Cytokines for Immune Protection from Acute Irradiation

涉及放射性材料的恐怖袭击的威胁和发生辐射事故的可能性要求改进辐射暴露受害者的治疗战略。造血细胞对辐射损伤高度敏感，辐射后它们的丢失会导致致命的感染。开发预防辐射造成的免疫损害并在辐射暴露后重建免疫功能的治疗方法将是一个重大的进步。该项目的目的是研究四种有希望的临床级细胞因子，它们可能显著改善致命剂量照射后的免疫重建，在公认的狗模型中。这四种细胞因子分别是FMS样酪氨酸激酶-3配体(Flt3Ligand[FL])、角质形成细胞生长因子(KGF)、白介素7(IL-7)和转铁蛋白(Tf)，无论是在致死剂量的全身照射(TBI)之前或之后。所有四种细胞因子在伽玛射线照射后都具有抗凋亡活性，并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)辐射暴露和造血的狗模型可以很好地预测人类的临床结果，(2)有大量关于急性辐射后狗的辐射防护的细胞因子的初步数据，(3)我们提出的所有四种人类细胞因子在狗身上都有交叉反应，(4)这些细胞因子已经在人类身上进行了研究，并处于临床开发的不同阶段。其目标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实现狗在其他致命剂量的照射后的存活。在特定目标1中，细胞因子将在脑损伤后给予；在特定目标2中，细胞因子将在颅脑损伤前后给予。在目标1中，我们将给予500cGyTBI，并用G-CSF加每个研究细胞因子治疗狗。在这个模型中，放射防护细胞因子被定义为与单独使用G-CSF相比能够显著提高存活率。在接下来的实验中，TBI剂量将连续增加100cGY，狗将接受放射防护细胞因子的组合治疗。主端点是 造血功能恢复，存活时间超过30天。次要终点是免疫重建。在研究完成后，我们将确定最佳的细胞因子治疗和在没有HSC支持的情况下可以可靠存活的最高剂量的TBI。

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.