Self-tolerance to the murine homologue of a tyrosinase-derived melanoma antigen: implications for tumor immunotherapy.
Self-tolerance to the murine homologue of a tyrosinase-derived melanoma antigen: implications for tumor immunotherapy.
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DOI：
10.1084/jem.191.7.1221
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发表时间：
2000-04-03
影响因子：
15.3
通讯作者：
Engelhard, V H
中科院分区：
文献类型：
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作者：
Colella, T A;Bullock, T N;Russell, L B;Mullins, D W;Overwijk, W W;Luckey, C J;Pierce, R A;Restifo, N P;Engelhard, V H
人酪氨酸酶衍生肽YMDGTMSQV存在于人组织相容性白细胞抗原（HLA）-A*0201+黑色素瘤的表面上，并且已经被认为是肿瘤抗原，尽管酪氨酸酶也在黑色素细胞中表达。为了获得关于对该抗原的免疫反应性和自身耐受性的信息，我们使用该肽FMDGTMSQV的鼠酪氨酸酶衍生的同源物以及表达HLA-A*0201重组分子AAD的转基因小鼠建立了模型。鼠肽的处理和AAD提出类似于其人类的对应。用编码鼠酪氨酸酶的重组牛痘病毒免疫后，我们在AAD转基因小鼠中检测到对FMDGTMSQV的强大的AAD限制性细胞毒性T淋巴细胞（CTL）应答，其中整个酪氨酸酶基因已被删除由辐射诱导的突变。在某些条件下激活后，在AAD+酪氨酸酶+小鼠中观察到残留反应。在AAD+酪氨酸酶+小鼠中，这些残留CTL中的至少一些具有高亲和力，并且在过继转移到AAD+酪氨酸酶+宿主中时诱导白癜风。总的来说，这些数据表明FMDGTMSQV在体内自然加工和呈递，并且这种呈递导致大量但不完全的自身耐受。该模型的相关性，以了解酪氨酸酶的人体免疫反应进行了讨论。
The human tyrosinase-derived peptide YMDGTMSQV is presented on the surface of human histocompatibility leukocyte antigen (HLA)-A*0201+ melanomas and has been suggested to be a tumor antigen despite the fact that tyrosinase is also expressed in melanocytes. To gain information about immunoreactivity and self-tolerance to this antigen, we established a model using the murine tyrosinase-derived homologue of this peptide FMDGTMSQV, together with transgenic mice expressing the HLA-A*0201 recombinant molecule AAD. The murine peptide was processed and presented by AAD similarly to its human counterpart. After immunization with recombinant vaccinia virus encoding murine tyrosinase, we detected a robust AAD-restricted cytotoxic T lymphocyte (CTL) response to FMDGTMSQV in AAD transgenic mice in which the entire tyrosinase gene had been deleted by a radiation-induced mutation. A residual response was observed in the AAD+tyrosinase+ mice after activation under certain conditions. At least some of these residual CTLs in AAD+tyrosinase+ mice were of high avidity and induced vitiligo upon adoptive transfer into AAD+tyrosinase+ hosts. Collectively, these data suggest that FMDGTMSQV is naturally processed and presented in vivo, and that this presentation leads to substantial but incomplete self-tolerance. The relevance of this model to an understanding of the human immune response to tyrosinase is discussed.