Phänotypische und funktionelle Charakterisierung von zytotoxischen T-Lymphozyten gegen Melanom-assoziierte Antigene bei gesunden Individuen und bei Melanompatienten vor und nach Peptidvakzinierung

针对黑色素瘤相关抗原的强大的系统性和局部T细胞免疫反应已在人类中反复发现。尽管晚期黑色素瘤的严重预后表明，可检测的免疫反应很少足以阻止肿瘤生长，但现在的新进展极大地促进了肿瘤特异性细胞毒性T细胞（CTL）的分析。此外，人们对最近在黑色素瘤患者甚至健康个体中发现的CTL的不同表型知之甚少。在提议工作的第一部分，申请人将表型和功能表征T细胞对自身抗原Melan-A/MART-1的反应，在三分之二的正常HLA-A2健康献血者中检测到高水平。第二部分将研究肽基疫苗接种前后黑色素瘤患者前哨淋巴结和外周血标本中CTL的不同功能阶段。综上所述，所提出的工作将为我们在生理和病理情况下对组织特异性自身抗原的特异性CTL反应动力学的理解提供重要信息，并将有助于改进癌症特异性免疫治疗方法的设计。

Powerful systemic and local T cell based immune responses against melanoma-associated antigens have been repeatedly identified in humans. New developments now greatly facilitate the analysis of tumor-specific cytotoxic T cells (CTL), although detectable immune responses are rarely sufficient to arrest tumor growth as apparent by the grim prognosis of advanced melanoma. Furthermore, very little is known about distinct phenotypes of CTL that have recently been found in melanoma patients and even healthy individuals. In the first part of the proposed work, the applicant will phenotypically and functionally characterize T cells reactive against the self-antigen Melan-A/MART-1 that are detectable at high levels in two thirds of normal HLA-A2 healthy blood donors. In the second part, the different functional stages of CTL in sentinel lymph nodes and peripheral blood specimens of melanoma patients before and after peptide-based vaccination will be studied. Taken together, the proposed work will provide important information in our understanding of the dynamics of the specific CTL response to tissue-specific self antigens under both physiological and pathological circumstances and will help to improve the design of specific immunotherapeutical approaches to cancer.