MECHANISM OF MELPHALAN-MEDIATED TUMOR ERADICATION

这项建议的主要目标是了解 一种广泛使用的抗癌药物马法兰(L- PAM)；将平衡从免疫抑制转变为有效 晚期给药小鼠的抗肿瘤免疫 肿瘤生长阶段。我们已经知道， 低剂量该烷化剂的免疫调节活性 在一些浆细胞瘤肿瘤模型中，不仅包括 消除抑制细胞的活性，但也诱导 在T细胞中表现出免疫增强活性 共表达Lyt2和L3T4抗原，即使这些细胞 驻留在次级淋巴器官中。实验将是 以确定胸腺在外观中的作用 具有这种不寻常表型的T细胞(即，表达 LYT_2和L3T_4抗原)。 小剂量后不久的成年荷瘤小鼠 化疗起于(A)大于或等于80% 胸腺内的淋巴细胞共同表达这两个标记，以及(B) 小剂量L-PAM诱导MOPC-315胸腺细胞分化 荷瘤小鼠(但不是来自正常小鼠)能够 产生增强的抗肿瘤细胞毒作用 当加入正常脾细胞的免疫培养时 以及“本土”肿瘤。此外，我们还将澄清 小剂量化疗对细胞组成的影响 肿瘤携带者的胸腺。作为这项研究的一部分，我们将 免疫学检测LYT2和L3T4表型 L-PAM治疗MOPC-315肿瘤的胸腺“活性”细胞 以及阐明低剂量的 L-PAM提取MOPC-315肿瘤患者胸腺细胞 在免疫上“活跃”。此外，我们将确定 这些“活跃”的胸腺细胞产生 产生增强的裂解活性。重点将放在 将我们的观察扩展到其他肿瘤模型。为了这个 目的，我们将使用精选的浆细胞瘤 它们的免疫原性。因此，从这些方面获得的结果 实验还将提供关于这种相关性的信息 肿瘤细胞免疫原性和随后的能力之间的关系 小剂量L-PAM治疗诱导“活动性”细胞的出现 荷瘤小鼠胸腺中的细胞。最后，我们会 确定胸腺对治疗的重要性 小剂量L-PAM治疗MOPC-315和MOPC-315的疗效 104E自治疗以来对肿瘤的疗效 治疗方案取决于T细胞依赖的能力 抗肿瘤免疫可根除大量致瘤负荷 在药物从流通中清除后仍然存在。

The main objective of this proposal is to understand the mechanism by which a widely used anticancer drug, melphalan (L- PAM); shifts the balance from immunosuppression to potent antitumor immunity when administered to mice at an advanced stage of tumor growth. We know already that the immunomodulatory activity of a low dose of this alkylating agent consists, in some plasmacytoma tumor models, not only of elimination of suppressor cell activity, but also of induction of appearance of immunopotentiating activity in T-cells that coexpress the Lyt 2 and the L3T4 antigens even when these cells reside in secondary lymphoid organs. Experiments will be performed to determine the role of the thymus in the appearance of T cells with such an unusual phenotype (i.e., expressing simultaneously the Lyt 2 and L3T4 antigens) in the spleens of adult tumor-bearing mice shortly after the low dose chemotherapy since (a) greater than or equal to 80% of the lymphocytes within the thymus coexpress both markers, and (b) the low dose L-PAM therapy renders thymocytes from MOPC-315 tumor-bearing mice (but not from normal mice) capable of bringing about the generation of enhanced antitumor cytotoxicity when added to the immunization culture of normal spleen cells and the "autochthonous" tumor. In addition, we will elucidate the effect of the low dose chemotherapy on the cellular composition of the tumor bearer thymus. As part of this study, we will determine the Lyt2 and L3T4 phenotype of the immunologically "active" cells in the thymus of L-PAM treated MOPC-315 tumor bearers as well as elucidate the mechanism by which the low dose L-PAM renders thymocytes from MOPC-315 tumor bearers immunologically "active". In addition, we will determine the mechanism by which these"active" thymocytes bring about the generation of enhanced lytic activity. Emphasis will be placed on extending our observations to other tumor models. For this purpose, we will employ selected plasmacytomas that differ in their immunogenicity. Thus, the results obtained from these experiments will also provide information as to the correlation between tumor cell immunogenicity and the subsequent ability of low dose L-PAM therapy to induce the appearance of "active" cells in the thymus of tumor-bearing mice. Finally, we will determine the importance of the thymus to the curative effectiveness of low dose L-PAM therapy of MOPC-315 or MOPC- 104E tumor bearers since the therapeutic effectiveness of this therapeutic protocol depends on the ability of T-cell-dependent antitumor immunity to eradicate a large tumorigenic load remaining after clearance of the drug from the circulation.