CELLULAR FUNCTION AND IMMUNE THERAPY IN THE TREATMENT OF CANCER

设计有效的免疫疗法来根除残留的恶性肿瘤 化疗后的细胞依赖于对免疫和 这一时期存在造血功能障碍。为此，我们 检查了癌症患者细胞功能的四个方面 治疗前和治疗后。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CD4T细胞 出现在化疗后时期是由于肿瘤的扩张 成熟的外周T细胞。扩增后的T细胞群体 后来数量下降，并容易发生细胞凋亡。两个临床病例 已经根据这些结果启动了研究。的第二个方面 细胞功能与T淋巴细胞的体外生成有关 明确细胞因子表型的人群：I型(Th1、Tc1)和II型 (Th2、Tc2)。Th1型CD4+T细胞同时介导致死性GVHD和CVL。 相比之下，CD8+细胞毒性T细胞分泌I型或II型 细胞因子被发现在减少移植物抗宿主病的情况下介导了强大的移植物抗宿主病效应。 现在已经为人类的生成创造了文化条件 细胞因子定义T细胞亚群作为临床研究的前奏。这个 这项工作的第三个方面涉及到对 化疗后的造血细胞数量。结果发现， 化疗对造血祖细胞的损害 造血细胞因子疗法。这样的治疗刺激了 造血的负性调节因子。这些结果对以下方面有影响 T细胞再生和造血干细胞的基因操作。 这项工作的第四个方面集中在抗原提呈细胞上。 生物学。已发现单核/巨噬细胞系的细胞是 树突状细胞前体细胞及钙离子载体治疗 这样的细胞会引发几乎一致的转化来获取单核细胞， 提供涉及肿瘤抗原的新的临床治疗方法 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.