Immunization Against Melanoma Differentiation Antigens

针对黑色素瘤分化抗原的免疫接种

• 批准号: 7317812
• 负责人: ALAN N. HOUGHTON
• 金额: $ 29.43万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-06-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7317812
• 关键词: Active Immunization; Address; Antigens; Area; Autoantigens; Autoimmunity; B-Lymphocytes; CD4 Positive T Lymphocytes; Cancer Immunology Science; Cells; Class; Differentiation Antigens; Family; Frequencies; Genes; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunization; Invasive; Lead; Libraries; Malignant Neoplasms; Measurable; Memory; Methods; Modeling; Monophenol Monooxygenase; Mus; Mutate; Mutation; Population; Role; Sorting - Cell Movement; T-Lymphocyte; Tumor Antigens; Tumor Immunity; base; cancer immunology function; combinatorial; immunogenic; improved; melanoma; mouse model; mutant; prevent; research study; response; tumor; tumor progression

DESCRIPTION (provided by applicant): Self antigens, in the form of differentiation antigens, and altered self antigens, in the form of mutations, are recognized on melanoma and other cancers by the immune system. Although mutations are an accepted basis for tumor-specific antigens, we and others have shown that recognition of differentiation antigens is also relevant to immunity to cancer. Recognition of these antigens presents problems, especially how one can overcome immune tolerance. We have used a mouse melanoma model to show that mice can be tolerant to the tyrosinase family of differentiation antigens. Tolerance can temporarily be broken by immunization with xenogeneic orthologues of antigen. However, our preliminary results suggest that a CD4+ cell population and B cells suppress immune responses to melanoma. Our first aim addresses the role of CD4+ and B cells n suppressing tumor immunity and memory responses, particularly to different action: antigens. Our next two aims turn to the consequences of immune recognition of mutations. We have developed methods to create combinatorial libraries of mutated differentiation antigens to address what types of mutations can lead to autoimmunity against the non-mutated parental antigen (aim 2) and what type of mutations can lead directly to tumor immunity (aim 3). In aim 4, we will continue to create more relevant mouse models of melanoma that develop endogenous invasive melanomas to study tumor immunity against differentiation and mutant antigens.

说明(申请人提供)：黑色素瘤和其他癌症的免疫系统识别以分化抗原形式的自身抗原和以突变形式的改变的自身抗原。虽然突变是肿瘤特异性抗原的公认基础，但我们和其他人已经证明，识别分化抗原也与癌症免疫力有关。对这些抗原的识别存在问题，特别是如何克服免疫耐受。我们已经使用了小鼠黑色素瘤模型来表明小鼠可以耐受酪氨酸酶家族的分化抗原。用异种抗原同源同源免疫可暂时打破耐受性。然而，我们的初步结果表明，CD4+细胞群和B细胞抑制了对黑色素瘤的免疫反应。我们的第一个目标是研究CD4+和B细胞在抑制肿瘤免疫和记忆反应中的作用，特别是对不同的作用：抗原。我们接下来的两个目标转向对突变的免疫识别的后果。我们已经开发了创建突变分化抗原组合库的方法，以解决哪些类型的突变可以导致对未突变的亲本抗原的自身免疫(目标2)，以及哪些类型的突变可以直接导致肿瘤免疫(目标3)。在目标4中，我们将继续建立更多相关的黑色素瘤小鼠模型，发展内源性侵袭性黑色素瘤，以研究肿瘤对分化和突变抗原的免疫。