This copy is for personal use only - distrib

© Med Sci Monit, 2004; 10(11): RA255-260 WWW. M ED S CI M ONIT .COM

PMID: 15507866 Review Article

Received: 2004.07.07
Atherosclerosis: immunopathogenesis
This copy is for personal use only - distribution prohibited.

Accepted: 2004.09.24
Published: 2004.11.01
and immunotherapy

SE
Ryuji Ohashi, Hong Mu, Qizhi Yao, Changyi Chen
Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey
Department of Surgery, Baylor College of Medicine, Texas, U.S.A.

Source of support: This work is partially supported by research grants from the National Institutes of Health RA

U
(Yao: AI 49116 and DE15543; and Chen: HL61943, HL60135, HL65916, HL72716, and EB-002436).

LY L
Summary
This copy is for personal use only - distribution prohibited.

Atherosclerosis is a chronic disease that causes various cardiovascular complications. Although the
N A initiation and progression of atherosclerosis largely depend on genetic factors and life styles, the
cellular and molecular mechanisms are still not clear. Recent studies have revealed that cellular
and humoral immunity plays crucial roles in atherogenic lesion formation, including macrophag-
O N
es, CD4+ and CD8+ T cells and dendritic cells as well as autoantigens such as heat shock protein
(HSP 60/65) and oxidized LDL. Furthermore, atherosclerosis is associated with microbial or vi-
ral infection. Given these recent advances, various modifications of the immune system in mouse
SO

models have been performed to determine the underlying mechanisms of atherogenesis and new
therapeutic strategies. Blocking of macrophage inducing factors or disruption of scavenger recep-
tors on macrophages such as SR-A and CD36 can inhibit atherosclerosis progression. Switching
the immune system of CD4+ T cells from Th1 to Th2 can induce secretion of anti-inflammatory
cytokine IL-10, leading to decreased atherosclerotic lesions. Eradication of microbes and viruses
can also reduce atherosclerosis. These investigations strongly support that immune responses are
R

important mechanisms of atherogenesis, and immunomodulation can be a new strategy to treat

atherosclerosis.
This copy is for personal use only - distribution prohibited.

PE

key words: atherosclerosis • cellular immunity • humoral immunity • immunopathogenesis •

immunotherapy

Full-text PDF: http://www.MedSciMonit.com/pub/vol_10/no_11/5954.pdf

Word count: 2940
Tables: —
Figures: —
References: 84
py is for personal use only - distribution prohibited.

Author’s address: Changyi (Johnny) Chen, M.D, Ph.D., Michael E. DeBakey, Department of Surgery, Baylor College of Medicine,
One Baylor Plaza, NAB 2010, Surgery, Houston, Texas 77030, U.S.A., e-mail: jchen@bcm.tmc.edu

Current Contents/Clinical Medicine • SCI Expanded • ISI Alerting System • Index Medicus/MEDLINE • EMBASE/Excerpta Medica • Chemical Abstracts • Index Copernicus RA255

