Mathematical Modeling of Early Cellular Innate and Adaptive Immune Responses to Ischemia/Reperfusion Injury and Solid Organ Allotransplantation.
Mathematical Modeling of Early Cellular Innate and Adaptive Immune Responses to Ischemia/Reperfusion Injury and Solid Organ Allotransplantation.
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DOI：
10.3389/fimmu.2015.00484
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发表时间：
2015
影响因子：
7.3
通讯作者：
Vodovotz Y
中科院分区：
文献类型：
--
作者：
Day JD;Metes DM;Vodovotz Y
本文用常微分方程组建立了器官移植早期炎症反应的数学模型。我们首先考虑仅与初始外科手术相关的炎症事件和随后的缺血/再灌注（I/R）事件，这些事件导致宿主和供体移植物的组织损伤。这些事件释放损伤相关的分子模式分子（DAMP），从而引发急性炎症反应。在该模型的模拟中，炎症的消退取决于由这些事件和患者的（共）病引起的组织损伤的严重程度。我们在没有抗原性同种异体移植物错配的情况下（但DAMP释放与移植前移植物损伤程度成比例），用T细胞的炎症效应增强了先前发表的急性炎症数学模型的一部分。最后，我们包括移植物的抗原错配，这导致刺激有效的记忆T细胞反应，导致从移植物中进一步释放DAMP，并伴随着同种异体移植物损伤的增加。最后阶段还包括监管机制。我们的模拟表明，手术损伤和I/R诱导的移植物损伤可以很好地耐受时，每一个单独存在的收件人，但他们的组合（沿着抗原错配）可能会导致急性排斥反应，在临床上看到的一个子集的患者。从我们的模拟中出现的一个现象是，低水平的DAMP释放可以使受体耐受不匹配的同种异体移植物，而不同的再刺激方案导致了夸大的排斥反应，与已发表的研究一致。我们认为，机械的数学模型可能作为一种辅助的患者或亚组特定的预测，模拟临床研究，和合理的免疫抑制设计。
A mathematical model of the early inflammatory response in transplantation is formulated with ordinary differential equations. We first consider the inflammatory events associated only with the initial surgical procedure and the subsequent ischemia/reperfusion (I/R) events that cause tissue damage to the host as well as the donor graft. These events release damage-associated molecular pattern molecules (DAMPs), thereby initiating an acute inflammatory response. In simulations of this model, resolution of inflammation depends on the severity of the tissue damage caused by these events and the patient’s (co)-morbidities. We augment a portion of a previously published mathematical model of acute inflammation with the inflammatory effects of T cells in the absence of antigenic allograft mismatch (but with DAMP release proportional to the degree of graft damage prior to transplant). Finally, we include the antigenic mismatch of the graft, which leads to the stimulation of potent memory T cell responses, leading to further DAMP release from the graft and concomitant increase in allograft damage. Regulatory mechanisms are also included at the final stage. Our simulations suggest that surgical injury and I/R-induced graft damage can be well-tolerated by the recipient when each is present alone, but that their combination (along with antigenic mismatch) may lead to acute rejection, as seen clinically in a subset of patients. An emergent phenomenon from our simulations is that low-level DAMP release can tolerize the recipient to a mismatched allograft, whereas different restimulation regimens resulted in an exaggerated rejection response, in agreement with published studies. We suggest that mechanistic mathematical models might serve as an adjunct for patient- or sub-group-specific predictions, simulated clinical studies, and rational design of immunosuppression.