INVARIANT CHAIN BASED VACCINE STRATEGIES

我们实验室最近的研究已经确定了一种独特的T细胞抗原识别模式，可以适应增强肿瘤相关抗原的特异性识别。我们的研究表明，来自环孢素诱导的自体移植物抗宿主病的自身反应性T细胞识别MHC II类不变链中称为CLIP的肽。尽管自身反应性T细胞部分通过经典机制识别CLIP，但CLIP的n端侧翼区域之间似乎也存在功能性超抗原样相互作用，该相互作用延伸到MHC II类肽结合槽和T细胞受体的v β段之外。初步研究表明，将CLIP的侧翼区域添加到标称抗原肽上可以增强其免疫原性。因此，该提议的中心假设是，通过添加CLIP的n端侧翼区域对肿瘤肽进行修饰将增强其免疫原性并引起有效的抗肿瘤免疫反应。目前的研究将集中于来自癌基因C-erbB-2的肽，也称为Her-2/neu作为模型系统。这种致癌基因在乳腺癌患者中引起微弱但无效的免疫反应。由于大鼠和人Her-2/neu具有显著的同源性，因此将利用大鼠模型来验证这一假设。Her-2/neu与CLIP的n端侧翼区域的嵌合结构将被用作疫苗。将通过评估抗体产生和CD4+和CD8+依赖的细胞免疫，以及该疫苗策略是否能引起有效的抗肿瘤反应，来确定引发最大免疫反应的最佳剂量和疫苗配方（佐剂、装载肽的肿瘤细胞、装载肽的树突状细胞）。这些研究将确定新的策略来增强肿瘤肽的免疫原性，这可能广泛适用于许多不同类型的癌症。

Recent studies in our laboratory have identified a unique mode of antigen recognition by T cells that may be adapted to augment specific recognition of tumor-associated antigens. Our studies have shown that the autoreactive T cells from Cyclosporine-induced autologous graft-vs-host disease recognize a peptide from the MHC class II invariant chain termed CLIP. Although the autoreactive T cells recognize CLIP, in part, via a classic mechanism, there also appears to be a functional superantigen-like interaction betwteen the N-terminal flanking region of CLIP that extends beyond the peptide binding groove of MHC class II and the Vbeta segment of the T cell receptor. Preliminary studies show that the addition of this flanking region of CLIP onto nominal antigenic peptides enhances their immunogenicity. The central hypothesis of this proposal, therefore, is that modification of tumor peptides by adding the N-terminal flanking region of CLIP will augment their immunogenicity and evoke a potent antitumor immune response. The present studies will focus on peptides from the oncogene, C-erbB-2 also known as Her-2/neu as a model system. This oncogene evokes a weak but ineffective immune response in patients with breast cancer. A rat model will be utilized to test this hypothesis since there is significant homology between rat and human Her-2/neu. Chimeric constructs of Her-2/neu with the N-terminal flanking region of CLIP will be utilized as a vaccine. The optimal dose and vaccine formulation (adjuvant, peptide loaded tumor cells, peptide loaded dendritic cells) that elicit the maximum immune response will be identified assessing antibody production and CD4+ and CD8+ dependent cellular immunity and whether this vaccine strategy evokes a potent antitumor response. These studies will identify novel strategies to enhance the immunogenicity of tumor peptides that may be broadly applicable to many different types of cancer.