INTERLEUKINS AND THEIR RECEPTORS IN TUMOR BIOLOGY AND AIDS

1)白介素4(IL-4)及其可溶性受体正在检测中 类风湿性关节炎、哮喘和癌症的系统性临床 通过注射或使用病毒载体进行基因转移。目前正在进行研究，以 IL-2的结构、功能、信号转导及靶向研究 4在免疫细胞和癌细胞上表达。的结构和功能 另一种与IL-4相关的白细胞介素IL-13的受体也在 调查过了。重组研究表明，IL-13R‘链 是非造血细胞中IL-4R的一种新成分，常见的 IL-2R链是造血细胞中IL-4R系统的组成部分。它是 同时也证明了IL-4R链是IL-13R的必需成分 系统。因此，IL-4R和IL-13R彼此共享不止一条链。 这些研究有助于解释疗效和毒性的机制。 当癌症患者使用异常低浓度的IL-4时。2) 了解IL-4信号转导的分子机制 和IL-13受体，我们研究了其磷酸化和活化。 JAK激酶与信号转导转录激活因子(STAT) 胞内蛋白质。我们的研究表明，IL-4和IL-13 利用相似的酪氨酸激酶和相同的STAT6在癌症中传递信号 细胞，这种模式不同于免疫细胞。IL-4可以利用 以IL-4R链为信号来源的IL-13R‘或IL-2R链 转导。IL-13还利用IL-4R和IL-13R‘链传递信号 转导。这些研究解释了为什么IL-4和IL-13是多余的 对多种细胞类型的影响。额外的重建实验 正在研究哪些激酶与不同的IL-2链有关 4和IL-13R复合体。3)IL-4和IL-13R定向靶向 假单胞菌外毒素、白喉毒素或受体导向 基因转移也在调查中。这两种受体 白细胞介素2在人类肿瘤细胞上大量表达，提供了一种 毒素治疗是基因治疗的有吸引力的靶点。活体实验 在裸鼠身上使用人脑肿瘤已显示出完全反应 在100%的动物中对环状置换的IL-4毒素有反应。Pre- 临床实验包括小鼠的药代动力学和毒理学， 大鼠脑内给药及鞘内和静脉注射。 已经在猴子身上进行了给药。基于这些结果，我们的 CBER批准了一期临床试验。我们已经治疗了一名患者 在加利福尼亚州圣莫尼卡的约翰·韦恩癌症研究所，使用 没有毒性的证据。正在招募更多的患者。这些 临床研究将有助于阐明该药物和其他药物的安全性 临床上各种INDS下的嵌合毒素。

1) Interleukin-4(IL-4) and its soluble receptor are being tested in the clinic for rheumatoid arthritis, asthma, and cancer by systematic injection or by gene transfer using viral vectors. Studies are underway to characterize structure, function, signal transduction and targeting of IL- 4 expressed on immune and cancer cells. The structure and function of receptor for IL-13, another IL-4 related interleukin, is also being investigated. Reconstitution studies have demonstrated that IL-13R' chain is a novel component of IL-4R in non-hematopoietic cells and the common IL-2R chain is a component of IL-4R systems in hematopoietic cells. It is also demonstrated that IL-4R chain is a necessary component of IL-13r system. Thus, IL-4R and IL-13R share more than one chain with each other. These studies help explain the mechanism of efficacy and toxicity seen when unusually low concentrations of IL-4 are used in cancer patients. 2) To understand the molecular mechanism of signal transduction by the IL-4 AND IL-13 receptor, we have studied the phosphorylation and activation of JAK kinases and signal transduction activator of transcription (STAT) intracellular proteins. Our studies demonstrate that both IL-4 and IL-13 utilize similar tyrosine kinases and same STAT6 for signalling in cancer cells and this pattern is different from immune cells. IL-4 can utilize either IL-13R' or IL-2R chain with IL-4R chain for its signal transduction. IL-13 also utilizes IL-4R and IL-13R' chain for signal transduction. These studies explain why IL-4 and IL-13 have redundant effect on a variety of cell types. Additional reconstitution experiments are underway to examine which kinases associate with various chains of IL- 4 and IL-13R complexes. 3) The IL-4 and IL-13R directed targeting of a Pseudomonas exotoxin, Diphtheria toxin, or alternatively receptor directed gene transfer is also being investigated. The receptors for these two interleukins are expressed in abundance on human tumor cells that offer an attractive target for toxin therapy for gene therapy. In vivo experiments in nude mice using human brain tumor has demonstrated complete responses in 100% of the animals in response to circular permuted IL-4 toxin. Pre- clinical experiments including pharmokinetics and toxicology in mice, intracerebral administration in rats and intrathecal and i.v. administration in monkeys have been performed. Based on these results, our phase 1 clinical trial was approved by CBER. We have treated one patient at John Wayne Cancer Institute, Santa Monica, CA at the lowest dose with no evidence of toxicity. Additional patients are being enrolled. These clinical studies will help elucidate safety profile of this and other chimeric toxins in clinic under various INDs.