Targeting IFN gamma and chemokines to treat vitiligo in a humanized mouse model

描述(申请人提供)：我的职业目标是更好地了解白癜风的自身免疫机制，利用动物模型开发新的治疗方法，并将这些治疗方法转化为人类患者。这个奖项提供的时间和支持将对我学习必要的技能，以产生白癜风的人源化小鼠模型，测试抗人类细胞因子和趋化因子阻断抗体作为新的治疗方法，并为未来的研究了解临床和转化性研究策略。在我的白癜风诊所所做的观察促使我假设皮肤来源的信号将T细胞招募到皮损皮肤。在我博士后培训期间开发的一种新的白癜风小鼠模型中，我发现依赖于干扰素-3的趋化因子对皮肤脱色素和T细胞募集至关重要。基于这些研究，我假设干扰素-3及其下游趋化因子是人类白癜风发生发展所必需的，并且干扰素-3-趋化素轴是新疗法的理想靶点。动物模型并不总是反映人类疾病的机制。为了弥合小鼠的基础研究和患者的临床试验之间的差距，需要建立一个有人体组织的白癜风模型。我的主要导师戴尔·格雷纳博士是具有人类免疫系统功能的人性化小鼠的先驱。移植到这个宿主上的人皮肤将完成一个完整的人类免疫皮肤轴，在这个轴上研究皮肤免疫。我们假设，这种人源化的小鼠将提供一个功能性的免疫皮肤轴，在临床研究之前，可以在这个轴上测试潜在的皮肤病新疗法。我的研究策略如下：具体目标1：建立并验证皮肤免疫系统功能相互作用的人源化小鼠模型。免疫缺陷小鼠将接受自体人类皮肤和外周血淋巴细胞。免疫皮肤轴的功能将通过特定皮肤的免疫挑战来验证。特定目的2：检测抗人干扰素-3、CXCL9、CXCL10和CXCR3的中和抗体，作为治疗人源化小鼠系统中白癜风的新方法。将在人源化的小鼠中诱发白癜风。人类干扰素-3-趋化素轴的成员将被封闭抗体中和，以确定它们是否是治疗白癜风的有效方法。未来的研究将在临床试验中测试这些抗体。本提案中的培训计划利用课程和强大的指导团队(Greiner、Harlan、Turka、Rothstein和Le Poole博士)，具有广泛的专业知识(人源化小鼠模型、自身免疫模型、自身免疫的翻译/临床研究、体内T细胞反应控制以及白癜风的基础/翻译研究)来填补我之前培训中的关键空白，以推进我的职业目标。这项提案将引入第一个具有完全免疫皮肤轴的小鼠模型，提供一个系统来研究人类免疫与皮肤的相互作用，并在人类环境中测试白癜风的新治疗方法。未来的研究将专注于将这些发现转化为临床研究，以便治疗这种毁灭性疾病的患者。

DESCRIPTION (provided by applicant): My career goal is to better understand the mechanisms of autoimmunity in vitiligo, develop new treatments using animal models, and translate these treatments to human patients. The time and support provided by this award will be critical for me to learn the skills necessary to generate a humanized mouse model of vitiligo, test anti-human cytokine and chemokine blocking antibodies as novel treatments, and gain an understanding of clinical and translational research strategies for future studies. Observations made in my vitiligo clinic prompted me to hypothesize that skin-derived signals recruit T cells to lesional skin. Using a new mouse model of vitiligo developed during my postdoctoral training, I discovered that IFN-3-dependent chemokines were critical for depigmentation and T cell recruitment to the skin. Based on these studies, I hypothesize that IFN-3 and downstream chemokines are required for the development of human vitiligo and that the IFN-3-chemokine axis is an ideal target for new treatments. Animal models do not always reflect human disease mechanisms. A vitiligo model with human tissues is needed to bridge the gap between basic studies in mice and clinical trials in patients. My primary mentor, Dr. Dale Greiner, is the pioneer of a humanized mouse with a functional human immune system. Human skin grafted onto this host will complete a fully human immune-skin axis in which to investigate skin immunity. We hypothesize that this humanized mouse will provide a functional immune-skin axis in which potential new therapies for skin diseases can be tested prior to clinical studies. My research strategy is as follows: Specific Aim 1: Generate and validate a humanized mouse model for skin-immune system functional interactions. Immunodeficient mice will receive autologous human skin and peripheral blood lymphocytes. The functionality of the immune-skin axis will be validated by skin-specific immune challenges. Specific Aim 2: Test neutralizing antibodies against human IFN-3, CXCL9, CXCL10, and CXCR3 as new treatments for vitiligo induced in the humanized mouse system. Vitiligo will be induced in humanized mice. Members of the human IFN-3-chemokine axis will be neutralized with blocking antibodies to determine if they are effective treatments for vitiligo. Future studies will test these antibodies in clinical trials. The training plan in this proposal takes advantage of coursework and a strong mentoring team (Drs. Greiner, Harlan, Turka, Rothstein, and Le Poole) with broad expertise (humanized mouse models, models of autoimmunity, translational/clinical research in autoimmunity, controlling T cell responses in vivo, and basic/translational research in vitiligo) to fill key gaps in my previous training to advance my career goals. This proposal will introduce the first mouse model with a fully immune-skin axis, providing a system to investigate human immune-skin interactions and test new treatments for vitiligo in a human environment. Future studies will focus on translating these findings to clinical studies in order to treat patients with this devastating disease.