IMMUNIZATION AGAINST MELANOMA DIFFERENTIATION ANTIGENS

自身抗原，以分化抗原的形式，通常被免疫系统识别在黑色素瘤和其他癌症上。目前尚不清楚这些抗原的识别是否与癌症免疫力有关。酪氨酸酶家族已经成为人类癌症分化抗原的原型。事实上，我们对这些抗原或其他分化抗原的免疫识别了解不多。对这些抗原的识别存在许多问题。首先，面对免疫耐受，如何识别这些抗原。第二，即使识别是可能的，这是否能产生免疫排斥癌症。最后，如果对分化抗原的免疫可以排斥癌症，那么潜在的自身免疫后遗症是什么。我们使用了小鼠黑色素瘤模型来表明小鼠对酪氨酸酶家族抗原具有耐受性。可以通过改变抗原形式的免疫来打破耐受性。这可以产生抗体和CD8+T细胞反应，能够排斥肿瘤。免疫需要CD4+细胞。我们的目标是：1)研究肿瘤免疫如何从自身免疫中解偶联；2)研究CD4+T细胞反应在肿瘤免疫抗分化抗原中的作用；3)建立内源性侵袭性黑色素瘤小鼠模型，研究肿瘤进展过程中不同阶段对分化抗原的免疫作用。

Self-antigens, in the form of differentiation antigens, are commonly recognized on melanoma and other cancers by the immune system. It has been unclear whether recognition of these antigens is relevant to immunity to cancer. The tyrosinase family has emerged as prototypes of differentiation antigens on human cancers. We actually do not know very much about immune recognition of these antigens, or other differentiation antigens. Recognition of these antigens presents many problems. First, how is recognition of these antigens possible in the face of immune tolerance. Second, even when recognition is possible, can this generate immunity that can reject cancer. Finally, if immunity to differentiation antigens can reject cancer, what are the potential autoimmune sequelae. We have used a mouse melanoma model to show that mice can be tolerant to tyrosinase family antigens. Tolerance can be broken by immunization wit altered forms of antigen. This can generate antibody and CD8+ T cell responses that are capable of rejecting tumors. CD4+ cells are required for immunity. Our aims are to: 1) Investigate how cancer immunity is uncoupled from autoimmunity; 2) Investigate the role of CD4+ T cell responses in tumor immunity against differentiation antigens.; and 3) Develop mouse models that develop endogenous invasive melanomas and study immunity against differentiation antigens at different steps in tumor progression.