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MHC Class II Antigen Processing and Immune Recognition of Melanoma

MHC II 类抗原加工和黑色素瘤的免疫识别

基本信息

批准号：
8131116
负责人：
KAREN TARASZKA HASTINGS
金额：
$ 12.42万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8131116
关键词：
Address Antigens Autoantigens B-Lymphocytes Benign CD4 Positive T Lymphocytes Clinical Development Differentiation Antigens Disease Progression Dopachrome isomerase Epitopes Generations Goals Histocompatibility Antigens Class II Human Immune Immune response Immunization Immunotherapy In Vitro Interferon Type II Knock-out Lead MHC Class II Genes Mediating Membrane Proteins Metastatic Melanoma Monophenol Monooxygenase Mouse Strains Outcome Oxidoreductase Pathway interactions Patients Process Research Personnel Resistance Role Skin Cancer Spontaneous Remission Sulfhydryl Compounds T-Cell Receptor T-Lymphocyte Tissue Microarray Tissue Sample Transgenes Transgenic Mice Tumor Antigens Tyrosinase related protein-1 Vitiligo Wild Type Mouse antigen processing central tolerance chemotherapeutic agent disulfide bond human TYRP1 protein human disease in vivo melanocyte melanoma mouse Tyrp1 protein mouse model peripheral tolerance programs response tumor

项目摘要

DESCRIPTION (provided by applicant): Melanoma is the most lethal form of skin cancer and is resistant to existing chemotherapeutic agents. Immunotherapy holds great promise in the treatment of metastatic melanoma because melanoma antigens have been identified and patients generate T and B cell responses specific for these antigens which in some cases lead to spontaneous remission. Effective immunotherapy requires presentation of tumor antigens in the context of MHC class II for the activation of CD4+ T lymphocytes to generate and sustain the anti-tumor immune response. Additionally, since many melanoma antigens represent self-antigens present in benign melanocytes, a productive anti-tumor response requires the avoidance of tolerance mechanisms which suppress the immune response to self-antigens. We propose to address the role of MHC class II antigen processing components, in particular gamma-interferon inducible lysosomal thiol reductase (GILT), in the immune recognition of melanoma. Melanoma antigens including tyrosinase, tyrosinase-related protein (TRP)-1, TRP-2 and gplOO are likely to be substrates for lysosomal reduction by GILT, because these melanosomal membrane proteins are present in the MHC class II loading compartment and contain internal disulfide bonds. We have demonstrated that GILT is essential for the MHC class II processing of TRP-1 in vitro. In this proposal, we plan to explore the role of GILT in the development of tolerance to TRP-1 using a TRP-1-specific T cell receptor transgenic mouse model. We next plan to determine the role of GILT in the overall immune response to tyrosinase, TRP-1, TRP-2 and gplOO and to evaluate the role of GILT in protection from melanoma challenge by comparing in vivo immune responses in GILT-deficient compared to wild-type mouse strains. To explore the relevance in human disease, we will determine the expression of GILT in human melanoma. These studies will identify key features of antigen processing required to generate an immune response to melanoma and may aid in the understanding of mechanisms that lead to immune evasion. The long-term goal of these studies is to aid the development of effective immunotherapy for melanoma.

描述（由申请人提供）：黑色素瘤是最致命的皮肤癌形式，对现有的化疗药物具有耐药性。免疫疗法在转移性黑素瘤的治疗中具有很大的希望，因为黑素瘤抗原已经被鉴定并且患者产生对这些抗原特异性的T和B细胞应答，这在某些情况下导致自发缓解。有效的免疫治疗需要在MHC II类的背景下呈递肿瘤抗原，以激活CD 4 + T淋巴细胞，从而产生和维持抗肿瘤免疫应答。此外，由于许多黑素瘤抗原代表存在于良性黑素细胞中的自身抗原，因此有效的抗肿瘤应答需要避免抑制对自身抗原的免疫应答的耐受机制。我们建议解决MHC II类抗原加工成分，特别是γ-干扰素诱导的溶酶体硫醇还原酶（GILT），在黑色素瘤的免疫识别中的作用。包括酪氨酸酶、酪氨酸酶相关蛋白（TRP）-1、TRP-2和gplOO的黑素瘤抗原可能是GILT的溶酶体还原的底物，因为这些黑素体膜蛋白存在于MHC II类装载区室中并且含有内部二硫键。我们已经证明，GILT是必要的MHC II类TRP-1在体外加工。在这个提议中，我们计划使用TRP-1特异性T细胞受体转基因小鼠模型来探索GILT在TRP-1耐受性发展中的作用。我们接下来计划确定GILT在对酪氨酸酶、TRP-1、TRP-2和gplOO的总体免疫应答中的作用，并通过比较GILT缺陷型小鼠品系与野生型小鼠品系的体内免疫应答来评估GILT在保护免受黑素瘤攻击中的作用。为了探索在人类疾病中的相关性，我们将确定GILT在人类黑色素瘤中的表达。这些研究将确定产生对黑色素瘤的免疫应答所需的抗原加工的关键特征，并可能有助于理解导致免疫逃避的机制。这些研究的长期目标是帮助开发有效的黑色素瘤免疫疗法。