Electronic PDF security powered by IndexCopernicus.com

This copy is for personal use only - distrib
Review Article
BACKGROUND
Atherosclerosis is a chronic disease that causes artery walls
to thicken and become less elastic. The resulting restriction
of blood flow can lead to various problems such as heart at-
tacks, renal failure, stroke and other serious cardiovascular
This copy is for personal use only - distribution prohibited.
complications. In general, the susceptibility to atherosclero-
sis depends on genetic factors, diet, smoking, diabetes, blood
pressure, high cholesterol, hyperhomocysteinemia, and lack
of exercise. In addition, recent studies are showing that in-
flammation and immune responses contribute to athero-
genesis. Microbial infection with activated immune system
is also associated with vascular lesions. These investigations
strongly support the hypothesis that immune responses are
important mechanisms of atherogenesis although many is-
sues have remained controversial and uncertain. Thereby,
modifications of this immune system can be new strategies
U
to prevent or reverse atherosclerosis. In fact, some reports
have already shown that atherosclerosis can be ameliorat-
ed by vaccination in animal models, which could have clin-
ical significance and applications. The present review will
LY L
focus on recent advances in immunopathogenesis of athero-
sclerosis as well as immunotherapy as a new strategy for the
This copy is for personal use only - distribution prohibited.
treatment of these vascular lesions.
N A
CELLULAR IMMUNITY IN ATHEROSCLEROSIS
AND APPLICATION FOR IMMUNE THERAPY
O N
The key initial event in the pathology of atherosclerosis ap-
pears to be damage to the endothelial cells of the vessels.
SO
The exact nature of endothelial cell damage is presently un-
known but it results in the cell-surface expression of mol-
ecules that mediate leukocyte adhesion such as intercel-
lular cell adhesion molecule-1 (ICAM-1) and vascular cell
adhesion molecule-1 (VCAM-1). Following damage to the
endothelium, mononuclear cells are recruited to the ves-
sel wall across the endothelium. They then accumulate fat-
R
ty materials in the intima forming intimal lesions, in which
large numbers of infiltrates are seen, and mostly consisted
of macrophages and T cells. Occasionally mast cells and B
This copy is for personal use only - distribution prohibited.
PE
cells are also recognized.
Macrophage
For many years, it has been known that macrophages appear
in most atherosclerotic lesions [1–3]. They produce free ox-
ygen radicals, proteases, compliment factors and cytokines.
They are also initiators of adaptive immune responses by dis-
playing MHC to T cells, which in turn induce cytokine se-
cretion, cytotoxicity, antibody production and other many
immune reactions. Accumulation of macrophages in athero-
sclerotic lesions indicates that immune reactions and anti-
gen presentation are occurring in the lesions. Circulating
monocytes are recruited into subintimal areas following
endothelial cell injury via chemoattractant molecules such
as monocyte chemoattractant protein-1 (MCP-1), and the
py is for personal use only - distribution prohibited.
monocytes differentiate into macrophages stimulated by
macrophage colony stimulating factor (M-CSF). MCP-1 be-
longs to the group of CC chemokines and acts via chemok-
ine receptor (CCR2). MCP-1 knock out (MCP-1–/–) mice
have been found to be protective from atherosclerosis due
to reduced macrophage infiltration, while overexpression of
MCP-1 augments the disease [4,5]. Similarly, CCR2–/– mice
on an apoE–/– background have decreased monocyte-macro-
RA256
Med Sci Monit, 2004; 10(11): RA255-260
phage recruitment and smaller atherosclerotic lesions [6].
Lack of M-CSF also prevents macrophage differentiation in
many organs, and M-CSF–/– mice lack osteoclasts and mac-
rophages in tissues. When M-CSF–/– mice were mated with
apoE–/– mice, the offspring developed very little atheroscle-
rosis despite high blood cholesterol levels [7]. Macrophage
migration inhibitory factor (MIF) is a pleiotropic macro-
phage and T cell cytokine. MIF is found to be crucial in
regulating immune-mediated diseases but until recently the
precise function of MIF in atherogenesis remains unclear.
Schober and colleagues found that blockade of MIF can sta-
SE
