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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供 该子项目的主要支持。 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源的子项目可能列出的总成本。 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 受 HIV 和 SIV 感染影响的最早器官之一是胃肠道，此外，大部分病毒复制发生在该区室中，导致 CD4+ T 细胞快速且永久消除，特别是那些共同表达病毒辅助受体 CCR5 的细胞。迄今为止尚不清楚的是，持续的病毒复制是否需要新的 CD4 靶标的不断涌入，这将通过阻断潜在靶细胞向肠道的运输来开启新的治疗前景。异二聚体整合素 ¿ 4¿7 尤其在肠道炎症综合征（如 IBD、UC 和克罗恩病）的治疗中受到特别关注。我们用针对 ¿7 的灵长类化单克隆抗体对 4 只恒河猴进行了预处理。 4-7 在感染 SIVmac239 之前，对这些猴子和仅给予 SIV 的对照动物进行了 SIV 复制和免疫反应的比较，阻断细胞向肠道的运输导致了急性 SIV 感染降低和延迟峰值的动态的显着差异。急性 SIV 复制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，未来的分析将调查细胞运输的长期阻断。慢性感染期间和粘膜挑战后的肠道。