Tempero R M, VanLith M L, Morikane K, Rowse G J, Gendler S J, Hollingsworth M A
Eppley Institute for Research in Cancer and Allied Disease, University of Nebraska Medical Center, Omaha 68198, USA.
J Immunol. 1998 Nov 15;161(10):5500-6.
A C57BL/6 mouse transgenic for human MUC1 (MUC1.Tg) was developed to evaluate MUC1-specific tumor immunity in an animal that expresses MUC1 as a normal self protein. Previous studies showed that MUC1.Tg mice, challenged with syngeneic tumors expressing MUC1 (B16.MUC1), developed progressively growing MUC1-positive tumors, whereas wild-type C57BL/6 (wt) mice developed MUC1-negative tumors at a significantly slower rate. The results of a limiting dilution CTL frequency assay were not informative, in that similar numbers of MUC1-specific CTL precursors (CTL) were detected in MUC1.Tg and wt mice. Tumor immunity in vivo was characterized by an adoptive transfer method to evaluate the degree of MUC1 or non-MUC1 tumor immunity in wt or MUC1.Tg mice. The results revealed that wt mice developed protective tumor immunity mediated by MUC1-specific CD4+ lymphocytes, while MUC1.Tg mice were functionally tolerant to MUC1 in vivo. The potential of adoptive immunotherapy to provide immunity to tumors expressing MUC1 and to produce undesirable autoimmunity in recipient MUC1.Tg mice expressing MUC1 as a self Ag was evaluated. Adoptive transfer of immune cells from wt mice primed in vivo with B16.MUC1 tumor cells into MUC1.Tg recipients resulted in significant increases in the survival of MUC1.Tg recipients compared with unmanipulated control MUC .Tg mice challenged with B16.MUC1 tumor cells. This response was specific for MUC1 since control tumors developed at equivalent rates in recipient or control MUC1.Tg mice. No gross or histologic evidence of autoimmunity was observed in recipient MUC1.Tg mice, indicating that tumor immune responses mediated by MUC1-specific CD4+ lymphocytes spare nontransformed epithelia-expressing MUC1.
构建了转人MUC1基因的C57BL/6小鼠（MUC1.Tg），以在将MUC1作为正常自身蛋白表达的动物中评估MUC1特异性肿瘤免疫。先前的研究表明，用表达MUC1的同基因肿瘤（B16.MUC1）攻击的MUC1.Tg小鼠会形成逐渐生长的MUC1阳性肿瘤，而野生型C57BL/6（wt）小鼠形成MUC1阴性肿瘤的速度明显较慢。有限稀释CTL频率测定的结果没有提供有用信息，因为在MUC1.Tg和wt小鼠中检测到的MUC1特异性CTL前体（CTL）数量相似。通过过继转移方法来表征体内肿瘤免疫，以评估wt或MUC1.Tg小鼠中MUC1或非MUC1肿瘤免疫的程度。结果显示，wt小鼠产生了由MUC1特异性CD4 +淋巴细胞介导的保护性肿瘤免疫，而MUC1.Tg小鼠在体内对MUC1具有功能耐受性。评估了过继免疫疗法为表达MUC1的肿瘤提供免疫以及在将MUC1作为自身抗原表达的受体MUC1.Tg小鼠中产生不良自身免疫的潜力。将体内用B16.MUC1肿瘤细胞致敏的wt小鼠的免疫细胞过继转移到MUC1.Tg受体中，与用B16.MUC1肿瘤细胞攻击的未处理对照MUC.Tg小鼠相比，MUC1.Tg受体的存活率显著提高。这种反应对MUC1具有特异性，因为对照肿瘤在受体或对照MUC1.Tg小鼠中以相同的速度生长。在受体MUC1.Tg小鼠中未观察到自身免疫的明显或组织学证据，表明由MUC1特异性CD4 +淋巴细胞介导的肿瘤免疫反应不会影响表达MUC1的未转化上皮细胞。