bilize atherosclerotic lesions in apoE–/– mice [8]. Collectively,
although roles of macrophages in atherogenesis have not
been entirely clarified, it is evident that suppression of the
macrophage inducing factors can be a strong therapeutic
tool for humans by reducing macrophage migration into
the atherosclerotic lesions.
Macrophages are known to express at least eight different
scavenger receptors (SR) which have very different struc-
tures and can bind and internalize a wide range of ligands
such as LDL [9]. Among them, SR-A and CD36 are known
to be important in atherogenesis as disruption of SR-A gene
shows a reduced size of atherosclerosis, suggesting a proath-
erogenic role for SR-A [10]. Similarly, CD36–/– mice dem-
onstrate the reduced atherosclerotic lesion development
when crossed with apoE–/– mice [11]. This indicates an im-
portant role of CD36 in atherogenesis. However, a recent
report demonstrates that inactivation of SR-B1 can augment
atherosclerotic lesions in apoE–/– mice [12]. This finding
suggests that SR-B1 has a protective role for atherogenesis
contrary to the proatherogenic role of SR-A and CD36. Thus,
modification of macrophage scavenger receptors could have
be therapeutic values for atherosclerosis.
CD4+ and Tr T cells
Recently, the importance of T cells in atherogenesis has
also been emphasized. A study demonstrates that dele-
tion of CD4+ and CD8+ cells reduces fatty streak forma-
tion in C57BL/6 mice, indicating that T cells may be in-
volved in fatty streak formation [13]. In particular, CD4+
T cells might be much responsible for atherogenesis since
they are ubiquitously seen in human atherosclerosis, and
exhibit reactivity to putative athero-antigens [14]. If CD4+
cells are transferred from immunocompetent to immune
deficient apoE–/– mice, atherosclerotic lesion worsens dras-
tically, suggesting a role of CD4+ cells in the development
of atherosclerosis [15].
CD4+ T cells can be divided into at least 2 different subsets,
Th1 and Th2 that counterbalance each other [16]. Th1,
the most prevalent type of CD4+ cell, induces macrophage
activation and promotes inflammation by secreting inter-
feron-g (IFN-g), an important proinflammatory cytokine.
However, Th2 cells suppress inflammation and dampen mac-
rophage activity via several different anti-inflammatory cy-
tokines including interleukin-4 (IL-4), interleukin-10 (IL-
10) and transforming growth factor-b (TGF-b). In a recent
study, apoE–/– mice were treated with an inhibitor of the
Th1 differentiation pathway (PTX) for 12 weeks and the an-
imals presented with reduced size of atherosclerotic lesions
by 60% as compared to controls [17]. They further showed
that addition of PTX to cultured spleen cells increased se-
Electronic PDF security powered by IndexCopernicus.com
This copy is for personal use only - distrib
Med Sci Monit, 2004; 10(11): RA255-260
cretion of IL-10, anti-inflammatory cytokine from Th2 cells,
indicating that PTX promoted Th2 function. These studies
suggest that switching the immune system from Th1 to Th2
might have an ameliorating effect on the atherogenesis by
inducing secretion of anti-inflammatory cytokines.
This copy is for personal use only - distribution prohibited.
Regulatory T (Tr) cells are a novel functionally distinct sub-
population of T cells that exert important regulatory func-
tions in various immunoinflammatory diseases [18–20].
Several subsets of Tr cells with distinct phenotypes and
distinct mechanisms of actions have now been identified.
Among those, type 1 Tr (Tr1) cells can inhibit immune re-
sponses by secreting TGF-b and IL-10 [21–26]. Recently,
Mallat et al reported that Tr1 regulatory immune response
plays a major role in atherosclerosis by demonstrating that
transferring Tr1 cells into apoE–/– mice led to reduction of
atherosclerotic lesions [27]. Terefore, Th2 subsets, Tr1 cells
U
might also be a candidate for future immune therapy.
CD8+ and gdT cells
LY L
CD8+ T cells can also be an important player in athero-
genesis. In apoE–/– mice, expression of foreign antigen on
This copy is for personal use only - distribution prohibited.
vascular smooth muscle cell (SMC) can lead to cytotoxic
N A
attack by CD8+ T cells, resulting in aggravation of athero-
sclerosis [28]. It is possible that CD8+ T cells cause some
of the widespread apoptosis and contribute to atheroscle-
O N
rosis progression [29].
