The role of beta-defensins in allogeneic transplantation

β-防御素在同种异体移植中的作用

• 批准号: 181826348
• 负责人: Professor Dr. Thomas Hehlgans
• 金额: --
• 依托单位: Institut für Immunologie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/181826348?language=en
• 关键词: role; beta; defensins; allogeneic; transplantation

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.

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。

项目成果

The Microbiome and Allogeneic Stem Cell Transplantation

• DOI: 10.1007/s40778-014-0006-9
• 发表时间: 2015-01
• 期刊: Current Stem Cell Reports
• 影响因子: 1.4
• 作者: Daniela Sporrer;A. Gessner;T. Hehlgans;P. Oefner;E. Holler

LTβR expression on hematopoietic cells regulates acute inflammation and influences maturation of myeloid subpopulations

造血细胞上的 LTβR 表达调节急性炎症并影响骨髓亚群的成熟

• DOI: 10.1177/1753425913497242
• 发表时间: 2013
• 期刊: Innate Immunity
• 影响因子: 3.2
• 作者: Wege AK;Huber B;Wimmer N;Männel DN;Hehlgans T.
• 通讯作者: Hehlgans T.

IL-10 from marginal zone precursor B cells controls the differentiation of Th17, Tfh and Tfr cells in transplantation tolerance.

边缘区前体B细胞的IL-10控制移植耐受性Th17，TFH和TFR细胞的分化。

• DOI: 10.1016/j.imlet.2016.01.002
• 发表时间: 2016-02
• 期刊: Immunology letters
• 影响因子: 4.4
• 作者: Lal G;Kulkarni N;Nakayama Y;Singh AK;Sethi A;Burrell BE;Brinkman CC;Iwami D;Zhang T;Hehlgans T;Bromberg JS
• 通讯作者: Bromberg JS

Human beta-defensin-2 and -3 enhance pro-inflammatory cytokine expression induced by TLR ligands via ATP-release in a P2X7R dependent manner.

• DOI: 10.1016/j.imbio.2016.06.006
• 发表时间: 2016-11
• 期刊: Immunobiology
• 影响因子: 2.8
• 作者: Daniel Wanke;Katrin Mauch-Mücke;E. Holler;T. Hehlgans

Antimicrobial Peptide Response to Blood Translocation of Bacterial DNA in Crohn's Disease Is Affected by NOD2/CARD15 Genotype

• DOI: 10.1002/ibd.21537
• 发表时间: 2011-08-01
• 期刊: INFLAMMATORY BOWEL DISEASES
• 影响因子: 4.9
• 作者: Gutierrez, Ana;Holler, Ernst;Frances, Ruben
• 通讯作者: Frances, Ruben