IMMUNE MODIFICATION OF CYTOMEGALOVIRUS INFECTION IN BONE MARROW

尽管最近在预防和治疗方面取得了进展，但CMV仍然是 异基因骨髓移植成功的主要障碍 (BMT)。研究表明，在这种情况下，CMV感染的结局 通过早期重建受体免疫来改善设置 CMV和减少CMV复制。此外，之前的研究在 人类和动物都证明了捐赠者的几个方面 对CMV的免疫力可以转移给骨髓移植受者，这种转移 改善结果。这项提案将探索修改捐赠者的能力 通过几种免疫策略对CMV进行免疫。我们将进一步测试 是否可将免疫接种转移给骨髓移植受者并更改 巨细胞病毒感染的结局。 我们假设对巨细胞病毒感染的免疫力可以通过 用特定病毒基因的DNA或H2相容的DNA免疫 表达特定基因产物的细胞载体。这一豁免权将是 表现为体液和细胞介导的反应以及 感染病程。我们进一步假设，这种免疫导致了 对巨细胞病毒免疫的改变可以从骨髓捐赠者转移到 接受同种异体移植的人。 本项目有三个具体目标；具体目标1：开发 获得巨细胞病毒最大表达的最佳表达载体(pp65， Pp150、pp28、pp71)和MCMV(Gb、Gh)蛋白。 一旦开发出最佳载体，我们将插入单纯疱疹病毒-1 将胸苷激酶(HSV1-tk)基因导入表达载体，提供 自杀成分。我们还将开发新的小鼠基因载体，用于 学习。具体目标2：我们将对表达载体进行鉴定 包含特定CMV基因(HCMV pp65、pp150、pp28、pp71；MCMV gB和 Gh)使用DNA在体内改变宿主免疫的能力 免疫和使用H2相容细胞载体表达特异性病毒 基因产品。具体目标3：使用已建立的小鼠模型 异基因骨髓移植后，我们将确定其疗效 将免疫诱导的免疫从供者转移到移植物 收件人。 这些研究将确定将供体免疫改变为 使用特定病毒基因的DNA或H2-DNA免疫的CMV 表达特定基因产物的兼容细胞载体和 随后转移免疫可诱导免疫受者产生免疫力 异基因骨髓移植受者。

Despite recent progress in prophylaxis and treatment, CMV continues to be a major obstacle to success in allogeneic bone marrow transplantation (BMT). Studies have shown that the outcome of CMV infection in this setting is improved by both early reconstitution of recipient immunity to CMV and reduction of CMV replication. Furthermore, previous studies in both humans and animals have demonstrated that several facets of donor immunity to CMV can be transferred to BMT recipients and that such transfer improves outcome. This proposal will explore the ability to modify donor immunity to CMV by several immunization strategies. We will further test whether immunization immunity an be transferred to BMT recipients and alter the outcome of CMV infection. We hypothesize that immunity to CMV infection can be altered by immunization with either DNA of specific viral genes or with H2-compatible cellular vectors expressing specific gene products. This immunity will be manifested by humoral and cell mediated responses and by alterations in the course of infection. We further hypothesize that this immunization induced alteration in immunity to CMV can be transferred from a bone marrow donor tot he recipient of an allogeneic transplant. There are three specific aims of this project; Specific Aim 1: To develop optimal expression vectors for obtaining maximal expression of HCMV (pp65, pp150, pp28, pp71) and MCMV (gB and gH) proteins in vitro and in vivo. once, an optimal vector is developed, we will insert the herpes simplex-1 thymidine kinase (HSV 1-tk) gene into the expression vector to provide a suicidal constituent. We will also develop new murine gene vectors for study. Specific Aim 2: We will evaluate the expression plasmids containing specific CMV genes (HCMV pp65, pp150, pp28, pp71; MCMV gB, and gH) for their ability to alter host immunity in vivo, using DNA immunization and using H2-compatible cell vectors expression specific viral gene products. Specific Aim 3: Using an established murine model of allogeneic bone marrow transplantation, we will determine the efficacy of transferring immunization-induced immunity from a donor to the transplant recipient. These studies will determine the feasibility of altering donor immunity to CMV using immunization with either DNA of specific viral genes or with H2- compatible cellular vectors expressing specific gene products and the subsequent transfer of immunization induced immunity to recipients of allogenic marrow recipients.