Mouse Core

人类黑色素瘤相关抗原的鉴定方面的研究工作已经导致了癌症治疗中新型过继免疫策略的发展，其涉及抗原特异性细胞的分离、其离体扩增和活化以及随后的自体施用以诱导抗肿瘤免疫应答。为了使过继性免疫治疗更广泛地可用，通过T细胞受体（TCR）基因治疗将肿瘤特异性免疫受体遗传转移到患者的自体T细胞中的策略正在被强烈追求。过继性T细胞免疫疗法的成功结果与效应T细胞群体的持久性有关。然而，几种生物学机制仍然可以解释未能实现有效的免疫保护。为了解决当使用高亲和力TCR用于过继性免疫治疗时可能出现的各种限制，我们最近开发了表达TIL 1383 ITCR的转基因小鼠模型，TIL 1383 ITCR是与人酪氨酸酶衍生肽YMDGTMSQV反应的相同的人HLA-A2限制性高亲和力TCR，其分离自患有转移性黑素瘤的患者的肿瘤浸润淋巴细胞（TILs）的I类限制性CD 4 + T细胞，正在临床试验中使用。表达TIL 1383 I TCR的转基因小鼠呈现了临床相关模型，其为我们提供了将TCR转导的T细胞与携带相同受体的正常未人工培养的T细胞群体进行比较的独特机会。因此，携带TIL 1383 I TCR的转基因小鼠（称为h3 T-人TIL衍生的酪氨酸酶TCR）模型将被广泛用作项目1-4提出的实验中比较的关键细胞来源。小鼠核心将为项目1-4和核心C提供质量受控的供体小鼠细胞。此外，核心将维持受体小鼠的繁殖菌落，产生额外的h3 T特异性品系，并根据个别项目的需要维持其他特异性品系。鼠标维护的集中操作将具有降低成本、由于集中质量控制而在项目之间保持一致以及便于研究者使用的优点。因此，该小鼠核心设施的目的是1）从携带TIL 13831 TCR的h3 T转基因小鼠提供质量受控的供体小鼠T细胞，2）维持用作受体品系的小鼠的繁殖集落，和3）为了开发新的TIL 13831 TCR转基因小鼠品系，并维持小鼠繁殖群，这些小鼠将被各个项目专门用于程序.

Seminal work on the identity of human melanoma associated antigen have led to the development of novel adoptive immunotherapeutic strategies in cancer treatment that involves isolation of antigen-specific cells, their ex vivo expansion and activation, and subsequent autologous administration for inducing anti-tumor immune responses. In an effort to make adoptive immunotherapy more broadly available, strategies to genetically transfer tumor specific immune receptors into patient's autologous T cells via T cell receptor (TCR) gene therapy are being pursued intensely. Successful outcome for adoptive T cell immunotherapy has been linked to persistence of the effector T cell population. However several biological mechanisms may still account for the failure to achieve efficient immune protection. To address various constraints that may arise when using the high affinity TCR for adoptive immunotherapy, we recently developed transgenic mouse model expressing TIL1383I TCR, same human HLA-A2 restricted high affinity TCR reactive to human tyrosinase-derived peptide YMDGTMSQV isolated from a class-l restricted CD4+ T cells of tumor infiltrating lymphocytes (TILs) of a patient with metastatic melanoma, that is being used in clinical trials. The transgenic mouse expressing the TIL1383I TCR presents a clinically relevant model, which provides us with a unique opportunity to compare TCR transduced T cells with a normal unmanlpulated population of T cells bearing the same receptor. Therefore, the TIL1383I TCR bearing transgenic mouse (referred as h3T - human TIL derived Tyrosinase TCR) model will be extensively used as a key source of cells for comparisons in experiments proposed by projects 1-4. The mouse core will provide quality-controlled donor mouse cells to projects 1-4 and Core C. In addition the core will maintain breeding colonies of recipient mice, generate additional h3T specialty strains, and maintain other specialty strains as needed for individual projects. The centralized operation of mouse maintenance will have the advantages of reduced cost, consistency among projects due to centralized quality control, and ease of use for the investigators. Thus, the aims of this mouse core facility are 1) To provide quality-controlled donor mouse T cells from TIL 13831 TCR bearing h3T transgenic mice, 2) To maintain breeding colonies of mice, which are used as recipient strains, and 3) To develop novel strains of TIL 13831 TCR transgenic mice and maintain breeding colonies of mice that will be specifically utilized by individual Projects in the Program.