Duke Human Vaccine Institute and Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
Department of Pathology/Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
Int J Radiat Oncol Biol Phys. 2023 Mar 15;115(4):945-956. doi: 10.1016/j.ijrobp.2022.10.024. Epub 2022 Oct 23.
The aim of this study was to develop an improved understanding of the delayed immunologic effects of acute total body irradiation (TBI) using a diverse cohort of nonhuman primates as a model for an irradiated human population.
Immune recovery was evaluated in 221 rhesus macaques either left unirradiated (n = 36) or previously irradiated (n = 185) at 1.1 to 8.5 Gy TBI (median, 6.5 Gy) when aged 2.1 to 15.5 years (median, 4.2 years). Blood was drawn annually for up to 5 years total between 0.5 and 14.3 years after exposure. Blood was analyzed by complete blood count, immunophenotyping of monocytes, dendritic cells (DC) and lymphocytes by flow cytometry, and signal joint T-cell receptor exclusion circle quantification in isolated peripheral blood CD4 and CD8 T cells. Animals were categorized by age, irradiation status, and time since irradiation. Sex-adjusted means of immune metrics were evaluated by generalized estimating equation models to identify cell populations altered by TBI.
Overall, the differences between irradiated and nonirradiated animals were subtle and largely restricted to younger animals and select cell populations. Subsets of monocytes, DC, T cells, and B cells showed significant interaction effects between radiation dose and age after adjustment for sex. Irradiation at a young age caused transient increases in the percentage of peripheral blood myeloid DC and dose-dependent changes in monocyte balance for at least 5 years after TBI. TBI also led to a sustained decrease in the percentage of circulating memory B cells. Young irradiated animals exhibited statistically significant and prolonged disruption of the naïve/effector memory/central memory CD4 and CD8 T-cell equilibrium and exhibited a dose-dependent increase in thymopoiesis for 2 to 3 years after exposure.
This study indicates TBI subtly but significantly alters the circulating proportions of cellular mediators of adaptive immune memory for several years after irradiation, especially in macaques under 5 years of age and those receiving a high dose of radiation.
本研究旨在通过使用非人类灵长类动物作为受照人群模型，深入了解急性全身照射（TBI）的延迟免疫效应。
我们评估了 221 只恒河猴的免疫恢复情况，其中 36 只为未照射组，185 只为照射组，照射剂量为 1.1 至 8.5Gy（中位数 6.5Gy），照射时年龄为 2.1 至 15.5 岁（中位数 4.2 岁）。在暴露后 0.5 至 14.3 年之间，每年采集一次血液，总采集时间长达 5 年。通过全血细胞计数、流式细胞术对单核细胞、树突状细胞（DC）和淋巴细胞进行免疫表型分析，以及在分离的外周血 CD4 和 CD8 T 细胞中定量信号连接 T 细胞受体排除环，对血液进行分析。根据年龄、照射状态和照射后时间将动物分类。通过广义估计方程模型评估免疫指标的性别调整均值，以确定 TBI 改变的细胞群体。
总的来说，照射组和未照射组之间的差异很小，主要局限于年幼的动物和特定的细胞群体。在调整性别后，单核细胞、DC、T 细胞和 B 细胞的亚群在辐射剂量和年龄之间存在显著的相互作用。年幼时照射会导致外周血髓样 DC 的比例短暂增加，并在 TBI 后至少 5 年内导致单核细胞平衡的剂量依赖性变化。TBI 还导致循环记忆 B 细胞的比例持续下降。年幼的照射动物表现出明显且持久的幼稚/效应记忆/中央记忆 CD4 和 CD8 T 细胞平衡破坏，并在暴露后 2 至 3 年内表现出胸腺生成的剂量依赖性增加。
本研究表明，TBI 会在照射后数年，特别是在 5 岁以下和接受高剂量辐射的猕猴中，轻微但显著地改变适应性免疫记忆的循环细胞比例。
