Research Scholar, Manipal University, Thrombosis Research Institute, Bangalore, India.
Molecular Immunology unit, Thrombosis Research Institute, London, UK.
Cardiovasc Drugs Ther. 2019 Aug;33(4):385-398. doi: 10.1007/s10557-019-06890-0.
The long-term effect of immune tolerance has not been explored so far in atherosclerosis. In the present study, we assessed the effect of mucosal tolerance to a multi antigenic construct expressing three peptides from ApoB, HSP60, and outer membrane protein from Chlamydia pneumonia (AHC) for 30 weeks at every 6-week interval to understand the kinetics of immune modulation in disease progression. The safety profile of the molecule was also evaluated in mice.
ApobLdlrHer/J mice (5-6 weeks) were orally dosed with multi antigenic construct (AHC) molecule on alternate days, followed by high-fat diet feeding to initiate atherosclerosis.
Treated animals showed an efficient reduction in plaque growth and lipid accumulation at 6 weeks (49%, p < 0.01) and 12 weeks (42.3%, p < 0.01) which decreased to 29% (p = 0.0001) at 18 weeks and at later time points. Macrophage accumulation was significantly lower at all time points (53% at 12 weeks to 27% at 30 weeks). Regulatory T cells increased in the spleen following treatment until 12 weeks (week 0 (2.57 ± 0.18 vs. 6.36 ± 0.03, p = 0.02), week 6 (4.52 ± 0.2 vs. 8.87 ± 0.32, p = 0.02), and week 12 (8.74 ± 0.37 vs. 15.4 ± 0.27, p = 0.02)) but showed a decline later. A similar trend was observed with tolerogenic dendritic cells. We observed an increase in antibody levels to low-density lipoprotein and oxidized LDL at later stages. AHC molecule was found to be safe in acute and repeated dose toxicity studies.
Our results suggest that immune tolerance to AHC protein by oral administration is able to provide efficient atheroprotection up to 18 weeks and moderately at later stages. Apart from immune regulatory cells, protective antibodies may also have a role in controlling atherosclerosis.
目前尚未研究免疫耐受在动脉粥样硬化中的长期作用。本研究评估了黏膜耐受多抗原构建体（表达载脂蛋白 B、热休克蛋白 60 和衣原体肺炎外膜蛋白的三种肽）的效果，每隔 6 周治疗一次，持续 30 周，以了解疾病进展中免疫调节的动力学。还评估了该分子在小鼠中的安全性概况。
apoB/LdlrHer/J 小鼠（5-6 周）隔日口服多抗原构建体（AHC）分子，然后给予高脂肪饮食以引发动脉粥样硬化。
治疗动物在 6 周（49%，p<0.01）和 12 周（42.3%，p<0.01）时有效减少斑块生长和脂质积累，在 18 周时减少到 29%（p=0.0001），在以后的时间点减少。所有时间点的巨噬细胞积累均显著降低（12 周时为 53%，30 周时为 27%）。治疗后脾脏中的调节性 T 细胞增加，直到 12 周（第 0 周（2.57±0.18 比 6.36±0.03，p=0.02），第 6 周（4.52±0.2 比 8.87±0.32，p=0.02）和第 12 周（8.74±0.37 比 15.4±0.27，p=0.02）），但后来下降。与耐受性树突状细胞观察到类似的趋势。我们观察到在后期阶段，抗低密度脂蛋白和氧化 LDL 的抗体水平增加。AHC 分子在急性和重复剂量毒性研究中被发现是安全的。
我们的结果表明，口服 AHC 蛋白的免疫耐受能够提供长达 18 周的有效动脉粥样硬化保护作用，并在后期阶段适度提供保护。除免疫调节细胞外，保护性抗体也可能在控制动脉粥样硬化中发挥作用。
