George A J, Folkard S G, Hamblin T J, Stevenson F K
Lymphoma Research Unit, Southampton General Hospital, U.K.
J Immunol. 1988 Sep 15;141(6):2168-74.
To develop a model for the active immunotherapy of human B cell malignancy we vaccinated tumor-bearing animals with a well defined tumor associated Ag, the idiotypic Ig. The tumor used was the mouse B cell lymphoma BCL1, a highly malignant tumor in which transfer of a single tumor cell to a syngeneic mouse is capable of causing disease and eventual death. Varying doses (10(2) to 10(4] of BCL1 cells were given to mice on day 0 of the experiment, and treatment by active immunization was initiated on day 3. Immunization with purified, tumor-derived, idiotypic IgM (BCL1 IgM) coupled to keyhole limpet hemacyanin (KLH) was highly effective in treating mice challenged with 10(2) or 10(3) BCL1 cells, but less effective in mice that had received 10(4) tumor cells. Immunization with unconjugated BCL1 IgM showed no signficant therapeutic benefit. Coupling of the IgM to KLH led to higher levels of anti-idiotypic antibody after immunization; however, the higher levels were probably not responsible for the control of the malignancy as there was no correlation in healthy immunized animals between the levels of anti-idiotypic antibody, measured immediately before tumor challenge, and survival. This lack of correlation is due to the emergence of variant tumors in such protected mice. A more significant factor in the therapeutic advantage of KLH conjugation could be that immunization with BCL1 IgM-KLH led to an earlier induction of the anti-idiotypic response than immunization with BCL1 IgM and, as the BCL1, lymphoma divides rapidly, the speed of induction of the immune response may be important in outstripping tumor cell growth. Mice with BCL1 tumour showed some evidence of immunosuppression as indicated by a reduced ability to mount an immune response against KLH. Although it is not possible to model spontaneous human lymphoma accurately, the generation of a functional anti-idiotypic response capable o eliminating a malignant animal lymphoma in situ opens up the possibility of a limited trial of active immunotherapy in selected human patients.
为开发一种针对人类B细胞恶性肿瘤的主动免疫疗法模型，我们用一种明确的肿瘤相关抗原——独特型免疫球蛋白（idiotypic Ig）对荷瘤动物进行免疫接种。所用肿瘤为小鼠B细胞淋巴瘤BCL1，这是一种高度恶性的肿瘤，将单个肿瘤细胞接种到同基因小鼠体内能够引发疾病并最终导致死亡。在实验第0天给小鼠接种不同剂量（10²至10⁴）的BCL1细胞，并于第3天开始主动免疫治疗。用与钥孔戚血蓝蛋白（KLH）偶联的纯化的、肿瘤来源的独特型IgM（BCL1 IgM）进行免疫接种，在治疗接种了10²或10³个BCL1细胞的小鼠时非常有效，但在接种了10⁴个肿瘤细胞的小鼠中效果较差。用未偶联的BCL1 IgM进行免疫接种未显示出明显的治疗益处。IgM与KLH偶联导致免疫接种后抗独特型抗体水平升高；然而，较高水平的抗体可能并非控制恶性肿瘤的原因，因为在健康免疫动物中，在肿瘤攻击前立即测量的抗独特型抗体水平与生存率之间没有相关性。这种缺乏相关性是由于此类受保护小鼠中出现了变异肿瘤。KLH偶联在治疗优势方面更重要的因素可能是，用BCL1 IgM-KLH进行免疫接种比用BCL1 IgM进行免疫接种能更早诱导抗独特型反应，而且由于BCL1淋巴瘤分裂迅速，免疫反应的诱导速度在超过肿瘤细胞生长方面可能很重要。患有BCL1肿瘤的小鼠表现出一些免疫抑制的迹象，表现为对KLH产生免疫反应的能力降低。虽然不可能准确模拟人类自发性淋巴瘤，但产生能够原位消除恶性动物淋巴瘤的功能性抗独特型反应为在选定的人类患者中进行主动免疫疗法的有限试验开辟了可能性。
