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]）， 在SJL/J品系小鼠中自发发育， 刺激自体CD 4细胞增殖，其分泌 肿瘤细胞所需的淋巴因子。 在确定的过程中， 环磷酰胺（Cy）治疗荷瘤SJL/J小鼠的疗效 主要来自对宿主非恶性淋巴系统的影响 而不是直接作用于肿瘤细胞，我们发现了一种新的 化疗/免疫机制，更好地了解这一点， 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， 通过Cy给药获得的荷瘤小鼠（107个RCS 5肿瘤 细胞第-1天，100 mg/kg Cy ip，第0天= RCS[Cy]处理）， 主要归因于：1）CD 8+群体的产生 特异性抑制SJL/J淋巴瘤刺激的 同源CD 4细胞，和; 2）优先Cy-mediated消除 CD 4细胞能够响应SJL/J淋巴瘤而增殖。 的 以下建议的目的是更好地了解 RCS[Cy]治疗证明有效的机制。 更具体地说，我们希望：1）定义导致 产生CD 8细胞，特异性抑制肿瘤刺激的 MLR; 2）确定这些细胞如何发挥功能以及它们识别什么，以及; 3） 基于T细胞受体的使用，它们是单克隆的还是少克隆的。 我们 也希望确定机制，无CD 8-抑制细胞 RCS[Cy]处理小鼠中的CD 4细胞群 在CD 4细胞中变得功能缺陷， SJL/J淋巴瘤。 我们研究了特异性CD 8抑制细胞在 该系统基于这样的假设，即抑制基因的特异性 细胞存在于它们的TCR对细胞表面上的独特型决定簇的识别中。 它们能够抑制的T细胞。 这一假设与 基本的免疫学原理 如果这一理论被发现适用于 我们的系统，制备单克隆抗独特型抗体的TCR 特异性CD 8抑制因子的克隆可能产生潜在的试剂， 能够调节特异性CD 8抑制因子功能的治疗价值 细胞克隆 基于独特型网络理论，这些相同的试剂可能是 与SJL/J淋巴瘤上仍然难以捉摸的决定簇反应， 刺激同系CD 4-细胞增殖，这对肿瘤至关重要 增长

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.