A therapeutic approach to enhance innate defense mechanisms against toxins and venoms - mast cell proteases to the rescue

一种增强针对毒素和毒液的先天防御机制的治疗方法 - 肥大细胞蛋白酶来救援

• 批准号: 125440970
• 负责人: Professor Dr. Martin Metz, Ph.D.
• 金额: --
• 依托单位: Klinik für Dermatologie, Venerologie und Allergologie (CCM)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/125440970?language=en
• 关键词: therapeutic; approach; enhance; innate; defense

Mast cells (MC) are important effector cells not only in allergic reactions but also in innate immune responses against bacteria. We and others have previously shown that the release of proinflammatory mediators from MC can combat bacterial infections by direct killing of the microbes and by recruitment of other inflammatory cells. Within the first funding period, we have identified MC as crucially important for the control of bacterial toxin mediated skin inflammation. Furthermore, we were able to show that MC can also control various endogenous and exogenous toxins such as neurotensin, vasoactive intestinal peptide and the venom from various snakes, scorpions, and Heloderma. As MC were able to dramatically reduce the toxicity associated with most of these toxins, we now aim to translate these findings into the human system, characterize the mechanisms of detoxification and to ultimately develop the basis for a pharmacologic approach for the treatment of local effects of toxins. Therefore, we will further develop and validate a model for toxicity testing without the need for vertebrates, identify and characterize the optimal MC derived protease and the cleavage specificity of these proteases and characterize in detail the inflammatory and anti-inflammatory potential of the respective proteases. With these investigations, we aim to provide proof of concept for a potential therapeutic approach using recombinant human proteases for the treatment of envenomations or other local intoxications.

肥大细胞(MC)是重要的效应细胞，不仅参与过敏反应，而且参与针对细菌的先天免疫反应。我们和其他人之前已经证明，MC释放的促炎介质可以通过直接杀死微生物和招募其他炎症细胞来对抗细菌感染。在第一个资助期内，我们已经确定MC对于控制细菌毒素介导的皮肤炎症至关重要。此外，我们还发现MC还可以控制各种内源性和外源性毒素，如神经降压素、血管活性肠肽和各种蛇、蝎子和螺旋体的毒液。由于MC能够显著降低与大多数这些毒素相关的毒性，我们现在的目标是将这些发现转化到人类系统中，表征解毒机制，并最终开发用于治疗毒素局部影响的药理学方法的基础。因此，我们将进一步开发和验证不需要脊椎动物的毒性测试模型，鉴定和表征最适的MC衍生蛋白酶和这些蛋白酶的切割特异性，并详细表征各自的炎症和抗炎潜力。通过这些研究，我们的目标是为使用重组人蛋白水解酶治疗毒液或其他局部中毒的潜在治疗方法提供概念证据。

项目成果

Mast cells orchestrate type 2 immunity to helminths through regulation of tissue-derived cytokines

• DOI: 10.1073/pnas.1112268109
• 发表时间: 2012-04-24
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Hepworth, Matthew R.;Danilowicz-Luebert, Emilia;Hartmann, Susanne
• 通讯作者: Hartmann, Susanne

Mast Cells Limit the Exacerbation of Chronic Allergic Contact Dermatitis in Response to Repeated Allergen Exposure

• DOI: 10.4049/jimmunol.1600236
• 发表时间: 2016-12-01
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Gimenez-Rivera, Vladimir-Andrey;Siebenhaar, Frank;Maurer, Marcus
• 通讯作者: Maurer, Marcus