Modulating tolerance in a spontaneous mouse model of autoimmune vitiligo

调节自发性小鼠自身免疫性白癜风模型的耐受性

基本信息

批准号：
8134274
负责人：
I. Caroline Le Poole
金额：
$ 32.12万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8134274
关键词：
Address Adolescence Adolescent Development Adoptive Cell Transfers Adoptive Transfer Affect Affinity Animals Antigens Appearance Attention Autoimmune Process Autoimmune Responses Automobile Driving Blood Circulation Breeding CCR CD4 Positive T Lymphocytes CD8B1 gene Cells Chimeric Proteins Coin Crossbreeding Cytotoxic T-Lymphocytes Data Development Disease Progression Employee Strikes Environment Epidermis Equilibrium Exhibits HLA A*0201 antigen HLA-A2 Antigen Hair follicle structure Homing Human Immune Immune Tolerance Immune response Individual Infiltration Inflammatory Interleukin-6 Measures Mediating Melanoma Cell Modeling Monophenol Monooxygenase Mouse Strains Mus Patients Pattern Phenotype Pigments Population Property Proteins Regulatory T-Lymphocyte Skin Skin Pigmentation Spleen T cell response T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Thymus Gland Transforming Growth Factor beta Transgenic Mice Transgenic Organisms Vaccines Vitiligo chemokine cytokine cytotoxicity design effective therapy immunogenic lymph nodes melanocyte melanoma melanoma-associated antigen mouse model novel offspring overexpression prevent promoter public health relevance receptor response trafficking treatment strategy tyrosinase peptide

项目摘要

DESCRIPTION (provided by applicant): A new, spontaneous mouse model for autoimmune vitiligo has been created by introducing a human T cell receptor to human tyrosinase (h3T) into mice, combined with transgenic expression of the associated human HLA-A*0201 molecule. Resulting h3TA2 mice develop rapid, symmetrical and progressive depigmentation of the pelage during adolescence, and cytotoxicity of circulating mouse T cells towards pigment cells, including human HLA-A2+ melanocytes and melanoma cells, is independent of CD4 or CD8 expression. This model is very suited to devise means of interfering with an ongoing immune response to melanocytes. The hypothesis to be tested within the current proposal is that encouraging a regulatory T cell response while interfering with a contribution for inflammatory Th17 in actively depigmenting mice can halt the progression of vitiligo. Preliminary data show that regulatory T cells, important to prevent autoimmune responses, are virtually lacking from the skin of human vitiligo patients. Likewise, in the mouse model, a reduced number of Treg was detectable in the circulation of actively depigmenting mice. The first objective of the current proposal is to further characterize and optimize the new mouse model with reference to the development and abundance of CD4+ T cell subsets and regulatory responses, and by further 'humanizing' the model by crossbreeding the h3TA2 model to mice that express melanocytes in the epidermis as a consequence of SCF expression under the k14 promotor. Next it is proposed to increase the abundance of Treg in depigmenting mice by adoptive transfer of traceable FoxP3-EGFP+ Treg, and by driving the development of naive T cells towards a regulatory phenotype and function by creating a favorable cytokine environment primarily under increased TGF-beta and reduced IL-6 concentrations, which will be addressed both in culture, and within the mouse model. Under the 3rd and final aim, regulatory T cells will be redirected towards the skin by overexpressing relevant skin homing receptors including but not limited to CCR-8 and CLA and/or chemokines such as CCL-1, in order to favor immune inhibition there where depigmentation is taking place. PUBLIC HEALTH RELEVANCE: The project entitled 'modulating tolerance in a spontaneous mouse model of autoimmune vitiligo' addresses the lack of a regulatory T cell response in vitiligo by elevating Treg concentrations and supporting their skin homing properties while interfering with inflammatory Th17 within a newly generated mouse model that encompasses a human transgenic T cell receptor reactive with a tyrosinase peptide recognized in the context of HLA-A2: the h3T-A2 mouse.

描述（由申请人提供）：通过将人酪氨酸酶（h3T）的人T细胞受体引入小鼠体内，并结合相关人HLA-A*0201分子的转基因表达，创建了一种新的自发性自身免疫性白癜风小鼠模型。由此产生的 h3TA2 小鼠在青春期出现快速、对称和进行性的皮毛脱色，循环小鼠 T 细胞对色素细胞（包括人 HLA-A2+ 黑素细胞和黑素瘤细胞）的细胞毒性与 CD4 或 CD8 表达无关。该模型非常适合设计干扰对黑素细胞正在进行的免疫反应的方法。当前提案中待测试的假设是，在主动脱色小鼠中，鼓励调节性 T 细胞反应，同时干扰炎症 Th17 的贡献，可以阻止白癜风的进展。初步数据表明，人类白癜风患者的皮肤实际上缺乏对预防自身免疫反应很重要的调节性 T 细胞。同样，在小鼠模型中，在主动脱色小鼠的循环中可检测到 Treg 数量减少。当前提案的第一个目标是根据 CD4+ T 细胞亚群的发育和丰度以及调节反应进一步表征和优化新的小鼠模型，并通过将 h3TA2 模型与表达表达的小鼠杂交来进一步“人性化”该模型k14 启动子下 SCF 表达导致表皮中的黑色素细胞。接下来，建议通过过继转移可追踪的 FoxP3-EGFP+ Treg 来增加脱色小鼠中 Treg 的丰度，并通过主要在 TGF-β 增加的情况下创建有利的细胞因子环境来驱动幼稚 T 细胞向调节表型和功能发展。并降低 IL-6 浓度，这将在培养物和小鼠模型中得到解决。根据第三个也是最后一个目标，调节性 T 细胞将通过过度表达相关皮肤归巢受体（包括但不限于 CCR-8 和 CLA 和/或趋化因子，如 CCL-1）而被重定向到皮肤，以有利于那里的免疫抑制。色素脱失正在发生。公共健康相关性：该项目名为“调节自身免疫性白癜风自发小鼠模型的耐受性”，通过提高 Treg 浓度并支持其皮肤归巢特性，同时干扰新生小鼠体内的炎症性 Th17，解决白癜风中缺乏调节性 T 细胞反应的问题该模型包含与 HLA-A2 环境中识别的酪氨酸酶肽发生反应的人类转基因 T 细胞受体：h3T-A2 小鼠。