MECHANISMS OF ORAL TOLERANCE

口服耐受的机制

• 批准号: 6288958
• 负责人: BRIAN KELSALL
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6288958
• 关键词: Peyer's patches; T cell receptor; T lymphocyte; apoptosis; genetically modified animals; immune tolerance /unresponsiveness; immunoregulation; interferon gamma; interferon inducers; interleukin 12; laboratory mouse; lymph nodes; lymphocyte proliferation; oral administration; oral tolerance; ovalbumin; tissue /cell culture; transforming growth factors

The administration of soluble protein antigens via the oral route has been described as a means of inducing systemic immunological tolerance (oral tolerance). The induction of oral tolerance to self-proteins is being explored as a means to treat autoimmune disease in humans. This project is focused on determining the immunolgical mechanisms of oral tolerance induction with the hope that the information gained will result in the development of optimal stategies for oral tolerance induction for the treatment of autoimmune diseases. We have determined the importance of IL-12 for the regulation of two mechanisms of oral tolerance, clonal deletion due to Fas-mediated apoptosis, and the generation of TGF-beta-producing regulatory T cells. We demonstrated that the administration of anti-IL-12 to intact OVA TCR-transgenic mice fed OVA, enhanced both TGF-beta production and apoptosis of antigen- specific T cells. Furthermore, we showed that na?ve (CD4+/MEL-14hi) OVA-TCR-T cells stimulated with OVA-pulsed dendritic cells in vitro produce 4-5 fold higher amounts of TGF-beta when cultured with anti-IL- 12 or anti-IFN-gamma. IL-4 was not required for TGF-beta production, however, it appeared to indirectly enhance TGF-beta production by promoting the growth of TGF-beta producing cells. Taken together, our findings demonstrate that IL-12 and IFN-gamma are important negative regulators of TGF-beta production both in vivo and in vitro. They thus explain the ability of anti-IL-12 treatment to enhance oral tolerance as discussed above. Finally, it was determined that IL-10, primarily by its ability to suppress IL-12 production, and IL-7, primarily by its ability to induce IL-4 production in the T cell priming cultures, can enhance the differentiation of TGF-beta-producing T cells, and that TGF-beta itself can prime T cells for their own production. This latter fact is important, as it suggests that the low level production of TGF- beta by one cell type, such as a T cell, could have dramatic effects on TGF-beta production by another cell, such as a B cell or antigen- presenting cell, the end result being an environment with high levels of TGF-beta that acts to suppress inflammation. - tolerance, mucosal immunity, apoptosis, IL-12, IL-4, IL-10, TGF-beta, autoimmunity, Peyer?s patch, fas antigen

通过口服途径施用可溶性蛋白抗原已被描述为诱导全身免疫耐受（口服耐受）的一种手段。正在探索诱导对自身蛋白的口服耐受作为治疗人类自身免疫性疾病的一种手段。该项目的重点是确定口服耐受诱导的免疫机制，希望所获得的信息将导致开发用于治疗自身免疫性疾病的口服耐受诱导的最佳策略。我们已经确定了 IL-12 对于调节口服耐受的两种机制、Fas 介导的细胞凋亡导致的克隆缺失以及产生 TGF-β 的调节性 T 细胞的生成的重要性。我们证明，给饲喂 OVA 的完整 OVA TCR 转基因小鼠施用抗 IL-12 可以增强 TGF-β 的产生和抗原特异性 T 细胞的凋亡。此外，我们表明，当与抗IL-12或抗IFN-γ一起培养时，体外用OVA脉冲的树突状细胞刺激的幼稚(CD4+/MEL-14hi)OVA-TCR-T细胞产生4-5倍量的TGF-β。 IL-4 并不是 TGF-β 产生所必需的，然而，它似乎可以通过促进 TGF-β 产生细胞的生长来间接增强 TGF-β 的产生。综上所述，我们的研究结果表明，IL-12 和 IFN-γ 在体内和体外都是 TGF-β 产生的重要负调节因子。因此，他们解释了如上所述的抗IL-12治疗增强口服耐受性的能力。最后，确定IL-10（主要通过其抑制IL-12产生的能力）和IL-7（主要通过其在T细胞启动培养物中诱导IL-4产生的能力）可以增强产生TGF-β的T细胞的分化，并且TGF-β本身可以启动T细胞自身的产生。后一个事实很重要，因为它表明一种细胞类型（例如 T 细胞）低水平产生 TGF-β，可能会对另一种细胞（例如 B 细胞或抗原呈递细胞）产生 TGF-β 产生巨大影响，最终结果是形成具有高水平 TGF-β 的环境，从而抑制炎症。 - 耐受性、粘膜免疫、细胞凋亡、IL-12、IL-4、IL-10、TGF-β、自身免疫、派尔氏集结、fas 抗原