SELECTIVE CYTOTOXICITY IN THE LYMPHATICS

皮下注射后，放射性标记的单抗结合 对淋巴结中的正常和肿瘤靶细胞有效(项目ET Z01 CB 08359-03 LTB)。这一发现促使我们尝试特定的治疗方法 使用单抗结合物。 一种由抗鼠MHC偶联的蓖麻毒素A链制成的免疫毒素 抗体已被证明对淋巴样细胞和类似细胞具有高度毒性 结果发现，单抗与蓖麻毒素A链偶联 体外抗小鼠淋巴细胞亚群的抗体。我们也一直在 能够通过某些药物的作用来增强这些毒素的效果 它们已知会影响细胞的生物学过程。这些研究导致了 一种新的细胞生物学途径假说(“中性旁路”) 毒素分子通过抗体结合进入细胞质 杀死一个细胞。 另一种体内特异性细胞杀伤的免疫结合物 由一种与抗体螯合的放射性化合物组成。我们有 选择性消融小鼠淋巴B淋巴细胞 皮下注射抗小鼠B细胞抗体 阿尔法粒子发射器212铋。它的相对效力 体内B细胞的结合物比T细胞的结合物高10倍 来自相同的节点。 为了评估抗体和抗体结合物对人类免疫功能的影响 体内，我们建立了两种淋巴结外T细胞活化模型。在……里面 其一，刺激物是植物凝集素刀豆蛋白A注入 另一个刺激因素是同种异体细胞。这两种刺激 诱导T细胞表达IL-2受体。刀豆蛋白A模型是 对环孢素A的抑制作用敏感，而 同种异体模型不是。

Following subcutaneous injection, radiolabeled monoclonal antibodies bind efficiently to normal and tumor target cells in the lymph nodes (Project et Z01 CB 08359-03 LTB). This finding prompted us to attempt specific therapy using monoclonal antibody conjugates. An immunotoxin made from the A-chain of ricin coupled to an anti-mouse MHC antibody has proved to be highly toxic for lymphoid cells and similar results have been found with ricin A-chain conjugated to monoclonal antibodies against subsets of mouse lymphocytes in vitro. We have also been able to augment the effects of these toxins by the action of certain drugs which are known to affect cell biological processes. These studies have led to a new hypothesis for the cell biological pathway (the "neutral bypass") by which toxin molecules enter the cytoplasm from antibody conjugates to kill a cell. A further type of immunoconjugate for specific cell killing in vivo consists of a radioactive compound chelated to an antibody. We have demonstrated selective ablation of lymph node B lymphocytes in mice injected subcutaneously with an anti-murine B cell antibody labeled with the alpha particle emitter 212 Bismuth. The relative potency of this conjugate for B cells in vivo was 10-fold higher than for T cells taken from the same nodes. In order to assess the effects of antibodies and antibody conjugates in vivo we have established two models of lymph node T cell activation. In one, the stimulus is the plant lectin concanavalin A administered into the footpad; the other stimulus is allogeneic cells. Both of these stimuli induce T cells to express receptors for IL-2. The concanavalin A model is susceptible to the inhibitory effects of cyclosporin A whereas the allogeneic model is not.