Abstract
Hypertension is a global public health issue and the most important preventable cause of cardiovascular diseases. Despite the clinical availability of many antihypertensive drugs, many hypertensive patients have poor medication adherence and blood pressure control due, at least partially, to the asymptomatic and chronic characteristics of hypertension. Immunotherapeutic approaches have the potential to improve medication adherence in hypertension because they induce prolonged therapeutic effects and need a low frequency of administration. The first attempts to reduce blood pressure by using vaccines targeting the renin-angiotensin system were made more than half a century ago; however, at the time, a poor understanding of immunology and the mechanisms of hypertension and a lack of optimal vaccine technologies such as suitable antigen design, proper adjuvants, and effective antigen delivery systems meant that attempts to develop antihypertensive vaccines failed. Recent advances in immunology and vaccinology have provided potential therapeutic immunologic approaches to treat not only infectious diseases but also cancers and other noncommunicable diseases. One important biotechnology that has had a major impact on modern vaccinology is virus-like particle technology, which can efficiently deliver vaccine antigens without the need for artificial adjuvants. A human clinical trial that indicated the effectiveness and safety of a virus-like particle-based antiangiotensin II vaccine marked a turning point in the field of therapeutic antihypertensive vaccines. Here, we review the history of the development of immunotherapies for the treatment of hypertension and discuss the current perspectives in the field.
Highlights
Hypertension is a global public health issue and the most important preventable cause of cardiovascular disease worldwide [1, 2]
In 1999, Zelezna et al demonstrated that immunization against angiotensin II type 1 receptor (AT1R) attenuated the development of hypertension in young spontaneously hypertensive rats (SHRs) [51]. eir AT1R vaccine was composed of bovine gamma globulinconjugated AT1R partial peptides corresponding to residues 14–23 of the N-terminal part of AT1 receptor together with Freund’s adjuvant
Three doses of AT1R-keyhole limpet hemocyanin (KLH) vaccine induced an effective immune response and antihypertensive effect equivalent to those provided by six doses of vaccine [54]. ree doses of subcutaneous immunization with 100 μg of AT1R-KLH in combination with Freund’s complete adjuvant (FCA) at first administration and Freund’s incomplete adjuvant (FIA) at following administrations to SHRs at 4, 6, and 8 weeks of age attenuated the elevation of blood pressure; this attenuation of hypertension was equivalent to that provided by continuous administration of candesartan cilexetil (0.1 mg·kg− 1·day− 1) and was sustained for 25 weeks after the final immunization [54]
Summary
Hypertension is a global public health issue and the most important preventable cause of cardiovascular disease worldwide [1, 2]. Erefore, new strategies to control hypertension that effectively decrease blood pressure and improve medication adherence are required. Immunotherapeutic approaches for the treatment of hypertension, which are often referred to as “hypertension vaccines,” have the potential to improve health outcomes, reduce healthcare costs, and increase medication adherence because they induce prolonged therapeutic effects and have a low frequency of administration [7]. In 1898, Tigerstedt and Bergmann first reported that intravenous injection of extract from rabbit kidney into other rabbits induced an increase in blood pressure [8] This finding was a landmark discovery in the pathogenesis of hypertension, it went unregarded for the few decades. Erefore, prompted by the successful development of vaccines for infectious diseases, active and passive immunotherapies targeting renin were examined as early approaches for the treatment of hypertension. We review the history of the development of immunotherapies for the treatment of hypertension (Figure 1) and discuss the current perspectives in the field
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