Development of a novel lymphocyte engineering approach for treatment of vitiligo

项目总结： 白癜风是一种常见的皮肤脱色素疾病，估计患病率为1%~4%。 全世界。白癜风的典型特征是无鳞的白色斑点，边缘明显锐利。 单侧分布在患者皮肤上，由皮肤黑素细胞系统性破坏所致。它有一个 对患者的生活产生了重大的生理和心理影响。尽管多个机制可以 共同促进白癜风的发展，越来越多的人达成共识，认为自身免疫反应在 在这一过程中发挥关键作用。越来越多的证据表明，自身反应性CD8+T细胞既是必要的，也是 足以破坏白癜风皮损中的功能性黑素细胞。 白癜风的治疗仍然是皮肤科医生面临的最困难的挑战之一。大致 40%的患者在治疗后第一年内复发。细胞与基因治疗 为各种其他晚期或致残性疾病提供了一种有前途的治疗方法。领养 工程淋巴细胞的转移，如嵌合抗原受体(CAR)T细胞，已经显示出巨大的 治疗恶性血液病取得成功。CAR T细胞已经被设计成针对激活的 心肌成纤维细胞与心脏纤维化和自身抗体产生的B细胞可能用于治疗天疱疮 俗气的人。然而，使用CAR T的治疗与全身性增加相关，有时甚至是致命的。 细胞因子毒性。在这一点上，自然杀伤(NK)细胞是强大的先天免疫效应细胞。NK细胞可以 不攻击健康的自身组织，也不会诱导炎性细胞因子风暴作为T细胞，使其能够 作为癌症以外的许多人类疾病的更安全的采用细胞疗法的潜在应用。的目标是 这项探索性的建议将检验汽车NK细胞工程治疗癌症的耐人寻味的可能性 白癜风。具体地说，我们计划测试一款基于β2微球蛋白的汽车设计，并与外源 不同黑素细胞抗原在工程化NK细胞中的表达我们假设自我的过度表达 融合了变性信号域的抗原可以通过工程化的 含有CAR-β2-微球蛋白的MHC I复合体，可导致自我反应性的识别和破坏 CD8+T细胞。我们的研究将为白癜风的治疗定义一个新的范例，并为 应用CAR-NK平台治疗其他涉及自身反应性T细胞的自身免疫性疾病

Project Summary: Vitiligo is a common skin depigmentation disorder with an estimated prevalence of 1~4% of the population worldwide. Vitiligo is phenotypically characterized by non-scaly, white macules with distinct sharp margins distributed unilaterally on the patients’ skin, caused by systematic destruction of skin melanocytes. It has a significant impact on the patients’ life both biologically and psychologically. Although multiple mechanisms may jointly contribute to the development of vitiligo, there is a growing consensus that autoimmune response plays a key role in this process. Mounting evidence suggest that self-reactive CD8+ T cells are both necessary and sufficient for destruction of functional melanocytes in vitiligo lesions. The treatment of vitiligo remains one of the most difficult challenges for dermatologists. Approximately 40% of patients have relapse of the disease within the first year after the treatment. Cell and gene therapy provide a promising therapeutic approach for a variety of otherwise terminal or disabling diseases. Adoptive transfer of engineered lymphocytes, such as chimeric antigen receptor (CAR) T cells has shown tremendous success in treatment of hematologic malignancies. CAR T cells have been engineered to target activated myofibroblasts for cardiac fibrosis and autoantibody-producing B cells for potential treatment of pemphigus vulgaris. However, treatment with CAR T is associated with severe and sometimes lethal increases in systemic cytokine toxicity. In this regard, natural killer (NK) cells are powerful innate immune effectors cells. NK cells do not attack healthy self-tissues, nor do they induce the inflammatory cytokine storm as T cells, enabling their potential application as a safer adoptive cell therapy for many human diseases beyond cancer. The objective of this exploratory proposal will be to examine the intriguing possibility of CAR NK cell engineering for treatment of vitiligo. Specifically, we plan to test a β2-microglobulin-based CAR design in conjunction with exogenous expression of different melanocyte antigens in engineered NK cells. We posit that overexpression of the self- antigen with a fusion of degron signal domain can lead to efficient antigen presentation through the engineered MHC I complex containing CAR- β2-microglobulin, which can lead to recognition and destruction of self-reactive CD8+ T cells. Our study will define a novel paradigm for vitiligo treatment and lay the essential groundwork for treatment of other autoimmune disease involving self-reactive T cells with CAR-NK platform.