gdT cell is another type of T cells with CD3+, CD4– and CD8–
SO
phenotype, and are important in mucosal immunity and in
the recognition of complex lipids as antigens. In fact, gdT
cells have been found at varying propotions in arterial in-
flammatory and atherosclerotic lesions [30-32]. Although
direct evidence has not been documented yet, one can spec-
ulate that gdT cells might have some roles in atherosclero-
sis. Further studies might possibly lead us to a new therapy
R
by blocking functions of these T cells.
Dendritic cells
This copy is for personal use only - distribution prohibited.
PE
Dendritic cells (DCs) were identified as antigen presenting
cells which express high levels of both MHC-I and -II mole-
cules [33]. While macrophages, monocytes and B cells have
been traditionally viewed as antigen presenting cells, DCs
are now considered the principle initiators of immune re-
sponses by virtues of the unique ability to activate T cells.
DCs are identified in arteries including aorta, coronary and
carotid arteries [34–36]. In the intima and adventitia of nor-
mal arteries, small numbers of DCs are present, and they
are called vascular DCs (VDCs) [34]. In atherosclerotic le-
sions, a number of DCs are observed by immunohistochem-
ical and ultrastructural studies [34–36]. Although the vast
majority of DCs do not accumulate substantial amount of
lipids, a small portion of DCs accumulates lipid and trans-
form into foam cells, contributing to atherogenesis [37].
py is for personal use only - distribution prohibited.
Studies on the functional significance of DCs in atheroscle-
rosis are still in infancy but it is reasonable that DCs in the
arterial wall are involved in antigen presentation as in other
organs [35]. In agreement with this idea, immunohistochem-
ical observation shows the numbers of DCs are increased in
para-aortic and jugulodigastric lymphe nodes attached to
atherosclerotic arterial wall segments [37]. Taken togeth-
er, targeting DCs, either within lymphoid organs or within
Ohashi R et al – Atherosclerosis: immunopathogenesis and immunotherapy
arterial wall, might enable the regulation of immune reac-
tions in atherogenesis. If VDCs constitue a unique subset
within the DC family, the isolation of VDCs from the arterial
wall might enable the identification of unique antigens on
their surface. This may lead to new strategies where VDCs
can be targeted to deliver biologically active substances to
atherosclerotic lesions.
AUTOANTIGENS AND HUMORAL IMMUNITY
IN ATHEROSCLEROSIS
SE
Evidence from human and animal studies indicates that some
autoantigens are involved in atherogenesis. Substantial evi-
dence indicates that two major autoantigens are implicated,
oxidized LDL (oxLDL) and HSP60, which can elicit specific
RA
antigeity via either humoral or cellular immune system.
OxLDL
Oxidation of lipoproteins and oxidative processes general-
ly play an important role in the initiation and progression
of atherosclerosis. Oxidation of LDL occurs in a wide range
of atherosclerotic lesions in human and animal models, and
by-products generated during the process have numerous
properties causing cytotoxic damage to vascular wall, inhi-
bition of vasodilatation in response to nitric oxide and etc
[38–40]. In addition to those detrimental effects, oxLDL
is involved in immune reactions occurring in atherosclero-
sis, supported by accumulating evidence. In a study on ani-
mal experiments, anti-oxLDL antibody is identified and ox-
LDL could be an autoantigen initiating immune reactions
[39]. Furthermore, anti-oxLDL antibody was found in pa-
tients with various vascular diseases including peripheral
vascular disease, coronary artery disease and other cardi-
ovascular compications [41–46]. In accordance with these
reports, administration of antibody against oxLDL dem-
onstrates reduced size of atherosclerotic lesions, confirm-
ing the involvement of humoral immunity in atherogene-
sis [47–49]. On the other hand, some evidence shows that
T cell-mediated cellular immunity is also implicated in ox-
LDL-induced immune reactions. A report shows that T cells
collected from human plaques can recognize oxLDL in an
HLADR dependent manner [50]. OxLDL-specific T cells
are also present in lymph nodes of apoE–/– mice [51,52]. In
addition, oxLDL induces activation of a subset of peripher-
al T cells [53]. Thus, both cellular and humoral systems are
