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全身性和局部性T细胞免疫反应在人类中被反复鉴定。新的发展现在极大地促进了对肿瘤特异性细胞毒性T细胞(CTL)的分析，尽管可检测的免疫反应很少足以阻止肿瘤的生长，这从晚期黑色素瘤的严峻预后中可见一斑。此外，人们对最近在黑色素瘤患者甚至健康人中发现的不同表型的CTL知之甚少。在拟议工作的第一部分，申请人将对对自身抗原Melan-A/Mart-1起反应的T细胞进行表型和功能表征，这些T细胞在三分之二正常的HLA-A2健康献血者中可检测到高水平的T细胞。第二部分将对黑色素瘤患者多肽疫苗接种前后前哨淋巴结和外周血标本中CTL的不同功能阶段进行研究。综上所述，这项拟议的工作将为我们理解在生理和病理环境下组织特异性自身抗原的特异性CTL反应的动态变化提供重要信息，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.