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

• 批准号: 8064251
• 负责人: I. Caroline Le Poole
• 金额: $ 34.57万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 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/8064251
• 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; 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; Life; 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

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）：通过将人类T细胞受体引入人类酪氨酸酶（H3T）的新型自发的自发性小鼠模型，并结合了相关的人HLA-A*0201分子的转基因表达。产生的H3TA2小鼠在青春期期间会产生幼体的快速，对称和进行性脱位，以及循环小鼠T细胞向色素细胞的细胞毒性，包括人HLA-A2+黑色素细胞和黑色素瘤细胞，独立于CD4或CD8表达。该模型非常适合设计干扰对黑素细胞的免疫反应的手段。在当前建议中要检验的假设是，鼓励调节性T细胞反应，同时干扰对炎症性Th17的贡献，在积极的脱位小鼠中可以停止白癜风的进展。初步数据表明，对于预防自身免疫反应的重要调节T细胞实际上缺乏人类白癜风患者的皮肤。同样，在小鼠模型中，可以在积极地吞噬小鼠的循环中检测到降低的Treg数量。当前提案的第一个目的是进一步表征和优化新的鼠标模型，以参考CD4+ T细胞子集和调节响应的发展和丰度，并通过将H3TA2模型进一步“人性化”该模型，以使SCF表达在K14促销病中表达表皮的小鼠杂交小鼠，以表达scdermis中的黑色素细胞。接下来，建议通过可追溯的FOXP3-P3-EGFP+ Treg的生育转移来增加Treg的丰度，并通过将天真T细胞的开发推向调节表型和功能，通过创建有利的细胞因子环境，主要在TGF-beta和降低的IL-6浓度下创建有良好的细胞因子环境，这些环境均与IL-6浓度降低，这些浓度均与文化相同，并在培养中及其内部，并在其内部进行了构图。在第三个也是最终目标下，调节T细胞将通过过表达相关的皮肤归巢受体（包括但不限于CCR-8和CLA和/或CCL-1）（例如CCL-1），将调节性T细胞重定向到皮肤，以便在发生降级的地方受到免疫抑制。 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 HLA-A2：H3T-A2鼠标。