involved in atherogenesis. Immunization against oxLDL or
suppressing oxLDL specific T cells should be an attractive
strategy for the treatment of atherosclerosis.
Heat shock proteins
Heat shock proteins (HSPs) have also been implicated in
the pathogenesis of atherosclerosis [54]. They are involved
in protein folding in the normal cells, are produced in large
amounts by injured cells, and serve as targets for autoim-
mune responses in many human diseases. In patients with
hypertension and early atherosclerosis, antibodies to HSPs
are recognized, supporting that HSPs may have a role in
atherogenesis [55,56]. In contrast to oxLDL, immunization
with HSP60 was found to increase fatty streak development in
hypercholesterolemic animals [57]. However a recent study
by Marron et al utilized mucosal immunization with HSP65
to see the effect on T cells since mucosal immunization of
RA257
Electronic PDF security powered by IndexCopernicus.com
This copy is for personal use only - distrib
Review Article
diabetes model is known to suppress inflammation via T cell
responses [58]. When LDL receptors knock out (LDLR–/–)
mice, which normally manifest severe atherosclerotic lesions,
are mucosally immunized with HSP65, the animals showed
ameliorated atherosclerotic lesions with reduced number
of T cells and an increase of anti-inflammatory cytokine IL-
This copy is for personal use only - distribution prohibited.
10. The finding suggests that this mucosal approach with
HSP might have induced deviation from Th1 to Th2, and
can be utilized for treatment of atherosclerosis.
INFECTION AND ATHEROSCLEROSIS
Bacterial infection
Chronic bacterial infection has been found to be significant-
ly associated with the development of atherosclerosis and
the clinical complications of unstable angina, myocardial in-
U
farction, and stroke. Particularly, Chlamydia pneumoniae (C.
pneumoniae) and Helicobacter pylori (H. pylori) are known to
be associated with atherogenesis and cause aortic and ab-
dominal aneurysms and coronary artery lesions [59–61]. In
LY L
animal model studies, C. pneumoniae can develop arterioscle-
rotic lesions [62]. To elucidate the underlying mechanisms
This copy is for personal use only - distribution prohibited.
of this phenomenon, Benagiano et al recently described the
N A
activation of Th1 cells in patients with C. pneumoniae infec-
tion. This finding evidences that C. pnemoniae may cause
atherogenesis via T cell dependent manner [63]. Since C.
O N
pneumoniae and H. pylori are two major infectious antigens,
treatment using antibiotics may dampen atherosclerosis.
Additionally, combined vaccination of both of them would
SO
possibly block progression of atherosclerosis.
Virus infection
Viruses have long been suspected as causes of atheroscle-
rosis and there have been a number of reports on involve-
ment of cytomegalovirus (CMV) and herpes simplex virus
R
(HSV). Antibody titres to CMV are increased in patients
with coronary and carotid artery atherosclerosis [64–66].
HSV has been identified in histological sections of coro-
This copy is for personal use only - distribution prohibited.
PE
nary bypass and cells harvested from carotid artery plaques
[67]. Currently influenza virus has attracted much attention
since influenza vaccination might inhibit coronary artery
disease in humans [68]. Influenza vaccination also reduces
atherosclerotic lesions in apoE–/– mice [69]. Although the
mechanisms whereby the above viruses induce atherogene-
sis are unclear, it is conceivable that they should play impor-
tant roles in atherosclerosis. Therefore, anti-virus therapy
or vaccination against virus infection can be a therapeutic
tool for atherosclerosis.
IMMUNOREGULATORY CELL SURFACE MOLECULES
Immune activation depends on interactions between pro-
teins displayed on the surfaces of adjacent cells as well as
on soluble cytokines. Such proteins include adhesion mole-
py is for personal use only - distribution prohibited.
cules such as ICAM-1 and E-selectin, and costimulatory mol-
ecules such as T cell proteins CD28 and CD40. CD40 can
be identified on B cells and DCs. It ligates the constitutive-
ly expressed T cell protein, CD40 ligand (CD40L), and is
necessary for T-B cell cooperation in the induction of anti-
body responses. CD40 is also constitutively expressed by en-
