IMMUNE RECONSTITUTION AFTER TRANSPLANTION

描述：(逐字改编自研究者的摘要)接受高剂量化疗(HDC)的癌症患者会经历长期的T细胞缺陷，这可能会使肿瘤疫苗接种无效。然而，由CD4+T细胞和CD8+细胞溶解T细胞(CTL)介导的诱导抗肿瘤T细胞反应的疫苗可能是联合HDC的一种有效治疗方法。当肿瘤负担最低时，疫苗将根除最小的残留疾病。该项目将确定是否有可能成功地结合HDC和自体干细胞移植进行免疫。树突状细胞(DC)是启动免疫反应所必需的抗原提呈细胞，和T细胞一样，DC似乎也受到化疗的影响。我们假设在接种时树突状细胞的数量以及天然T细胞的数量与成功免疫的能力之间存在关联。作为推论，我们预测，以非特异性方式改变DC或初始T细胞的数量将影响同时接种疫苗的成功。我们将使用两种实验方法来检验这一假设。首先，在我们机构正在进行的一项I期临床研究中，我们将确定：1)接受大剂量化疗的患者是否可以接种；2)特异性免疫的能力是否与血液中原始T细胞或树突状细胞的数量有关；3)干细胞移植是否可以作为治疗免疫细胞的来源。接受HDC和干细胞移植的乳腺癌患者将接种破伤风类毒素和肿瘤相关MUC-1多肽疫苗。将测量抗原特异性体液免疫反应和T细胞介导的免疫反应。其次，我们将使用MHC Class I限制性TCR转基因小鼠的临床前小鼠模型来具体测试骨髓移植后树突状细胞如何诱导CTL介导的抗肿瘤反应。将操纵初始T细胞和不同类型DC的水平来测量依赖CTL的抗肿瘤反应。将直接测量抗原特异性T细胞，以测试免疫失败是由于缺乏T细胞、树突状细胞还是由于疫苗诱导的耐受。总之，本项目的研究结果将有助于调节移植后的免疫恢复，以改善目前转移性乳腺癌的治疗。

DESCRIPTION: (adapted verbatim from the investigator's abstract) Cancer patients treated with high-dose chemotherapy (HDC) experience long-lasting T cell defects that can make tumor vaccination futile. Yet, vaccines inducing antitumor T cell responses mediated by CD4+ T cells and CD8+ cytolytic T cells (CTLs) might represent an effective treatment combined with HDC. Vaccines would eradicate minimal residual disease when tumor burden is at its lowest. This project will define if it is possible to successfully immunize in conjunction with HDC and autologous stem cell transplantation. Dendritic cells (DCs) are antigen-presenting cells that are essential for priming immune responses, and like T cells, DCs seem to be affected by chemotherapy. We hypothesize that there will be an association between numbers of DCs, as well as of native T cells present at the time of vaccination and the ability to successfully immunize. As a corollary, we predict that changing numbers of DCs or of naive T cells in a nonspecific manner will impact on the success of a concurrent vaccination. We will use two experimental approaches to test this hypothesis. First, in an ongoing Phase I clinical study at our institution, we will determine, 1) if patients undergoing high-dose chemotherapy can be immunized; 2) if there is an association between the ability to specifically immunize and the numbers of naive T cells or of dendritic cells in the blood; 3) if the stem cell graft can serve as a source of immune cells for therapy. Breast cancer patients undergoing HDC and stem cell transplantation will be vaccinated against tetanus toxoid and against the tumor-associated Muc-1 peptide. Antigen-specific humoral and T cell-mediated immune responses will be measured. Second, we will use a preclinical mouse model using MHC Class I-restricted TCR transgenic mice to specifically test how CTL-mediated antitumor responses can be elicited by DCs after bone marrow transplantation. Levels of naive T cells and of different types of DCs will be manipulated to measure CTL-dependent antitumor response. Antigen-specific T cells will be directly measured, to test if failure to immunized is caused by a lack of T cells or of DCs or due to vaccine-induced tolerization. Altogether, results obtained in this project will help regulate the immune recovery posttransplantation to improve the current treatment of metastatic breast cancer.