Mechanism of Resistance to MMTV Induced Mammary Tumors

MMTV诱发乳腺肿瘤的耐药机制

• 批准号: 6514810
• 负责人: Tatyana V Golovkina
• 金额: $ 27.06万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514810
• 关键词: adenocarcinoma; antiviral antibody; breast neoplasms; gene mutation; host organism interaction; immunogenetics; laboratory mouse; microorganism immunology; molecular cloning; mouse mammary tumor virus; neoplasm /cancer immunology; neutralizing antibody; viral carcinogenesis; virus infection mechanism; virus related neoplasm /cancer

DESCRIPTION (provided by applicant): Mouse Mammary Tumor Virus (MIMTV) is an exogenous milk-transmitted retrovirus that induces mammary gland tumors in some strains of laboratory mice. MMTV is carried from the gut of suckling pups to the mammary glands by lymphocytes. Susceptibility to exogenous MMTV infection and subsequent mammary tumorigenesis differs drastically, from absolute resistance to high susceptibility. For example, mice of the C3H/HeN or BALB/cJ strains are highly susceptible, whereas mice of the I/LnJ strain are highly resistant. We found that IJLnJ mice neonatally infected with MMTV produced avirulent virus particles, as they were coated with anti-virus antibodies of IgG2a isotype. The same antibodies were found in the sera of infected IJLnJ mice and were capable of neutralizing MMTV infection. The antibodies were reactive against env and gag gene products. Imrnunoglobulin isotope distribution was found to be normal in sera of uninfected I/LnJ mice, and immunization with virion proteins did not cause a bias production of anti-virus antibodies towards IgG2a isotype. Furthermore, JILnJ mice infected with another retrovirus, murine leukemia virus, also produced anti-virus neutralizing antibodies of IgG2a isotype specific for Env. Thus, it appears that the production of anti-virus antibodies of IgG2 isotype is a specialized response to retrovirus infection in I/LnJ mice. We established that a single gene (virus infectivity controller or vic) determines the production of these neutralizing antibodies in MMTV-infected JILnJ mice. The vic' about (resistant) allele found in JJLnJ mice is recessive to the vicS (susceptible) allele in C3WHeN or BALB/cJ mice. We plan to investigate the molecular mechanism of anti-virus antibody production and clone the gene conferring the resistant phenotype in I/LnJ mice.

描述(申请人提供)：小鼠乳腺肿瘤病毒(MIMTV)是 外源性牛奶传播逆转录病毒可导致某些人的乳腺肿瘤 实验室小鼠的品系。MMTV是从哺乳幼崽的肠道携带到 由淋巴细胞构成的乳腺。对外源性MMTV感染的易感性 而随后的乳腺肿瘤发生与绝对的 对高敏感性的抗性。例如，C3H/HEN或BALB/CJ小鼠 品系高度敏感，而I/LnJ品系的小鼠高度敏感 抵抗力强。我们发现新生感染MMTV的IJLnJ小鼠产生了 无毒病毒颗粒，因为它们被包被抗病毒抗体 IgG2a亚型。在感染的IJLnJ患者的血清中也发现了相同的抗体 并能中和MMTV感染。抗体是 对env和gag基因产物有反应。免疫球蛋白同位素 未感染的I/LnJ小鼠的血清呈正态分布， 病毒粒子蛋白免疫不会引起抗病毒的偏向产生 抗IgG2a亚型抗体。此外，JILnJ小鼠感染了另一种 逆转录病毒，小鼠白血病病毒，也产生了抗病毒中和 针对环境病毒的IgG2a亚型抗体。因此，看起来 产生IgG2同型的抗病毒抗体是一种特殊的反应 对I/LnJ小鼠逆转录病毒感染的影响。我们证实了单一基因(病毒 感染性控制器或VIC)决定了这些中和剂的生产 感染MMTV的JILnJ小鼠的抗体。受害者发现约(抗性)等位基因 在JJLnJ小鼠中，C3WHeN或C3WHeN的Vics(易感)等位基因是隐性的 Balb/CJ小鼠。我们计划研究其抗病毒的分子机制。 猪瘟耐药表型相关基因的克隆及抗体产生 I/LnJ小鼠。