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Erschienen in: Cardiovascular Drugs and Therapy 4/2019

22.07.2019 | ORIGINAL ARTICLE

Long-Term Efficacy and Safety of Immunomodulatory Therapy for Atherosclerosis

verfasst von: Lakshmi Narasimha Thota, Thiruvelselvan Ponnusamy, Xinjie Lu, Lakshmi Mundkur

Erschienen in: Cardiovascular Drugs and Therapy | Ausgabe 4/2019

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Abstract

Background and Aims

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.

Methods

Apobtm2SgyLdlrtm1Her/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.

Results

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.

Conclusions

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.
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Metadaten
Titel
Long-Term Efficacy and Safety of Immunomodulatory Therapy for Atherosclerosis
verfasst von
Lakshmi Narasimha Thota
Thiruvelselvan Ponnusamy
Xinjie Lu
Lakshmi Mundkur
Publikationsdatum
22.07.2019
Verlag
Springer US
Erschienen in
Cardiovascular Drugs and Therapy / Ausgabe 4/2019
Print ISSN: 0920-3206
Elektronische ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-019-06890-0

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