CHEMO/IMMUNOTHERAPY OF A T CELL DEPENDENT B CELL TUMOR

B细胞淋巴瘤(以前称为网状细胞肉瘤[RCS]) SJL/J系小鼠自发发育通过以下途径促进自身生长 刺激固有的CD4细胞增殖，这种细胞分泌 肿瘤细胞所需的淋巴因子。在确定的过程中 环磷酰胺对荷瘤SJL/J小鼠的治疗作用 主要来源于对宿主非恶性淋巴系统的影响 我们没有对肿瘤细胞产生直接影响，而是发现了一种新的 化疗/免疫治疗机制，对其更好的理解可以 帮助开发更有效的治疗类似人类的方法 淋巴瘤。初步数据显示，显著提高了存活率 通过环磷酰胺给药获得荷瘤小鼠(107 RCS5肿瘤 细胞-第1天，100 mg/kg环磷酰胺，第0天=RCS[Cy]治疗) 主要归因于：1)CD8+人群的产生 特异性抑制SJL/J-淋巴瘤刺激的细胞增殖 同基因的CD4细胞，以及；2)细胞因子介导的优先消除 SJL/J淋巴瘤后，CD4细胞能够增殖。这个 接下来的提案的目的是为了更好地了解 RCS[Cy]治疗被证明是有效的机制。 更具体地说，我们希望：1)定义导致 产生CD8细胞，特异性抑制肿瘤刺激 MLR；2)确定这些细胞的功能及其识别的内容，以及；3) 无论它们是基于T细胞受体使用的单克隆性还是少克隆性。我们 也希望确定其机制，不存在CD8抑制细胞 RCS[Cy]对小鼠CD_4细胞数量的影响 在CD4细胞中出现功能缺陷，这些细胞因 SJL/J淋巴瘤。特异性CD8抑制细胞在慢性粒细胞白血病中作用的研究 这一系统是基于这样一种假设：抑制者的特异性 细胞通过它们的TCR识别独特型决定簇上的 它们能够抑制T细胞。这一假设是一致的。 有基本的免疫学原理。如果发现这一理论适用于 我们的TCRs抗独特型单抗的制备 特异性CD8抑制子的克隆可能产生潜在的试剂 特异性CD8抑制子功能调节的治疗价值 细胞克隆。根据独特型网络理论，这些相同的试剂可能是 对SJL/J淋巴瘤仍难以捉摸的决定因素的反应 刺激同基因的CD4细胞增殖对肿瘤至关重要 成长。

B-cell lymphomas (formerly called reticulum cell sarcomas [RCS]) which develop spontaneously in SJL/J strain mice promote their own growth by stimulating proliferation of autochthonous CD4 cells, which secrete lymphokines required by the tumor cells. In the course of determining that the efficacy of cyclophosphamide (Cy) treatment of tumor-bearing SJL/J mice was derived primarily from effects on the host nonmalignant lymphoid system rather than from direct effects on tumor cells, we uncovered a novel chemo/immunotherapeutic mechanism, a better understanding of which could aid in the development of more effective means of treating analogous human lymphomas. Preliminary data indicate that the markedly increased survival of tumor-bearing mice obtained through Cy administration (107 RCS5 tumor cells day-1, 100mg/kg of Cy ip, day 0 = RCS[Cy] treatment) can be attributed primarily to: 1) the generation of a CD8+ population specifically suppressive of the SJL/J-lymphoma-stimulated proliferation of syngeneic CD4 cells, and; 2) the preferential Cy-mediated elimination of CD4 cells able to proliferate in response to SJL/J lymphomas. The objective of the ensuing proposal is to obtain a better understanding of the mechanisms by which the RCS[Cy} treatment proves to be efficacious. More specifically, we wish to: 1) define the signals which lead to the generation of CD8 cells, specifically suppressive of the tumor-stimulated MLR; 2) determine how these cell function and what they recognize, and; 3) whether they are mono-or pauci- clonal based on T-cell receptor usage. WE also wish to determine the mechanism, free of CD8-suppressor-cell influences, by which the CD4 cell population in RCS[Cy]-treated mice becomes functionally deficient in CD4 cells that proliferate in response to SJL/J lymphomas. Our study of the role of specific CD8 suppressor cells in this system is based upon the hypothesis that the specificity of suppressor cells resides in recognition by their TCRs of idiotypic determinants on the T-cells they are capable of suppressing. This hypothesis is consistent with basic immunologic tenets. Should this theory by found applicable in our system, preparation of monoclonal antiidiotypic antibodies to the TCRs of clones of specific CD8 suppressors may yield reagents of potential therapeutic value able to regulate the function of specific CD8 suppressor cell clones. Based on idiotypic network theory, these same reagents may be reactive with the still elusive determinants on SJL/J lymphomas which stimulate the syngeneic CD4-cell proliferation which is so vital to tumor growth.