DNA VACCINATION WITH ALTERED ANTIGENS

分化抗原已成为肿瘤治疗的靶点。我们将研究旨在打破耐受性和增强针对黑色素瘤分化抗原的免疫效力的DNA疫苗，目标包括酪氨酸、gp75Trp-1、Trp-2和gp100。这些抗原覆盖黑素细胞/黑色素瘤分化的早期和晚期，是为克服肿瘤异质性而专门选择的。这些分化抗原被黑色素瘤患者的抗体和CD4+和CD4+T细胞识别。这增加了疫苗可以被设计成具有一般体液和细胞反应，包括辅助性和细胞毒性T细胞的可能性。我们在实验室模型中的结果表明，DNA免疫可以诱导针对肿瘤分化抗原的抗体和T细胞反应，但需要编码改变的抗原的基因。为了有效的豁免权。由于分化抗原是自身抗原，很可能是弱免疫原性的，我们将研究和比较三种DNA疫苗增强免疫原性和/或克服免疫耐受的方法：1.异种DNA免疫；2.编码抗原的DNA呈递室的DNA免疫；3.编码异源多肽的DNA小基因免疫；4.GM-CSF DNA增强免疫。我们期待这些方法将导致黑色素瘤抗原DNA疫苗的发展。

The differentiation antigens have emerged as targets for cancer therapy. We will investigate DNA vaccines that are designed to break tolerance and enhance potency of immunization against melanoma differentiation Melanoma differentiation antigens will be targeted, including tyrosine, gp75TRP-1, TRP-2 and gp100. These antigens cover early and late stages of melanocyte/melanoma differentiation and are specifically selected to overcome tumor heterogeneity. These differentiation antigens are recognized by antibodies and both CD4+ and CD4+ T cells of patients with melanoma. This raises the possibility that vaccines can be designed that general humoral and cellular responses, including helper and cytotoxic T cells. Our results in laboratory models show that both antibody and T cells responses can be induced against tumor differentiation antigens by DNA immunization, but genes encoding altered antigens are required. for effective immunity. Because differentiation antigens are self antigens that are likely to be weakly immunogenic, we will investigate and compare three approaches of DNA vaccination to enhance immunogenicity and/or overcoming immune tolerance: 1. Immunization with xenogeneic DNA; 2. Immunization with DNA encoding antigens that sort to antigen presenting compartments; 3. Immunization with DNA minigenes encoding heteroclitic peptides, and 4. Augmentation of immunity by GM-CSF DNA. We expect that these approaches will lead to development of DNA vaccine of antigens of melanoma.