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

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 最早受艾滋病毒和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这个隔间，导致CD4T细胞迅速和永久消除，特别是那些共同表达病毒共受体CCR5的细胞。目前尚不清楚的是，持续的病毒复制是否需要不断涌入新的CD4靶点，这将通过阻止潜在靶细胞进入肠道打开新的治疗前景。在决定肠道运输的分子中，异二聚体整合素获得了特别的关注，特别是在治疗肠炎综合征如IBD、UC和克罗恩病方面。在感染SIVmac239SIV之前，我们用一种针对SIVmac239SIV的特异性单抗对4只恒河猴进行了预处理，比较了这些猕猴和只给予SIV的对照动物对病毒的复制和免疫应答。阻断细胞对肠道的运输导致SIV急性感染的动态发生深刻的改变，降低和推迟了SIV的复制高峰，并导致主要复制部位从肠道向中枢淋巴器官转移。这项初步研究的结果已被《免疫学杂志》接受。未来的分析将调查慢性感染期间和粘膜攻击后细胞对肠道交通的长期阻断。

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.