Contribution of T cells to immune complex-induced tissue damage

T 细胞对免疫复合物诱导的组织损伤的贡献

• 批准号: 242863856
• 负责人: Professor Dr. Ralf Joachim Ludwig
• 金额: --
• 依托单位: Klinik für Dermatologie, Allergologie und Venerologie (Hautklinik)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/242863856?language=en
• 关键词: Contribution; cells; immune; complex; induced

Autoimmune bullous dermatoses (AIBD) are characterized by autoantibodies against cutaneous structural proteins and mucocutaneous tissue injury. Despite improved therapeutic options, mortality of patients with AIBD is still significantly increased, which can be partially attributed to the extent of immunosuppressive therapy. Therefore and due to the rising incidence there is a clear and so far unmet medical need for the development of effective and save therapeutic strategies for these patients. In addition, the understanding of AIBD pathogenesis is far from complete. While the contribution of T cells to the loss of tolerance and maintenance of the autoimmune response has clearly been demonstrated, it remains unclear, if T cells contribute to the immune complex-induced, neutrophil-dependent tissue injury in AIBD. Interestingly, detailed investigation of the dermal leukocyte infiltration in patients with bullous pemphigoid, an AIBD with autoantibodies directed against type XVII collagen, clearly documented, that the vast majority (60%) of the inflammatory cells are CD3+ cells. We recently demonstrated an increased expression of CD3 in the skin of mice with experimental epidermolysis bullosa acquisita (EBA), an AIBD with autoantibodies directed against type VII collagen (COL7). Based on this observation, we addressed the functional contribution of T cells in experimental EBA induced by transfer of anti-COL7 antibodies into T cell-deficient and control mice. In this model, we observed a significant reduction of EBA severity in T cell deficient mice. Control experiments showed, that this effect was independent on an immune response against the transferred antibody, differences in neutrophil counts, or the mouse strain used. Based on these data, we here now aim to test the following hypothesis: (i) T cells modulate neutrophil-depended, immune complex-induced tissue damage, (ii) Different T cell subsets differentially modulate neutrophil-depended, immune complex-induced tissue damage; i.e. activated and/or Th17 T cells enhance, while Treg inhibit tissue injury, and (iii) Targeting different T cell subsets can be used therapeutically in AIBD. Given, that these assumptions can be experimentally validated, modulation of T cell subsets in AIBD may offer novel therapeutic options that target both the generation/maintenance of the loss of tolerance, as well as the autoantibody-induced, neutrophil-dependent tissue injury.

自身免疫性大胆皮肤病（AIBD）的特征是针对皮肤结构蛋白和粘膜皮肤组织损伤的自身抗体。尽管治疗方案提高了，但AIBD患者的死亡率仍然显着增加，这可以部分归因于免疫抑制治疗的程度。因此，由于发病率的上升，到目前为止，医疗需要开发有效并为这些患者节省治疗策略。另外，对AIBD发病机理的理解远非完整。尽管已经明确证明了T细胞对自身免疫反应的耐受性和维持的贡献，但尚不清楚T细胞是否有助于AIBD中的免疫复合物诱导的中性粒细胞依赖性组织损伤。有趣的是，对大胆的肺炎类动物的皮肤白细胞浸润的详细研究，该患者是一种针对第XVII型胶原蛋白的自身抗体的AIBD，清楚地证明，绝大多数炎性细胞（60％）是CD3+细胞。最近，我们证明了用实验性表皮溶液Accuisita（EBA）（EBA）的CD3表达增加，这是一种针对VII型胶原蛋白（COL7）的自身抗体的AIBD。基于这一观察结果，我们解决了通过将抗Col7抗体转移到T细胞缺陷和对照小鼠中引起的T细胞在实验EBA中的功能贡献。在此模型中，我们观察到T细胞缺陷小鼠的EBA严重程度显着降低。对照实验表明，这种作用独立于针对转移的抗体，中性粒细胞计数的差异或所使用的小鼠菌株的免疫反应。基于这些数据，我们现在旨在检验以下假设：（i）T细胞调节中性粒细胞抑制的，免疫复合物诱导的组织损伤，（ii）不同的T细胞子集对中性粒细胞 - 二甲基二甲状腺差异，免疫复合物诱导的组织损伤；即激活和/或Th17 T细胞增强，而Treg抑制组织损伤，并且（iii）靶向不同的T细胞亚群可以在AIBD中使用治疗。 鉴于这些假设可以经过实验验证，AIBD中T细胞子集的调节可能会提供新颖的治疗选择，以靶向耐受性丧失的产生/维持以及自身抗体诱导的中性粒细胞依赖性组织损伤。