The role of beta-defensins in allogeneic transplantation

防御素是由宿主编码的小抗菌肽，在抗微生物先天免疫中起重要作用。除了这些多肽的直接杀微生物作用外，β -防御素家族的成员显然具有促进局部先天炎症和全身适应性免疫反应的能力。这些功能似乎是通过它们作为单核细胞、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NOD基因的单核苷酸多态性（snp）与同种异体移植后患者严重的移植物抗宿主病（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定趋化因子受体（如CCR6和/或CCR2）相互作用在骨髓移植（BMT）中发挥重要作用。本研究的目的是鉴定和功能表征β -防御素和β -防御素受体在同种异体移植中的作用。同种异体骨髓移植后患者β -防御素诱导的NOD表达与NOD基因snp负相关的相关性将通过小鼠同种异体骨髓移植模型进行检验。此外，将评估β -防御素在异体移植后促进局部先天性炎症和全身适应性免疫反应的能力。我们将详细分析β -防御素转基因小鼠的表达，以表征β -防御素诱导的细胞和分子机制。作为一种翻译方法，我们将分析1)GvHD靶组织和BMT患者细支气管肺泡液中的人β -防御素表达，以及2)肝移植受者血清中的人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.