Table 2. Oral, active and passive immunizations.

Target	Treatment	Immunological/metabolic effect	Effect on atherosclerosis	Experimental model	Diet	Reference
HSP65	Oral administration of HSP65	Induction of tolerance, 4-fold ↑ production of IL-4 by lymph node cells in HSP65-fed and immunized mice	61% ↓ in fatty streak formation in aortic origin	Female LDLR–/– mice	Western type diet	Harats et al., 2002 [56]
HSP65	Oral (O) or nasal (N) admin stration of HSP65	Induction of tolerance (↓ proliferation; IFN-γ production and ↑ in IL-10 production by lymph node cells (N) to HSP65), ↓ anti-HSP65 IgG and ↑ IgG1	↓ Lesion size in aortic arch (O,N), ↓ macrophages and CD4+ T-cells(N), ↓ IFN-γ and ↑ IL-10 expression (N), co-localization of IL-10 with macrophages and SMCs	Female LDLR–/– mice	High cholesterol diet	Maron et al., 2002 [57]
HSP60	Oral administration of HSP60, HSP60* (253–268)	Induction of tolerance (↓ splenocytes proliferation to HSP60), ↑ TGF-β and IL-10 by mesenteric lymph node cells, ↑ CD4+CD25+Foxp3+ cells in blood, spleen and mesenterlc lymph nodes	↓ Lesion size in aortic orgin (HSP60–27% ↓) and in carotid artery (HSP60–81%, HSP60*–83%), ↓ intima/lumen ratio (HSP60–69% and HSP60*–74%), ↑ mRNA expression of CTLA-4, CD25, Foxp3	Male LDLR–/– mice (+CA collar)	Western type diet	van Puijvelde et al., 2007 [58]
HSP65	Nasal administration of HSP65	Induction of tolerance (↓ splenocytes proliferation to HSP65), 7-fold ↑ in IL-10 production by T-cells, ↓ serum lipids (TC, HDL-C, LDL-C)	↓ Lesion size in aorta (from 63% to 13%)	Male NZW rabbits	High cholesterol diet	Xiong et al., 2009 [63]
β2-GPI	Oral administration of human and bovine β2-GPI	Induction of tolerance, ↓ lymph node proliferation to β2GPI and reactivity to OxLDL, ↑ of IL-4 and ↑ IL-10 production in lymph node cells	Suppression of early atherosclerotic lesions (45% ↓ with human β2GPI, 57% ↓ with bovine β2GPI)	Female LDLR–/– mice	Western type diet	George et al., 2004 [59]
OxLDL	Oral administration of human oxidized LDL	Induction of tolerance, ↓ CD4+CD25+Foxp3+ T-cells in spleen and mesenteric lymph nodes, 6-fold ↑ of TGF-β in lymph node cells after re-stimulation with OxLDL	↓ Initiation (30% ↓ aortic root, 71% ↓ carotid artery) and progression (45% ↓ aortic root), ↑ mRNA expression of CD25, Foxp3 and CTLA	LDLR–/– mice (+CA collar)	Western type diet	Van puijvelde et al., 2006 [60]
MDA-LDL	Immunization with homologous MDA-LDL	Induction of anti-MDA-LDL antibodies (IgG)	↓ In lesion size (entire aorta: 48% vs. 68%, arch and thoracic aorta: 57% vs. 79%, abdominal aorta: 36% vs. 52%)	Male and female LDLR–/– WHHL rabbits	Normal chow diet	Palinski et al., 1995 [27]
LDL and OxLDL	Immunization with homologous LDL and CuOx-LDL	Induction of antibodies against OxLDL (IgG)	↓ Lesion size in proximal aorta 74% (LDL) and 48% (CuOx-LDL)	Male NZW rabbits	High cholesterol diet	Ameli et al., 1996 [28]
MDA-LDL	Immunization with homologous MDA-LDL	Induction of anti-MDA-LDL antibodies (IgG)	53% ↓ Lesion size (aortic origin)	Female apoE–/– mice	Normal chow diet	George et al., 1998 [30]
LDL and OxLDL	Immunization with homologous LDL and CuOx-LDL	Induction of antibodies against OxLDL (IgG)	↓ Neointimal area (58% ↓ with OxLDL, 19% ↓ with LDL)	Male NZW rabbits (femoral artery balloon injury)	High cholesterol diet	Nilsson et al., 1998 [29]
LDL and MDA-LDL	Immunization with MDA-LDL	↑ Anti-MDA-LDL IgG (↑ of IgG1 and IgG2a Abs) and ↑ IgG to other oxidative neoepitopes, ↑ IgM (to CuOx-LDL and 4HNE-LDL)	↓ Lesion size aortic origin (46% ↓ with MDA-LDL and 37% ↓ with LDL)	Male LDLR–/– mice	High cholesterol diet	Freigang et al., 1998 [31]
Plaque homogenates and MDA-LDL	Immunization with homologous plaque homogenates and MDA-LDL	↑ Anti-MDA-LDL IgG and anti-cardiolipin IgG and association with ↓ serum cholesterol, activation of lymph node cells with MDA-LDL	39% ↓ Lesion size (homogenate) 46% ↓ (MDA-LDL) in aortic origin, ↓ CD8+ cells	Male apoE–/– mice	Western diet.	Zhou et al., 2001 [32]
