Kim Jeremiah Y, Rosenberger Matthew G, Chen Siquan, Ip Carman Km, Bahmani Azadeh, Chen Qing, Shen Jinjing, Tang Yifeng, Wang Andrew, Kenna Emma, Son Minjun, Tay Savaş, Ferguson Andrew L, Esser-Kahn Aaron P
Pritzker School of Molecular Engineering, University of Chicago, 5640 South Ellis Avenue, Chicago, Illinois 60637, United States.
ACS Cent Sci. 2023 Feb 23;9(3):427-439. doi: 10.1021/acscentsci.2c01351. eCollection 2023 Mar 22.
Stimulation of the innate immune system is crucial in both effective vaccinations and immunotherapies. This is often achieved through adjuvants, molecules that usually activate pattern recognition receptors (PRRs) and stimulate two innate immune signaling pathways: the nuclear factor kappa-light-chain-enhancer of activated B-cells pathway (NF-κB) and the interferon regulatory factors pathway (IRF). Here, we demonstrate the ability to alter and improve adjuvant activity via the addition of small molecule "immunomodulators". By modulating signaling activity instead of receptor binding, these molecules allow the customization of select innate responses. We demonstrate both inhibition and enhancement of the products of the NF-κB and IRF pathways by several orders of magnitude. Some modulators apply generally across many receptors, while others focus specifically on individual receptors. Modulators boost correlates of a protective immune responses in a commercial flu vaccine model and reduced correlates of reactogenicity in a typhoid vaccine model. These modulators have a range of applications: from adjuvanticity in prophylactics to enhancement of immunotherapy.
激活先天免疫系统在有效的疫苗接种和免疫治疗中都至关重要。这通常是通过佐剂来实现的，佐剂是一类通常能激活模式识别受体（PRR）并刺激两条先天免疫信号通路的分子：活化B细胞的核因子κB轻链增强子通路（NF-κB）和干扰素调节因子通路（IRF）。在此，我们展示了通过添加小分子“免疫调节剂”来改变和提高佐剂活性的能力。通过调节信号活性而非受体结合，这些分子能够定制特定的先天免疫反应。我们证明了NF-κB和IRF通路产物的抑制和增强幅度达到了几个数量级。一些调节剂能广泛作用于许多受体，而另一些则专门针对个别受体。在商用流感疫苗模型中，调节剂增强了保护性免疫反应的相关指标，在伤寒疫苗模型中则降低了反应原性的相关指标。这些调节剂具有一系列应用：从预防性疫苗的佐剂作用到免疫治疗的增强作用。
