CELLULAR FUNCTION AND IMMUNE THERAPY IN THE TREATMENT OF CANCER

设计有效的免疫疗法以根除残留的恶性肿瘤 化疗后的细胞依赖于对免疫和 在此期间出现造血功能障碍。 为此，我们 研究了癌症患者细胞功能的四个方面 在治疗前后。 首先，我们通过临床前研究确定了 动物模型和临床研究表明，大多数CD 4 T细胞 在化疗后阶段出现的是来自于 成熟的外周T细胞 扩增产生的T细胞群 后来数量下降，易发生凋亡。 两项临床 基于这些结果，已经开始了研究。 的第二刻面 细胞功能涉及T淋巴细胞的体外生成 确定细胞因子表型的人群：I型（Th 1，Tc 1）和II型 (Th2、Tc 2）。 Th 1型CD 4 + T细胞介导致死性GVHD和CVL。 相比之下，分泌I型或II型的CD 8+细胞毒性T细胞， 发现细胞因子介导有效的GVL效应，同时降低GVHD。 现在已经为人类的产生建立了文化条件 作为临床研究的前奏曲的曲马多定义的T细胞亚群。 的 工作的第三个方面涉及表征 化疗后的造血细胞群。 结果发现 化疗对造血祖细胞的损害发生， 造血细胞因子疗法 这种处理刺激了 造血的负调节因子 这些结果对 T细胞再生和造血干细胞的基因操作。 第四方面的工作集中在抗原呈递细胞 生物学 已经发现单核细胞/巨噬细胞谱系的细胞被激活， 树突状细胞前体，以及钙离子载体处理 这样的细胞引起几乎均匀的转化以收获单核细胞， 为涉及肿瘤抗原的新的临床治疗提供途径 疫苗。

The design of effective immune therapies to eradicate residual malignant cells following chemotherapy is dependent upon understanding immune and hematopoietic dysfunctions present in this period. Toward this end, we have examined four facets of cellular function in patients with cancer before and after therapy. First, we have determined through preclinical animal models and clinical studies that the majority of CD4 T cells present in the post-chemotherapy period are derived from expansion of mature peripheral T cells. Population of T cells derived from expansion later decline in number and are susceptible to apoptosis. Two clinical studies have been initiated based on these results. The second facet of cellular function concerns the in vitro generation of T lymphocyte populations of defined cytokine phenotype: Type I (Th1, Tc1) and Type II (Th2, Tc2). CD4+ T cells of Th1-type mediated both lethal GVHD and CVL. In contrast, CD8+ cytotoxic T cells secreting either Type I or Type II cytokines were found to mediate potent GVL effects with reduced GVHD. Culture conditions have now been established for the generation of human cytokine-defined T cell subsets as a prelude to clinical studies. The third facet of the work concerns characterizing alterations in hematopoietic cell populations following chemotherapy. It was found that chemotherapy damage to hematopoietic progenitors occurred despite hematopoietic cytokine therapy. Such treatment stimulated production of negative regulators of hematopoiesis. These results have implications for T cell regeneration and for gene manipulation of hematopoietic stem cells. The fourth facet of the work has focused on antigen presenting cell biology. It has been found that cells of monocyte/macrophage lineage ar precursors of dendritic cells, and that calcium ionophore treatment of such cells provokes almost uniform conversion to harvest monocyte cells, provide approaches for new clinical therapies involving tumor antigen vaccines.