NONHUMAN PRIMATE CYTOKINES, CHEMOKINES & SECONDARY SIGNAL MOLECULES

非人灵长类细胞因子、趋化因子

• 批准号: 2711860
• 金额: $ 9.14万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2711860
• 关键词: AIDS; Primates; animal tissue; biological products; biotechnology; blood; communicable diseases; endocrine gland /system; genetics; immunology; lymphatic system; technology /technique development; virus

cDNAs coding for various cytokines were cloned and sequenced from nonhuman primates. In addition to the previously characterized IL-1I, IL-1J, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12I, IL-12J, IL-15, IFNK, TNFI, TGFJ and B7-1 from macaques and mangabeys, we have extended these analyses to the cytokines IL-7, IL-16 and IL-18, the chemokines MIP-1I, MIP-1J, RANTES and SDF-1 as well as the receptors CCR-2B, CCR-5, fusin, B7.2, CTLA-4 and the hematopoietic growth factors GM-CSF, SCF and Flt3-ligand to delineate differences accounting for epitope differences and bioactivity of nonhuman primate cytokines/chemokines. There is a particular interest in cytokines that play a deterministic role in modulating the type of immune response to certain pathogens including SIV. In this regard, efforts have been devoted at expressing recombinant macaque IL-2, IL-4, IL-10, IL-12, IL-15, IL-16, IL-18 and IFNK as these factors may open very potent therapeutic pathways in wide ranging cli nical applications such as transplantation, oncology, hematology and infectious diseases. Numerous studies related to humans in these fields utilize nonhuman primate models. Yet recent data shows that injection of human recombinant cytokines most often does not allow repeated or long-term treatment due to rapid development of an immune response towards these "foreign" molecules, resulting in inactivation and clearance of these cytokines. Furthermore the immune response of primate cells to the stimulation by certain human cytokines has been found to be markedly lower than the response of equivalent cells from human origins. Recombinant macaque IL-2, IL-4 and IL-12 are currently being utilized in vivo to potentiate SIV immunizations in collaboration with 2 research teams in Europe and with Dr. Vogel's research group at the NIH. IL-12 is also currently being assessed therapeutically in SIV infected macaques with Dr. Hillyer at the Yerkes Center. Furthermore, in collaboration with Dr. Hoff man (NMRI, US Navy), we were able to show that a single injection of IL-12 was sufficient to prevent development of infection by the malarial agent Plasmodium cynomolgi in rhesus macaques. These studies bear the potential to rapidly translate into therapeutic applications for the treatment of human diseases.

对编码多种细胞因子的cDNA进行了克隆和测序 非人灵长类动物。除了先前表征的IL-1I外， IL-1J、IL-2、IL-4、IL-5、IL-6、IL-8、IL-10、IL-12I、IL-12J、IL-15、 来自猕猴和短尾猴的IFNK，TNFi，TGFJ和B7-1，我们有 将这些分析扩展到细胞因子IL-7、IL-16和IL-18， 趋化因子MIP-1I、MIP-1J、RANTES和SDF-1及其受体 Ccr-2B、Ccr-5、Fusin、B7.2、CTLA-4与造血生长 GM-CSF、SCF和Flt3-Ligand因子的差异 非人灵长类表位差异及生物活性的解释 细胞因子/趋化因子。人们对细胞因子特别感兴趣 它们在调节免疫类型方面起着决定性的作用 对包括SIV在内的某些病原体的反应。在这方面，努力 致力于表达重组猕猴IL-2，IL-4，IL-10， IL-12、IL-15、IL-16、IL-18和IFNK作为这些因子可能会非常开放 广泛的临床应用中的有效治疗途径 如移植、肿瘤学、血液学和传染病。 在这些领域中，许多与人类有关的研究都利用了非人类 灵长类模型。然而，最近的数据表明，注射人类 重组细胞因子通常不允许重复或长期的 由于对这些疾病的免疫反应迅速发展而导致的治疗 “外来”分子，导致这些分子的失活和清除 细胞因子。此外，灵长类细胞对 某些人类细胞因子的刺激已被发现明显 比人类来源的同等细胞的反应要低。 目前正在利用重组猕猴IL-2、IL-4和IL-12 与2,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000 欧洲的研究团队和沃格尔博士的研究小组在 国家卫生研究院。IL-12目前也正在SIV接受治疗评估 被耶克斯中心的希勒博士感染的猕猴。此外， 在霍夫曼博士(NMRI，美国海军)的合作下，我们能够 表明一次注射IL-12就足以预防 我国食蟹猴疟原虫感染的研究进展 恒河猴。这些研究有可能迅速 转化为治疗人类疾病的应用 疾病。