Anti-Inflammatory mechanisms of soybean-derived Bowman-Birk protease inhibitor

大豆鲍曼-伯克蛋白酶抑制剂的抗炎机制

基本信息

批准号：
7893121
负责人：
A.M. Rostami
金额：
$ 38.24万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7893121
关键词：
Accounting Address Adverse effects Affect Affinity Anti-Inflammatory Agents Anti-inflammatory Antigen Presentation Antigen Presentation Pathway Antigen-Presenting Cells Antigens Autoimmune Diseases Autoimmune Process Benign Prostatic Hypertrophy Binding Blood Circulation Bowman-Birk inhibitor CD4 Positive T Lymphocytes CD8B1 gene Cathepsin G Cell physiology Cells Chymase Clinical Cytokine Suppression Data Demyelinations Dendritic Cells Diabetes Mellitus Disease Disease Progression Elastases Experimental Models Human Immune Immune response Immune system In Vitro Inflammation Inflammatory Interleukin-10 Mediating Modeling Multiple Sclerosis Mus Nature Neuraxis Neurologic Onset of illness Oral Oral Leukoplakia Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Phase Play Prevention Production Proliferating Property Protease Inhibitor Proteins Publishing Resistance Rodent Model Role Serine Proteinase Inhibitors Site Soybeans Splenocyte T cell response T-Lymphocyte Testing Time To autoantigen Toxic effect Translating Treatment Protocols Trypsin Ulcerative Colitis Up-Regulation adaptive immunity antigen processing base chymotrypsin gastrointestinal system in vivo insight mast cell mouse model multicatalytic endopeptidase complex nervous system disorder neutrophil prevent public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Bowman-Birk Inhibitor (BBI) is an orally active serine protease inhibitor derived from soybeans. BBI concentrate (BBIC) is an extract of soybeans enriched in BBI. In human trials for non-neurological autoimmune disorders, BBIC has been shown to exert potent anti-inflammatory effects without associated toxicity. We have shown that in several rodent models oral BBI/BBIC dramatically reduced autoimmune inflammation of the central nervous system. It is of major significance that after disease onset, when clinical deficits have already developed, administration of BBI rapidly ameliorated clinical signs and prevented disease progression. This feature of BBI therapy is central to its suitability for treating patients who have already shown clinical signs of disease. Even though BBIC has been clinically tested, mechanisms of its anti-inflammatory action are poorly understood in both neurological and non-neurological autoimmune diseases. Here we propose to investigate effects of BBI on immune cells in vivo and in vitro using a mouse model of multiple sclerosis (MS) mediated predominantly by CD4+T cells, and a model of diabetes mediated predominantly by CD8+T cells. In specific aim 1 we will test the hypothesis that increase in IL-10 production is an important mechanism for anti-inflammatory effects of BBI in EAE. This hypothesis is based on our discovery that BBI induces IL-10 production by immune cells in vivo and in vitro. It has been shown that BBI inhibits antigen processing, but its effect on functions of antigen presenting cells is unknown. In aim 2 we will test the hypothesis that BBI suppresses antigen presentation. Thus far, there is no study that addresses direct effects of BBI on T cells. Taking in account the crucial role of T cells in adaptive immunity, in aim 3 we will test the hypothesis that BBI directly suppresses T cells. We expect that these studies will yield in depth insights into mechanistic aspects of anti-inflammatory actions of BBI, and facilitate its use as a supplementary treatment for MS, as well as other inflammatory conditions. Public Health Relevance: Bowman-Birk Inhibitor (BBI) is an orally active protease inhibitor from soybeans. In human trials for autoimmune disorders, BBI has been shown to have anti-inflammatory effects without associated toxicity. Even though BBI has already been clinically tested, mechanisms of its anti-inflammatory action are poorly understood. Here we propose to investigate effects of BBI on immune cells in experimental models of multiple sclerosis and diabetes. In our previous study we discovered that BBI increases production of interleukin 10 (IL-10). IL-10 has well known anti-inflammatory properties, and we will investigate if this molecule plays a role in beneficial effects of BBI. Published data and preliminary studies indicate that BBI has an effect on two crucial types of immune cells; so called antigen presenting cells and T cells. The second portion of this proposal is dedicated to mechanistic studies of effects that BBI has on these cells. We believe that these studies will provide in depth insights into anti-inflammatory actions of BBI, and facilitate its use as a supplementary treatment for inflammatory diseases.

描述（由申请人提供）：Bowman-Birk抑制剂（BBI）是一种来自大豆的口服丝氨酸蛋白酶抑制剂。 BBI浓缩物（BBIC）是富含BBI的大豆的提取物。在非神经学自身免疫性疾病的人体试验中，BBIC已被证明会发挥有效的抗炎作用而没有毒性。我们已经表明，在几种啮齿动物模型中，口服BBI/BBIC急剧减少了中枢神经系统的自身免疫性炎症。重要的是，疾病发作后的临床缺陷已经出现，BBI迅速改善临床体征并预防疾病进展。 BBI疗法的这一特征对于治疗已经显示出临床疾病迹象的患者的适用性至关重要。即使对BBIC进行了临床测试，在神经系统和非神经学自身免疫性疾病中，其抗炎作用的机制也很少了解。在这里，我们建议使用多发性硬化症（MS）的小鼠模型主要由CD4+T细胞介导的小鼠模型，并研究BBI对体内免疫细胞的影响，以及主要由CD8+T细胞介导的糖尿病模型。在特定目标1中，我们将测试以下假设：IL-10产生的增加是BBI在EAE中抗炎作用的重要机制。该假设是基于我们发现BBI在体内和体外诱导免疫细胞产生的IL-10。已经表明，BBI抑制抗原加工，但其对抗原呈递细胞功能的影响尚不清楚。在AIM 2中，我们将测试BBI抑制抗原表现的假设。到目前为止，尚无研究来解决BBI对T细胞的直接影响。考虑到T细胞在自适应免疫中的关键作用，在AIM 3中，我们将测试BBI直接抑制T细胞的假设。我们预计这些研究将深入了解BBI抗炎作用的机理方面，并促进其用作MS的补充治疗以及其他炎症条件。公共卫生相关性：Bowman-Birk抑制剂（BBI）是来自大豆的口服蛋白酶抑制剂。在人体自身免疫性疾病的试验中，BBI已被证明具有抗炎作用而没有毒性。即使BBI已经在临床上进行了测试，但其抗炎作用的机制知之甚少。在这里，我们建议研究BBI对多发性硬化和糖尿病实验模型中免疫细胞的影响。在我们先前的研究中，我们发现BBI增加了白介素10（IL-10）的产生。 IL-10具有众所周知的抗炎特性，我们将研究该分子在BBI的有益作用中起作用。已发表的数据和初步研究表明，BBI对两种关键类型的免疫细胞有影响。所谓的抗原呈递细胞和T细胞。该提案的第二部分致力于BBI对这些细胞的作用的机械研究。我们认为，这些研究将深入了解BBI的抗炎作用，并促进其用作炎症性疾病的补充治疗方法。