Data_Sheet_4_Complex Stability and an Irrevertible Transition Reverted by Peptide and Fibroblasts in a Dynamic Model of Innate Immunity.pdf

We here apply a control analysis and various types of stability analysis to an in silico model of innate immunity that addresses the management of inflammation by a therapeutic peptide. Motivation is the observation, both in silico and in experiments, that this therapy is not robust. Our modeling results demonstrate how (1) the biological phenomena of acute and chronic modes of inflammation may reflect an inherently complex bistability with an irrevertible flip between the two modes, (2) the chronic mode of the model has stable, sometimes unique, steady states, while its acute-mode steady states are stable but not unique, (3) as witnessed by TNF levels, acute inflammation is controlled by multiple processes, whereas its chronic-mode inflammation is only controlled by TNF synthesis and washout, (4) only when the antigen load is close to the acute mode's flipping point, many processes impact very strongly on cells and cytokines, (5) there is no antigen exposure level below which reduction of the antigen load alone initiates a flip back to the acute mode, and (6) adding healthy fibroblasts makes the transition from acute to chronic inflammation revertible, although (7) there is a window of antigen load where such a therapy cannot be effective. This suggests that triple therapies may be essential to overcome chronic inflammation. These may comprise (1) anti-immunoglobulin light chain peptides, (2) a temporarily reduced antigen load, and (3a) fibroblast repopulation or (3b) stem cell strategies.

本研究针对一款用于探究治疗性肽调控炎症过程的固有免疫（innate immunity）硅基模型（in silico model），开展了控制分析与多类稳定性分析。本研究的动机源于硅基模拟与实体实验中的共同观测结果：该炎症治疗方案并不具备鲁棒性。

本研究的建模结果揭示了如下机制：
(1) 急性与慢性炎症表型的生物学现象，本质上可反映一种固有的复杂双稳态（bistability），且两种表型间的转换具有不可逆性；
(2) 该模型的慢性炎症表型拥有稳定且有时为唯一的稳态（steady states），而急性炎症表型的稳态虽稳定但并不唯一；
(3) 以肿瘤坏死因子（TNF）水平为观测指标可见，急性炎症受多类进程调控，而慢性炎症仅受TNF合成与清除过程调控；
(4) 仅当抗原负荷（antigen load）接近急性炎症表型的转换临界点时，诸多进程才会对细胞与细胞因子（cytokines）产生极强的调控作用；
(5) 不存在低于某一水平的抗原暴露量，使得仅通过降低抗原负荷即可触发向急性炎症表型的逆向转换；
(6) 添加健康成纤维细胞（fibroblasts）可使急性向慢性炎症的转换变为可逆，但(7) 存在一段抗原负荷区间，使得该治疗方案在此区间内无法生效。

上述结果提示，攻克慢性炎症或许需要采用三联疗法，具体可包括：(1) 抗免疫球蛋白轻链（immunoglobulin light chain）肽类药物，(2) 暂时性降低抗原负荷，以及(3a) 成纤维细胞再定植策略或(3b) 干细胞（stem cell）治疗方案。