IL-1 HOMOLOGUES PROMOTE THE ACUTE INFLAMMATORY RESPONSE

IL-1 同系物促进急性炎症反应

• 批准号: 7128913
• 负责人: MICHAEL T LOTZE
• 金额: $ 28.17万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-06 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7128913
• 关键词: T lymphocyte; biomarker; clinical trials; dendritic cells; drug screening /evaluation; human subject; human therapy evaluation; immunologic substance development /preparation; inflammation; interleukin 1; interleukin 18; leukocyte activation /transformation; melanoma; natural killer cells; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; patient oriented research; proteomics; tumor antigens

We now have ten separate members of the extended IL-1 family [IL-1Fx] identified including IL-18 as the most distantly related member. The biologic role of many of these cytokines is unclear but IL-1alpha/IL-1F1, IL-1beta/IL-1F2, IL-18/IL-1F4, and IL-1H4/IL-1F7 promote antitumor responses when used as genetic constructs. We have previously shown in vitro that the antitumor effects of rIL-18 delivered in murine tumor models can be mimicked with coculture of murine DCs, NK cells, tumor, T-cells and IL-18, leading to the generation of tumor specific T-cells. IL-18 gene therapy is dependent on DC and NK cells, Fas signaling but not on NKT cells nor IFNgamma nor IL-12. A novel IL-1 homologue, IL-1H4/IL-1F7 also mediates antitumor effects, which are IL-12-dependent and Fas dependent, demonstrating a mixture of biologic effects attributable to IL-12 and IL-18. We will now explore these cytokines in human in vitro studies with DC and NK cells interacting to promote a T-cell response to human melanoma. We will thus explore whether the other IL-1 homologues including IL-1alpha, IL-1beta, IL1RA, IL-1F5/IL-1F9 and IL-1H4 [IL-1F7] mediate similar or dissimilar effects in in vitro culture. We will evaluate the critical components of the coculture system in human in vitro cultures with human melanoma. We will also evaluate whether IL-12 production is enhanced in an IFNgamma dependent manner in such cultures generating successful development of specific T-cells in NK and DC cultured with tumor. We will contrast the role of the IL-1 family members in cooperation with Project I to assess similar readouts in murine melanoma and the relative contributory roles of the TNF family members and the extended IL-12 family members with Project II. An important question will be to test these premises in vivo in patients with melanoma and we will assess this in innovative clinical protocols assessing local tumor response in patients with multiple cutaneous melanoma metastases and contrast with ex vivo strategies in patients with melanoma in Project II. We will test these notions in the following Specific Aims: Aim 1. Evaluate IL-1 homologues and their ability to promote NK and DC activation, polarization; Aim 2. Develop specific T-cell reactivity to autologous and MHC matched melanoma in vitro with IL-1 homologues; Aim 3. Integrate NK and DC biomarkers with IL-1 homologues and proteomic assays in treated melanoma patients and Aim 4. Administer ANK/DC to melanoma patients in sequential clinical trials.

现在，我们有十个分别的IL-1家族[IL-1FX]的独立成员，其中包括IL-18是最远的相关成员。许多这些细胞因子的生物学作用尚不清楚，但是IL-1Alpha/IL-1F1，IL-1BETA/IL-1F2，IL-18/IL-1F4和IL-1H4/IL-1F7在遗传时用作抗肿瘤反应，促进抗肿瘤反应构造。我们先前在体外表明，在鼠肿瘤模型中递送的RIL-18的抗肿瘤作用可以与鼠DC，NK细胞，肿瘤，T细胞，T细胞和IL-18的共培养模仿，从而导致肿瘤特异性T-特异性T-细胞。 IL-18基因疗法取决于DC和NK细胞，FAS信号传导，但不取决于NKT细胞或IFNGAMMA或IL-12。一种新型的IL-1同源物，IL-1H4/IL-1F7也介导抗肿瘤 效应，依赖性IL-12依赖性和FA，表明归因于IL-12和IL-18的生物学效应的混合物。现在，我们将通过直流和NK细胞相互作用以促进对人类黑色素瘤的T细胞反应，在人类体外研究中探索这些细胞因子。因此，我们将探讨其他IL-1同源物在内的IL-1Alpha，IL-1Beta，IL1RA，IL-1F5/IL-1F9和IL-1H4 [IL-1F7]是否介导了体外培养中的相似或不同作用。我们将评估人类黑色素瘤人类体外培养物中共培养系统的关键成分。我们还将评估在这种培养物中以IFNGAMMA的方式增强IL-12的产生，从而成功地开发了NK的特定T细胞 DC用肿瘤培养。我们将与IL-1家族成员与项目合作的作用进行对比，以评估鼠类黑色素瘤的类似读数以及TNF家族成员的相对贡献作用以及扩展的IL-12家族成员与II项目。一个重要的问题是，在黑色素瘤患者中测试这些前提，我们将通过创新的临床方案进行评估，评估多发性皮肤黑色素瘤转移患者的局部肿瘤反应，并与Project II中黑色素瘤患者的离体策略对比。我们将在以下特定目的中测试这些概念：目标1。评估IL-1同源物及其促进NK和DC激活，极化的能力； AIM 2。在体外与IL-1同源物在体外与自体和MHC相匹配的特异性T细胞反应性； AIM 3。将NK和DC生物标志物与治疗的黑色素瘤患者中的IL-1同源物和蛋白质组学测定相结合，并在顺序的临床试验中将ANK/DC与黑色素瘤患者施用。