ROLE OF T AND B CELLS IN MOUSE MAMMARY TUMOR VIRUS INFECTION

T 和 B 细胞在小鼠乳腺肿瘤病毒感染中的作用

• 批准号: 6580351
• 负责人: SUSAN R ROSS
• 金额: $ 10.37万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6580351
• 关键词: B lymphocyte; SCID mouse; T lymphocyte; breast neoplasms; cellular immunity; enzyme linked immunosorbent assay; genetically modified animals; gut associated lymphoid tissue; immunocytochemistry; integrins; mammary gland; microorganism immunology; mouse mammary tumor virus; mucosal immunity; newborn animals; selectins; superantigens; thymus; viral carcinogenesis; virus diseases; virus infection mechanism; virus related neoplasm /cancer; virus replication

Mouse mammary tumor virus (MMTV) was the first virus shown to cause cancer in mammals and is transmitted through milk. MMTV has long been studied as a prototype for viruses that are acquired through the gut- associated lymphoid tissue or GALT. MMTV contains a viral protein, called the superantigen (Sag), that enables it to infect lymphoid cells, first in the gut and then systematically. We believe that this allows MMTV to spread from the gut to the mammary gland via infected lymphocytes. One of the goals of this project is to determine specifically which type of lymphocytes are important for delivery MMTV to the mammary cell and how they accomplish this transfer. Trafficking of infected lymphocytes to the mammary gland will be studied in vivo and the effects of disrupting this trafficking on virus transfer to this tissue will be examined, using antibody blocking techniques and beta7-integrin/L-selectin knockout mice that have disrupted homing of lymphocytes to mucosal tissue. We will also use genetically-marked viruses to look at the specific lymphocyte subsets that are infected and to determine how virus transfer between different cells occur. In addition to MMTV's interaction with lymphoid cells at early stages of infection, be believe that this virus also subverts the immune system at later stages and this ultimately affects its ability to cause mammary tumors. Thus, another aim of this proposal is to determine whether MMTV induces immune tolerance and whether Sag- mediated deletion of T cells plays a role in this process. Because mice are currently the best genetically-manipulatable and immunologically well- characterized species available, our studies on how MMTV utilizes and subverts the immune system will further our understanding of the relationship between the cell type, site of infection and host response to retroviral infection.

小鼠乳腺肿瘤病毒（MMTV）是第一个被证明可导致哺乳动物癌症的病毒，并通过乳汁传播。 MMTV 长期以来一直被作为通过肠道相关淋巴组织或 GALT 获得的病毒的原型进行研究。 MMTV 含有一种称为超抗原 (Sag) 的病毒蛋白，使其能够首先感染肠道中的淋巴细胞，然后全身感染。我们相信这使得 MMTV 通过受感染的淋巴细胞从肠道传播到乳腺。该项目的目标之一是明确哪种类型的淋巴细胞对于将 MMTV 传递到乳腺细胞至关重要，以及它们如何完成这种转移。将在体内研究受感染淋巴细胞向乳腺的贩运，并使用抗体阻断技术和破坏淋巴细胞归巢到粘膜组织的β7-整合素/L-选择素敲除小鼠，检查破坏这种运输对病毒转移到该组织的影响。我们还将使用基因标记的病毒来观察被感染的特定淋巴细胞亚群，并确定病毒在不同细胞之间的转移是如何发生的。除了在感染早期阶段 MMTV 与淋巴细胞相互作用外，相信这种病毒还会在后期破坏免疫系统，最终影响其引起乳腺肿瘤的能力。因此，该提议的另一个目的是确定 MMTV 是否诱导免疫耐受以及 Sag 介导的 T 细胞删除是否在此过程中发挥作用。由于小鼠是目前最好的遗传可操作且免疫学特征明确的物种，因此我们对 MMTV 如何利用和颠覆免疫系统的研究将进一步了解细胞类型、感染部位和宿主对逆转录病毒感染的反应之间的关系。