IMMUNIZATION AGAINST MELANOMA DIFFERENTIATION ANTIGENS

自体抗原，以分化抗原的形式，通常在黑色素瘤和其他癌症中被免疫系统识别。目前还不清楚这些抗原的识别是否与癌症免疫有关。酪氨酸酶家族已成为人类癌症分化抗原的原型。实际上，我们对这些抗原的免疫识别，或其他分化抗原了解的并不多。识别这些抗原存在许多问题。首先，面对免疫耐受，如何识别这些抗原。其次，即使识别是可能的，它能产生免疫系统来拒绝癌症吗？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？我们使用小鼠黑色素瘤模型来证明小鼠可以耐受酪氨酸酶家族抗原。可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。CD4+细胞是免疫所必需的。我们的目标是：1)研究癌症免疫是如何与自身免疫分离的；2)探讨CD4+ T细胞应答在肿瘤对分化抗原免疫中的作用；3)建立内源性侵袭性黑色素瘤小鼠模型，研究肿瘤发展不同阶段对分化抗原的免疫反应。

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.