Intranasal Immunization With an Apolipoprotein B-100 Fusion Protein Induces Antigen-Specific Regulatory T Cells and Reduces Atherosclerosis

Abstract

Objective-Atherosclerosis is an inflammatory disease. Autoimmune responses to low-density lipoproteins (LDL) contribute to its progression, whereas immunization with LDL may induce atheroprotective or proatherogenic responses. The objective of this study was to develop an atheroprotective vaccine by targeting a peptide of the LDL protein constituent apolipoprotein B-100 (apoB-100) to the nasal mucosa to induce a protective mucosal immune response. Methods and Results-A peptide comprising amino acids 3136 to 3155 of apoB-100 (p210) was fused to the B subunit of cholera toxin (CTB), which binds to a ganglioside on mucosal epithelia. The effect of nasal administration of the p210-CTB fusion protein on atherogenesis was compared with that of an ovalbumin peptide fused to CTB and with untreated controls. Immunization with p210-CTB for 12 weeks caused a 35% reduction in aortic lesion size in Apoemice. This effect was accompanied by induction of regulatory T cells that markedly suppressed effector T cells rechallenged with apoB-100 and increased numbers of interleukin (IL)-10 ϩ CD4 ϩ T cells. Furthermore, a peptidespecific antibody response was observed. Atheroprotection was also documented in apoe Ϫ/Ϫ mice lacking functional transforming growth factor-␤ receptors on T cells. Conclusion-Nasal

Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance

“…In previous studies, intranasal inoculation with HSP65 or an apolipoprotein B-100 peptide or oral feeding with ␤2-glycoprotin I resulted in some degree of amelioration of atherosclerosis that correlated with indications of increased IL-10 expression (9,(12)(13)(14). However, none of these studies demonstrated a causative role for IL-10 in the induction of immune tolerance.…”

“…Recognition of the autoimmune aspects of atherosclerosis has suggested the possibility of employing immunomodulatory approaches to ameliorate symptoms. That such an approach is feasible has been borne out in studies in which blockage of T cells reactive to native lipoprotein ApoB100 (4) or mucosal or subcutaneous immunization with HSP65 (9, 10), oxidized LDL (11), native ␤2-glycoprotein I (12), or apolipoprotein B-100 peptide (13,14) have been shown to be atheroprotective. Collagens can compose up to 60% of the total protein content in atherosclerotic plaques (15) and stimulate the growth and inflammation of atheromas (16).…”

Current prospects and future challenges for nasal vaccine delivery

“…67 More recently it has been shown that a similar tolerance induction can be achieved via nasal delivery through activation of the DCs in the draining lymph nodes to enhance induction of FoxP3CT-cells. 68 Examples of successful nasal delivery include immunization to suppress atherosclerosis 69,70 and arthritis. 71 The effect of adjuvant on tolerance is discussed in a later section.…”

A plant-made cholera toxin B subunit enhances mucosal wound healing and protects against ulcerative colitis and colon cancer.

“…Atherosclerosis, an inflammatory condition, has recently become a target for rCTB fusion proteins (66)(67)(68). In 2010, a mouse model of atherosclerosis showed protection by nasal administration of an rCTB fusion protein (p210-CTB) (67).…”

“…In 2010, a mouse model of atherosclerosis showed protection by nasal administration of an rCTB fusion protein (p210-CTB) (67). The p210 portion is derived from the apolipoprotein B-100 (ApoB100) peptide sequence as an alternative to a low density lipoprotein.…”