CELLULAR FUNCTION AND IMMUNE THERAPY IN THE TREATMENT OF CANCER

“设计有效的免疫疗法， 根除化疗后残留的恶性细胞， 依赖于对免疫和造血的理解 在这一时期出现的功能障碍。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，我们已经确定， 临床前动物模型和临床研究，大多数 化疗后时期存在的CD 4 + T细胞来源于 在成年患者中，来自成熟外周T细胞的扩增。 来自扩增的T细胞群体后来下降， 数量和易受凋亡。两项临床研究表明， 基于这些结果， 最大化成人患者T细胞免疫活性的策略 用化疗治疗，并研究NK细胞生物学， 再生细胞功能的第二个方面涉及到 确定的细胞因子的T淋巴细胞群的体外产生 表型：I型（Th 1，Tc 1）和II型（Th 2，Tc 2）。CD4+ T Th 1型细胞介导致死性GVHD和GVL。在 相反，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， GVHD。现在已经建立了用于 产生人精氨酸定义的T细胞亚群作为 临床研究。工作的第三个方面涉及到 造血细胞群的改变 化疗结果发现，化疗对 造血祖细胞出现，尽管造血细胞因子 疗法这样的治疗刺激了负性细胞的产生。 造血调节因子趋化因子米格最近被 被认为是一种负调节剂。这些结果 对T细胞再生和基因操作的影响 造血干细胞第四个方面的工作重点是 关于抗原呈递细胞生物学。已经发现， 单核细胞/巨噬细胞谱系是树突细胞的前体，并且 用钙离子载体处理这些细胞， 向树突状表型细胞的均匀转化。的应用 这些发现的临床研究正在进行中。"

"The design of effective immune therapies to eradicate residual malignant cells following chemotherapy is dependent on 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 in adult patients 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 with the intent to derive strategies to maximize T cell immunocompetence in adult patients treated with chemotherapy and to investigate NK cell biology and regeneration. 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 GVL. 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. The chemokine Mig has been newly identified as one such negative regulator. 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 are precursors of dendritic cells, and that calcium ionophore treatment of such cells provokes almost uniform conversion to cells of dendritic phenotype. Application of these findings to clinical studies is in progress."