Adawi A, Zhang Y, Baggs R, Rubin P, Williams J, Finkelstein J, Phipps R P
Cancer Center, University of Rochester School of Medicine, Rochester, New York, 14642, USA.
Clin Immunol Immunopathol. 1998 Dec;89(3):222-30. doi: 10.1006/clin.1998.4606.
This study investigated whether CD40-CD40 ligand (L) interactions are important in mediating ionizing radiation-induced lung toxicity. Radiotherapy is a key component in the management of malignant diseases and is a conditioning regimen for bone marrow transplantation. Unfortunately, radiation therapy is particularly toxic to the lung, potentially inducing a fatal pneumonitis and fibrosis, thus limiting its effectiveness. There are no therapies that protect against the development of radiation-induced lung toxicity. Using a mouse model of radiation-induced lung toxicity, a monoclonal anti-CD40L antibody (MR1) that disrupts CD40-CD40L interactions was tested for the ability to reduce lung injury. C57BL/6 mice were pretreated with either nothing, MR1, or hamster IgG 24 h prior to a single dose of 15 Gray ionizing radiation to the thorax. During the following 26 weeks, mice continued to receive MR1 or hamster IgG twice per week. MR1 protected against death from radiation pneumonitis and fibrosis and dramatically reduced lung pathology as evidenced by a limited influx of inflammatory cells, minimal collagen deposition, and septal thickening. MR1 also prevented radiation-induced pulmonary mastocytosis and blunted expression of cyclooxygenase-2, a proinflammatory enzyme responsible for prostaglandin synthesis. Disruption of CD40-CD40L interactions may offer a new mode of intervention to protect against radiation-induced pulmonary toxicity.
本研究调查了CD40 - CD40配体（L）相互作用在介导电离辐射诱导的肺毒性中是否重要。放射治疗是恶性疾病治疗的关键组成部分，也是骨髓移植的预处理方案。不幸的是，放射治疗对肺尤其具有毒性，可能诱发致命的肺炎和纤维化，从而限制了其有效性。目前尚无预防辐射诱导的肺毒性发生的治疗方法。利用辐射诱导的肺毒性小鼠模型，测试了一种破坏CD40 - CD40L相互作用的单克隆抗CD40L抗体（MR1）减轻肺损伤的能力。在对C57BL / 6小鼠胸部进行单次15格雷电离辐射前24小时，分别给予其无处理、MR1或仓鼠IgG进行预处理。在接下来的26周内，小鼠继续每周接受两次MR1或仓鼠IgG。MR1可预防因放射性肺炎和纤维化导致的死亡，并显著减轻肺部病理变化，表现为炎症细胞浸润有限、胶原沉积极少以及间隔增厚。MR1还可预防辐射诱导的肺肥大细胞增多症，并减弱环氧化酶 - 2（一种负责前列腺素合成的促炎酶）的表达。破坏CD40 - CD40L相互作用可能提供一种新的干预模式，以预防辐射诱导的肺毒性。