PC epitopes	Immunization with heat inactivated PC-containing pneumococci	Induction of PC-specific Abs, molecular mimicry between S. pneumoniae and OxLDL, ↑ anti-OxLDL IgM (T15id+ IgM), ↑ OxLDL-specific T15id+ IgM secreting cells (spleen and bone marrow)	22% ↓ Lesion size (aortic rorigin)	Male LDLR–/– mice	High cholesterol diet	Binder et al., 2003 [41]
MDA-LDL	Immunization with homologous MDA-LDL	↑ Anti-MDA-LDL Abs (IgM, IgG1 >>IgG2a), ↑ plasma IL-5, ↑ secretion of MDA-LDL specific Th2 cytokines, ↑ T15id+ IgM, ↑ plasma IgM/apoB immune complexes	25% ↓ Lesion size (aortic origin)	Female LDLR–/– mice	High chlesterol diet	Binder et al., 2004 [34]
MDA-LDL	Immunization with homologous MDA-LDL	↑ Anti-MDA-LDL IgG (IgM, IgG2b> IgG1>IgG2a Ab titer), lower IgM, IgG2a, IgG2b titer in CD4–/–apoE–/– vs. apoE–/–	39% ↓ Lesion size (aortic origin) for CD4–/–apoE–/– and 23% ↓ lesion size for apoE–/–	Female CD4–/– apoE–/– and apoE–/– mice	Normal chow diet	Zhou et al., 2005 [33]
PC-KLH	Immunization with PC-KLH	↑ Anti-PC and anti-OxLDL Abs (IgM and IgG), ↑ splenic mature B -cells	↓ 40% Lesion size (aortic origin), ↓ expression of MHCII, presence of T15d+Abs, B-cellclusters	Female apoE–/– mice	Normal chow diet	Caligiuri et al., 2007 [42]
MDA-modified apoB100 peptides	Immunization with different native and MDA-modified apoB100 peptides	↑ IgG Abs against native and MDA-modified apoB100 peptides	60% ↓ lesion size in descending aorta, ↑ collagen in subvalvular plaques (P143, P210), no ↓ in lesion size (5 peptide mixture)	Male apoE–/– mice	Normal chow diet	Fredrikson et al., 2003 [44]
MDA-modified apoB100 peptides	Immunization with MDA-modified apoB100 peptides (P45 and P74, control P240)	50-fold ↑ anti-peptide IgG1 (P45, P74)	↓ Lesion size (48% ↓ with P45, 31% ↓ with P74), ↓ macrophage content	apoE–/– mice		Fredrikson et al., 2005 [45]
MDA-modified apoB100 peptides	Immunization with apoB100 peptides (P45 and P210)	↑ Anti-LDL and anti-OxLDL IgM in P45, similar trend with P210, no change in anti-MDA-LDL IgG or IgM Abs	↓ Lesion size (66% ↓ with P45, 59% ↓ with P210)	Male LDLR–/–/human apo B-100 mice		Fredrikson et al., 2008 [46]
PC epitopes	Murine T15id+ anti-PC IgM	↑ Anti-PC IgM titers	43% ↓ vein graft lesion size, ↓ neointimal thickness, ↓ inflammatory cell content, no effect on established atherosclerosis in aortic origin	Male apoE–/– mice (vein graft model)	Western type diet	Faria-Neto et al., 2006 [47]
MDA-modified apoB100 peptide	Recombinant human anti-MDA-apoB100 peptide IgG1 (IEl-E3)	↑ Human anti-MDA -modified apoB100 IgG1 titers	41% ↓ lesion size (descending aorta), ↓ macrophages, ↓ in IEl-E3 immunoreactivity in plaque	Male apoE–/– mice	High cholesterol diet	Schiopu et al., 2004 [48]
MDA-modified apoB100 peptide	Recombinant human anti-MDA-apoB100 peptide IgG1 (IEl-E3 and 2D03)	↑ Human anti-MDA -modified apoB100 IgG1 titers	Regression of established plaques (50% – 2D03, 36% – IEl-E3), ↓ macrophages, ↑ ABCA-1 expression	Male Apobec-1–/–/LDLR–/– mice	High cholesterol and normal chow diet	Schiopu et al., 2007 [49]
MDA-modified apoB100 peptides	Recombinant human anti-MDA-apoB100 peptide IgG1 (2D03)	↑ Human anti-MDA -modified apoB100 IgG1 titers, ↓ plasma levels of oxidized LDL	95% ↓ injury-induced atherosclerosis, no influence on neointima,	LDLR–/–/human apoB100+/+ (CA collar)	Normal chow diet	Ström et al., 2007 [73]

Abbreviations: HSP, heat shock protein; NZW, New Zealand White; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HSP60*, HSP60 peptide (256–268); CD4⁺CD25⁺Foxp3⁺ cell, regulatory T-cells; β2-GPI, β2-glycoprotein I; Ox LDL, Oxidized LDL; TGF-β, Transforming growth factor beta; MDA-LDL, malondialdehyde-modified LDL; WHHL, watanabe heritable hyperlipidemic; CuOx-LDL, copper-oxidized LDL; 4HNE-LDL, 4-hydroxynonenal modified LDL; VCAM-1, vascular cell adhesion molecule-1; ICs, immune complexes; PC, phosphorylcholine; KLH, keyhole limpet hemocyanin; MHC, major histocompatibility complex.