Beekman Chris, Carrasco-Rojas Natalia, Withrow Julia, Dawson Robert, Bolch Wesley E, Paganetti Harald
Department of Radiation Oncology, Mass General Hospital/Harvard Medical School, Boston, Massachusetts.
Department of Biomedical Engineering, University of Florida, Gainesville, Florida.
Int J Radiat Oncol Biol Phys. 2025 Apr 14. doi: 10.1016/j.ijrobp.2025.03.080.
To develop a computational framework to investigate the implications of lymphocyte recirculation for understanding radiation-induced lymphopenia (RIL) and to compare model predictions with preclinical in vivo studies.
A whole-body compartmental model of lymphocyte migration in mice was developed, and unknown rate parameters were fitted to published experimental data. Using a stochastic representation of the model in combination with detailed mouse phantom meshes, implicit lymphocyte trajectories were computed. In parallel, a module was developed to reproduce small animal irradiation plans using either photon or proton beams. Combining these computational tools, we calculated the dose distribution of the recirculating lymphocyte pool in different irradiation scenarios and simulated the subsequent redistribution of viable lymphocytes. The relative importance of irradiation of secondary lymphoid organs (SLOs) versus the blood was investigated through in silico replications of 3 preclinical studies in which mice were locally irradiated.
Lymphocyte recirculation between the blood and SLOs attenuates lymphocyte depletion in 1 compartment by distributing the loss throughout the system. Because only a relatively small fraction (∼17% for mice) of the recirculating lymphocyte pool is in the blood at any given time, with most lymphocytes in the SLOs, the effect of SLO irradiation is greater than that of the blood. Predicted depletion trends correlated with those observed in preclinical studies but underestimated the degree of lymphopenia. The finding that proton beams can avert lymphopenia after whole-brain irradiation by sparing head and neck lymph nodes was reproduced.
The occurrence of RIL is associated with worse outcomes in patients with cancer but remains poorly understood. Therefore, a computational framework to replicate preclinical studies was developed to systematically investigate this phenomenon. Our simulations indicate that irradiation of SLOs contributes more to lymphocyte dose than blood irradiation. However, the expected cytotoxicity associated with the replicated preclinical studies could not fully account for the degree of lymphopenia observed.
建立一个计算框架，以研究淋巴细胞再循环对理解辐射诱导淋巴细胞减少症（RIL）的影响，并将模型预测结果与临床前体内研究进行比较。
建立了小鼠淋巴细胞迁移的全身房室模型，并将未知速率参数拟合到已发表的实验数据。结合详细的小鼠体模网格，使用模型的随机表示来计算隐式淋巴细胞轨迹。同时，开发了一个模块，用于使用光子或质子束重现小动物照射计划。结合这些计算工具，我们计算了不同照射场景下再循环淋巴细胞池的剂量分布，并模拟了存活淋巴细胞的后续重新分布。通过对3项小鼠局部照射的临床前研究进行计算机模拟，研究了次级淋巴器官（SLO）照射与血液照射的相对重要性。
血液与SLO之间的淋巴细胞再循环通过将损失分布于整个系统来减轻一个房室中的淋巴细胞耗竭。由于在任何给定时间，再循环淋巴细胞池中只有相对较小的一部分（小鼠约为17%）在血液中，而大多数淋巴细胞在SLO中，因此SLO照射的影响大于血液照射。预测的耗竭趋势与临床前研究中观察到的趋势相关，但低估了淋巴细胞减少的程度。质子束可通过 sparing 头颈部淋巴结避免全脑照射后淋巴细胞减少的这一发现得到了重现。
RIL的发生与癌症患者的较差预后相关，但仍了解不足。因此，开发了一个复制临床前研究的计算框架来系统地研究这一现象。我们的模拟表明，SLO照射对淋巴细胞剂量的贡献比血液照射更大。然而，与复制的临床前研究相关的预期细胞毒性不能完全解释观察到的淋巴细胞减少程度。
