AN ANIMAL MODEL OF NATURALLY OCCURRING TUMOR IMMUNITY

副肿瘤性小脑变性(PCD)为人类自然发生的乳腺肿瘤免疫提供了一个重要而独特的例子。PCD的特征是针对一种通常在小脑表达的名为CDR2的肿瘤抗原产生高滴度抗体。PCD患者对肿瘤产生有效的免疫反应，然后出现严重的神经功能障碍。当CDR2被认为是乳腺或卵巢肿瘤中的外来抗原时，有人认为是免疫系统启动了PCD。我们假设PCD中发生的肿瘤免疫和神经元破坏不是抗CDR2抗体的结果，而是杀死表达CD2的细胞的细胞毒性T细胞(CTL)的结果。这一假说部分是基于研究人员未能通过诱导cdr2抗体来创建PCD的动物模型，部分是基于我们发现的cdr2特异性CTL能够杀死PCD患者的肿瘤。我们建议通过建立PCD的动物模型来检验这一假说，并加深我们对乳腺肿瘤免疫的理解。由于我们也发现CDR2在神经正常个体的乳腺肿瘤中表达，我们的研究为人类乳腺癌免疫提供了一种新的和重要的方法。

Paraneoplastic cerebellar degeneration (PCD) provides an important and unique example of naturally occurring breast tumor immunity in humans. PCD is characterized by a high titer antibody directed against a tumor antigen termed cdr2 that is normally expressed in the cerebellum. PCD patients develop an effective immune response to their tumors, and then come to clinical attention with severe neurologic dysfunction. It is proposed that the immune system initiates PCD when cdr2 is recognized as a foreign antigen in breast or ovarian tumors. We have hypothesized that the tumor immunity and neuronal destruction that occurs in PCD is not a result of antibodies against cdr2, but instead results from cytotoxic T cells (CTLs) that kill cdr2 expressing cells. This hypothesis is based in part on the failure of investigators to create an animal model of PCD by inducing cdr2 antibodies, and in part on our finding of cdr2-specific CTLs capable of killing tumors in PCD patients. We propose to test this hypothesis and deepen our understanding of breast tumor immunity by generating an animal model of PCD. Since we also find cdr2 expression in breast tumors obtained from neurologically normal individuals, our studies provide a new and important approach to breast cancer immunity in humans.