PS-BPB03-3: MODIFIED ANGIOTENSIN II PEPTIDE VACCINE FOR HYPERTENSION

Abstract

We and others recently reported that an angiotensin II vaccine for hypertension successfully attenuated elevated blood pressures in an animal model without any immunogenic side effects. In this system, an immunogenic molecule (i.e., KLH) with adjuvants provides an antigen that supports the activation of helper T cells. We recently developed a novel peptide, AJP001, that possesses both a mouse T-cell epitope and adjuvant action. Direct conjugation to the antigen is useful for peptide vaccines without the addition of adjuvants. In this study, the efficacy of an angiotensin II and AJP001-conjugated peptide vaccine (AJP001- angiotensin II) was evaluated in mice. The anti-angiotensin II antibody titer was measured in Balb/C mice following three injections of AJP001-angiotensin II at 2-week intervals. SBP was measured during vaccination of Balb/C mice treated with angiotensin II infusion. AJ-angiotensin II treatment resulted in an increase in the anti-angiotensin II antibody titer in a dose-dependent manner without the addition of adjuvants. In the analysis of the humoral immune response, AJP001-angiotensin II mainly elicited IL-4 and IL-10 production, as measured by an enzyme-linked immune absorbent spot assay, which suggests the induction of a Th2 response. Importantly, cotreatment with purified antibodies attenuated angiotensin II-induced extracellular signal-regulated kinase phosphorylation in cultured vascular smooth muscle cells. The SBP in immunized mice was significantly lower than that in nonimmunized mice (135.9 ± 8.5 vs. 154.9 ± 16.8 mmHg, P = 0.02). Furthermore, angiotensin II-induced perivascular fibrosis in the heart was significantly attenuated in immunized mice, which also exhibited decreased mRNA expression of collagen I/III and transforming growth factor-beta. It may be a simple and useful therapeutic peptide vaccine, and we now further modify the T cell epitope for clinical trials.