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Long-Term Efficacy and Safety of Immunomodulatory Therapy for Atherosclerosis

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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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Acknowledgments

We are extremely grateful to late Professor Vijay V Kakkar, Scientific Chairman, Thrombosis Research Institute, Bangalore for his constant encouragement and support. The support from Bharathi foundation for PhD students is gratefully acknowledged.

Funding

This work was supported by Thrombosis Research Institute, London and Bangalore, and Department of Biotechnology, Ministry of Science and Technology, Government of India (BT/01/CDE/08/07), and Bharathi Mittal foundation.

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Authors and Affiliations

  1. Research Scholar, Manipal University, Thrombosis Research Institute, Bangalore, India

    Lakshmi Narasimha Thota & Thiruvelselvan Ponnusamy

  2. Molecular Immunology unit, Thrombosis Research Institute, London, UK

    Xinjie Lu

  3. Molecular Immunology unit, Thrombosis Research Institute, Narayana Hrudayalaya, 258/A, Bommasandra Industrial Area, Anekal Taluk, Bangalore, 560099, India

    Lakshmi Mundkur

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  1. Lakshmi Narasimha Thota
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Contributions

The study was planned by LM and LNT. Experiments were carried out by LNT. The first draft of the manuscript was written by LNT. The manuscript was improvised by LM and LNT.

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Correspondence to Lakshmi Mundkur.

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Animal studies were performed and followed according to the CPCSEA guidelines and institute animal ethics committee.

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Thota, L.N., Ponnusamy, T., Lu, X. et al. Long-Term Efficacy and Safety of Immunomodulatory Therapy for Atherosclerosis. Cardiovasc Drugs Ther 33, 385–398 (2019). https://doi.org/10.1007/s10557-019-06890-0

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