Cytokines for Immune Protection from Acute Irradiation

用于急性辐射免疫保护的细胞因子

• 批准号: 6998631
• 负责人: GEORGE Earl GEORGES
• 金额: $ 150万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2010-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6998631
• 关键词: animal mortality; apoptosis; bioterrorism /chemical warfare; colony stimulating factor; cytokine; disease /disorder model; dogs; drug screening /evaluation; fibroblast growth factor; growth factor receptors; hematopoiesis; immune response; immunomodulators; immunopharmacology; interleukin 7; nonhuman therapy evaluation; protein tyrosine kinase; radiation recovery; radioprotective agents; transferrin; whole body irradiation dosage; whole body irradiation effect

The threat of terrorist attacks involving radioactive material and the potential for radiation accidents require the development of improved treatment strategies for victims of radiation exposure. Hematopoietic cells are highly sensitive to radiation damage, and their loss after radiation exposure results in lethal infections. Development of treatment that prevents immune damage from radiation and reconstitutes immune function after radiation exposure would be a significant advance. The aim of this project is to study four promising, clinical-grade cytokines that are likely to significantly improve immune reconstitution after lethal dose irradiation in the well-established dog model. The four cytokines are fms-like tyrosine kinase-3 ligand (Flt3 ligand [FL]), keratinocyte growth factor (KGF), interleukin (IL)-7, and transferrin (Tf) given alone or in combination either before or after exposure to lethal doses of total body irradiation (TBI). All four cytokines have anti-apoptotic activity after gamma irradiation and have direct or indirect beneficial effects on lymphocytes and other immune cells. We will study these cytokines in the dog since (1) the dog model of radiation exposure and hematopoiesis has been highly predictive of human clinical outcomes, (2) there is extensive preliminary data with cytokines for radioprotection of the dog after acute radiation, (3) all four of the human cytokines we have proposed are cross-reactive in the dog, and (4) these cytokines have been studied in humans and are in various stages of clinical development. The goal is to achieve survival of dogs after an otherwise lethal dose of irradiation with sustained immune reconstitution without hematopoietic stem cell (HSC) transplantation. In Specific Aim 1, cytokines will be given after TBI and in Specific Aim 2, cytokines will be given before and after TBI. In Aim 1, we will give 500 cGy TBI and treat dogs with G-CSF plus each study cytokine. In this model, a radioprotective cytokine is defined as achieving significantly improved survival compared to G-CSF alone. In the subsequent experiments, the TBI dose will be successively increased by 100 cGy increments and dogs will be treated with a combination of radioprotective cytokines. The primary endpoint is recovery of hematopoiesis and survival beyond day 30. The secondary endpoint is immune reconstitution. Upon study completion, we will have identified the optimal cytokine treatment and the highest dose of TBI that can be reliably survived without HSC support.

涉及放射性物质的恐怖主义袭击的威胁和发生辐射事故的可能性要求为辐射照射受害者制定更好的治疗战略。造血细胞对辐射损伤高度敏感，辐射暴露后造血细胞的损失会导致致命的感染。开发能够防止辐射造成免疫损伤并在辐射照射后重建免疫功能的治疗方法将是一项重大进展。该项目的目的是研究四种有希望的临床级细胞因子，它们可能在成熟的狗模型中显著改善致死剂量照射后的免疫重建。这四种细胞因子是fms样酪氨酸激酶-3配体（Flt3配体[FL]）、角化细胞生长因子（KGF）、白细胞介素(IL)-7和转铁蛋白（Tf），在暴露于致死剂量的全身照射（TBI）之前或之后单独或联合使用。这四种细胞因子在辐照后均具有抗凋亡活性，对淋巴细胞和其他免疫细胞有直接或间接的有益作用。我们将在狗身上研究这些细胞因子，因为(1)狗的辐射暴露和造血模型已经高度预测了人类的临床结果，(2)有大量关于细胞因子在急性辐射后对狗的辐射防护的初步数据，(3)我们提出的所有四种人类细胞因子在狗身上都是交叉反应的，(4)这些细胞因子已经在人类身上进行了研究，并且处于临床发展的不同阶段。目的是在不进行造血干细胞（HSC）移植的情况下，通过持续的免疫重建，使狗在接受致死剂量的照射后存活。在Specific Aim 1中，细胞因子将在TBI后给予，而在Specific Aim 2中，细胞因子将在TBI前后给予。在目标1中，我们将给予500 cGy TBI，并用G-CSF加每种研究细胞因子治疗犬。在该模型中，与单独使用G-CSF相比，放射保护细胞因子被定义为能够显著提高生存率。在随后的实验中，TBI剂量将以100 cGy的增量依次增加，狗将接受放射保护细胞因子的联合治疗。主要终点是