Decrease in Blood Pressure and Regression of Cardiovascular Complications by Angiotensin II Vaccine in Mice

Futoshi Nakagami,Hiroshi Koriyama,Mariko Kyutoku,Takashi Miyake,Munehisa Shimamura,Tomohiro Katsuya,Ryuichi Morishita,Hiromi Rakugi,Mariana Kiomy Osako,Hironori Nakagami,Ali A Sovari

doi:10.1371/journal.pone.0060493

Abstract

Vaccines have been recently developed to treat various diseases such as cancer, rheumatoid arthritis and Alzheimer’s disease in addition to infectious diseases. However, before use in the clinical setting, vaccines targeting self-antigens must be demonstrated to be effective and safe, evoking an adequate humoral immune response from B cells while avoiding T cell activation in response to self. Although the vaccine targeting angiotensin II (Ang II) is efficient in rodents and humans, little is known regarding the immunological activation and safety of the vaccine. In this study, we evaluated the efficiency and safety of an Ang II peptide vaccine in mice. Immunization with Ang II conjugated to keyhole limpet hemocyanin (KLH) successfully induced the production of anti-Ang II antibody, which blocked Ang II signaling in human aortic smooth muscle cells. However, Ang II itself did not activate T cells, as assessed by the proliferation and lymphokine production of T cells in immunized mice, whereas KLH activated T cells. In an Ang II-infused model, the non-immunized mice showed high blood pressure (BP), whereas the immunized mice (Ang II-KLH) showed a significant decrease in systolic BP, accompanied by significant reductions in cardiac hypertrophy and fibrosis. Importantly, anti-Ang II antibody titer was not elevated even after the administration of large amounts of Ang II, indicating that Ang II itself boosted antibody production, most likely due to less activation of T cells. In addition, no accumulation of inflammatory cells was observed in immunized mice, because endogenous Ang II would not activate T cells after immunization with Ang II-KLH. Taken together, these data indicate that vaccines targeting Ang II might be effective to decrease high BP and prevent cardiovascular complications without severe side effects.

Highlights

Decrease in Blood Pressure by angiotensin II (Ang II) vaccine We examined the antibody production of B cells by evaluating anti-Ang II antibody titers in response to vaccination with Ang II, keyhole limpet hemocyanin (KLH), and Ang II-KLH with or without adjuvant
Ang IIKLH with adjuvant induced the production of anti-Ang II antibodies at day 42 after vaccination (Figure 1A)
The antibody titers in the Ang II-KLH with adjuvant group increased as the dose of the antigen increased (Figure 1B)

Summary

Introduction

Vaccines are common therapies to prevent infectious diseases, they have recently been expanded to treat diseases such as cancer, rheumatoid arthritis and Alzheimer’s disease by targeting self-antigens.[1,2,3,4,5,6] For example, the amyloid beta vaccine effectively reduced amyloid plaques and recovered memory functions in several animal models of Alzheimer’s disease.[3,4,5] the clinical trial of this vaccine was halted when 6 % of the participants developed aseptic meningoencephalitis, despite amyloid plaque reduction in the patients.[4,7] The postmortem examination of the brains of two patients who suffered from aseptic meningoencephalitis due to the vaccine revealed T lymphocyte infiltration into the brain.[8,9] This finding may suggest that the adverse effects of the vaccine were due to a T-cell-mediated autoimmune response.[4,8,9,10] This theory is supported by the presence of a T-cell epitope in the amyloid beta used for immunization, which was considered responsible for eliciting autoimmunity. The vaccine was modified to exclude T-cell epitopes, thereby avoiding T-cell activation without disrupting the B-cell epitopes responsible for antibody production.[11]

Methods

Results

Conclusion