cellular and molecular mechanisms induced by beta-defensins. As a translational approach, human beta-defensin expression will be analyzed 1) in GvHD target tissues and in bronchioalveolar fluid of BMT patients, and 2) in serum of liver transplant recipients.