THE ANTI-ALPHA-4/BETA-7 MONOCLONAL ANTIBODY PROJECT

抗 ALPHA-4/BETA-7 单克隆抗体项目

• 批准号: 8357511
• 负责人: Aftab A. Ansari
• 金额: $ 5.95万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357511
• 关键词: Acute; Affect; Attention; CD4 Positive T Lymphocytes; Cells; Chemokine (C-C Motif) Receptor 5; Chronic; Control Animal; Crohn' s disease; Funding; Future; Gastrointestinal tract structure; Grant; HIV; Immune response; Immunology; Infection; Inflammatory; Integrins; Journals; Lymphatic; Macaca mulatta; Monkeys; Monoclonal Antibodies; National Center for Research Resources; Organ; Pilot Projects; Primates; Principal Investigator; Research; Research Infrastructure; Resources; SIV; Site; Source; Syndrome; United States National Institutes of Health; Viral; Virus; cost; novel therapeutics; trafficking

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. One of the earliest organs affected by HIV and SIV infection is the GI tract. Moreover, the bulk of viral replication occurs in this compartment leading to rapid and permanent elimination of CD4+ T cells, in particular those co expressing the viral co-receptor CCR5. What is not clear to date is whether the continuous viral replication requires a constant influx of new CD4 targets or not, which would open a novel therapeutic vista by blocking traffic of potential target cells to the gut. Among the molecules dictating traffic to the gut the heterodimeric integrin ¿4¿7 has gained particular attention especially in the therapy of gut inflammatory syndromes such as IBD, UC and Crohn's Disease. We have pre-treated 4 rhesus macaques with a primatized monoclonal antibody specific to ¿4¿7prior to infection with SIVmac239 SIV replication and immune responses to the virus were compared in these monkeys and control animals given SIV only. Blocking cell traffic to the gut resulted in profound differences in the dynamic of the acute SIV infection lowering and delaying the peak of acute SIV replication and causing a shift of the main replication site from the gut to central lymphatic organs. Results of this pilot study have been accepted in the Journal of Immunology. Future analyses will investigate prolonged blockade of cell traffic to the gut during chronic infection and after mucosal challenge.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 最早受HIV和SIV感染影响的器官之一是胃肠道。此外，大部分病毒复制发生在该隔室中，导致CD 4 + T细胞的快速和永久消除，特别是共表达病毒共受体CCR 5的那些。目前尚不清楚的是，持续的病毒复制是否需要新的CD 4靶点的不断涌入，这将通过阻断潜在靶细胞向肠道的运输开辟新的治疗前景。在决定肠道运输的分子中，异二聚体整合素4 7特别在治疗肠道炎性综合征如IBD、UC和克罗恩病中获得了特别的关注。我们在用SIVmac 239感染之前用特异于<$4 <$7的灵长类单克隆抗体预处理了4只恒河猴，SIV复制和对病毒的免疫应答在这些猴子和仅给予SIV的对照动物中进行了比较。阻断细胞运输到肠道导致急性SIV感染的动力学的深刻差异，降低和延迟急性SIV复制的峰值，并导致主要复制位点从肠道转移到中央淋巴器官。这项初步研究的结果已被《免疫学杂志》接受。未来的分析将研究慢性感染期间和粘膜激发后细胞运输到肠道的长期阻断。