Development of a novel lymphocyte engineering approach for treatment of vitiligo

开发治疗白癜风的新型淋巴细胞工程方法

• 批准号: 10640098
• 负责人: Xiaoyang Wu
• 金额: $ 18.04万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-07 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10640098
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Adult; Affect; Aftercare; Antigen Presentation; Antigens; Appearance; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Autologous; B-Lymphocytes; Biology; CD8-Positive T-Lymphocytes; Cell Line; Cell Therapy; Cell Transplantation; Cells; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; Consensus; DNA; Dermatologist; Development; Disease; Dopachrome isomerase; Effector Cell; Engineering; Future; Hematologic Neoplasms; Immune; Immune Tolerance; Immunization; Immunosuppressive Agents; In Vitro; Inflammatory; Infusion procedures; Janus kinase; Knock-in; Lesion; Life; Light; Lymphocyte; MHC Class I Genes; Malignant Neoplasms; Melanoma Cell; Modeling; Mus; Myofibroblast; Natural Killer Cells; Oral; Pathogenesis; Patients; Pemphigus Vulgaris; Pharmacologic Substance; Phenotype; Phototherapy; Play; Population; Prevalence; Process; Property; Quality of life; Recurrent disease; Regulatory T-Lymphocyte; Relapse; Research; Signal Transduction; Skin; Social Interaction; T-Cell Receptor; T-Lymphocyte; Terminal Disease; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Treatment Efficacy; United States; Vitiligo; autoreactive T cell; beta-2 Microglobulin; chimeric antigen receptor; chimeric antigen receptor T cells; coronary fibrosis; cytokine; cytokine release syndrome; cytotoxicity; design; disabling disease; engineered NK cell; experience; gene therapy; genome editing; gp100 Antigen; human disease; in vivo; melanocyte; melanoma; novel; overexpression; psychologic; response; self esteem; skin disorder; success; therapeutically effective

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.

项目概要： 白癜风是一种常见的皮肤色素脱失性疾病，估计患病率为1~4% 国际吧白癜风的表型特征是无鳞、白色斑点，边缘明显锐利 单侧分布于患者皮肤，由皮肤黑素细胞的系统性破坏引起。它有一个 对患者的生理和心理生活产生重大影响。虽然多种机制可能 共同促进白癜风的发展，有一个越来越多的共识，即自身免疫反应发挥了重要作用。 在这个过程中的关键作用。越来越多的证据表明，自身反应性CD 8 + T细胞是必要的， 足以破坏白癜风病变中的功能性黑素细胞。 白癜风的治疗仍然是皮肤科医生最困难的挑战之一。约 40%的患者在治疗后的第一年内复发。细胞和基因治疗 为多种其他终末期或致残性疾病提供了一种有前途的治疗方法。养父 工程化淋巴细胞，如嵌合抗原受体（CAR）T细胞的转移已经显示出巨大的 在治疗血液恶性肿瘤方面取得成功。CAR T细胞已经被工程化以靶向激活 用于心脏纤维化的肌成纤维细胞和用于天疱疮的潜在治疗的自身抗体产生B细胞 普通的然而，CAR T治疗与严重的，有时是致命的全身性炎症增加有关。 细胞因子毒性在这方面，自然杀伤（NK）细胞是强大的先天免疫效应细胞。NK细胞确实 不攻击健康的自身组织，也不像T细胞那样诱导炎症细胞因子风暴， 作为更安全的过继细胞疗法用于癌症以外的许多人类疾病的潜在应用。的目标 这一探索性的建议将是研究CAR NK细胞工程治疗的有趣的可能性， 白癜风具体来说，我们计划测试基于β2-微球蛋白的CAR设计与外源性 不同黑素细胞抗原在工程化NK细胞中的表达。我们认为过度的自我- 具有降解决定子信号结构域融合的抗原可以通过工程化的 含有CAR- β2-微球蛋白的MHC I复合物，可导致识别和破坏自身反应性 CD 8 + T细胞。我们的研究将为白癜风治疗定义一个新的范例，并为以下方面奠定必要的基础： 用CAR-NK平台治疗涉及自身反应性T细胞的其他自身免疫性疾病。