dothelial cells [70] and can be activated by stimulation with
proinflammatory cytokines such as IFN-g [71]. Interestingly,
RA258
Med Sci Monit, 2004; 10(11): RA255-260
CD40 and CD40L are present on vascular cells and macro-
phages of atherosclerosis lesions and their activation may be
involved in the progression of atherosclerotic disease [71].
In humans, increased plasma levels of CD40L has been ob-
served in unstable angina [72] and hypercholesterolemia
[73]. Soluble CD40L is regarded as a strong prognostic val-
ue for cardiovascular disease [74]. Animal experiments con-
firmed that anit-CD40L antibody injections reduced fatty
streak development in LDLR–/– mice [75]. CD40L–/–-apoE–/–
compound knock out mice exhibited slower induction of
lesions than CD40L+/+-apoE–/– controls [76]. These data
SE
suggest that CD40 should play a significant role in athero-
genesis and that inhibition of the CD40 pathway might be
a means of treating atherosclerosis. However, the mecha-
nism of action for inhibitors such as anti-CD40L antibodies
remains unclear and could involve not only immunomodu-
lation but also direct effects on vascular cells.
OTHER THERAPEUTIC POTENTIAL OF VACCINATION
Intravenous injection of immunoglobulin (ivIg) is now
used as a therapy for autoimmune and systemic inflamma-
tory disease [77,78]. The mode of action of ivIg is still un-
clear but it should probably involve both Fc and V region-
dependent mechanisms [79]. Fc fragment of Ig may block
Fc receptors on phogocytic cells of the reticuloendothelial
system, inhibit antibody synthesis by B cells, modulate sup-
pressor and helper functions of T cells, affect the produc-
tion of cytokines by monocyte/marophage, and interfere
with compliment-mediated tissue damage. Modulation of
B and T cell functions including cytokine production has
been observed during ivIg treatment in rodent models of au-
toimmune diseases [80,81]. Nicoletti at al transferred poly-
clonal immunoglobulins containing anti-oxLDL antibodies
and observed reduced atherosclerosis in apoE–/– mice [82].
Therefore immunoglobulin may also be an effective way to
prevent atherosclerosis. Immunomodulation can also be an
attractive therapeutic principle, and certain drugs target-
ing lipid and carbohydrate metabolism may excert immu-
nomodulatory effects. Statins act as repressors of MHC-II me-
diated T cell activation [83] and can improve the outcome
of cardiac transplantation [84]. It is tempting to speculate
that some of beneficial effects of these compounds may be
due to their immunomodulatory effects rather than their
action on cholesterol or glucose metabolism.
CONCLUSIONS
Recent studies have demonstrated both inflammation and
immune responses are key pathogenesis mechanisms of
atherosclerosis. Macrophages, T cells, dendritic cells, au-
toantigens, and microbial or viral infection are involved
in all stages of atherosclerotic lesion formation. Thereby,
there seems no doubt that immunotherapy including vac-
cination will be a potential therapeutic tool for atheroscle-
rosis in the near future. However, there are some issues we
have to solve before we proceed to using it in humans. For
example, most of the animal models reported so far do
not reflect real human atherosclerotic lesions in that they
do not progress to atherosclerotic plaques and subsequent
rupture, which can be a cause of death for humans. Thus,
we need to invent the animal models which mimic human
lesions before we test the efficacy of the therapy. Secondly,
we must identify any possible side effects caused by vaccina-
Electronic PDF security powered by IndexCopernicus.com
This copy is for personal use only - distrib
Med Sci Monit, 2004; 10(11): RA255-260
tion. Most of the papers have not mentioned side effects by
vaccination but they may occur if administered in the long-
er terms as therapy. To minimize those effects, we need to
perform many trials using other different kinds of animals,
which would enable us to invent most safe and efficient way
to deliver vaccines into human bodies.
This copy is for personal use only - distribution prohibited.
REFERENCES:
1. Gerrity RG: The role of the monocyte in atherogenesis: II.
Migration of foam cells from atherosclerotic lesions. Am J Pathol,
1981;103: 191–200
2. Faggiotto A, Ross R, Harker L: Studies of hypercholesterolem-
ia in the nonhuman primate. I. Changes that lead to fatty streak for-
mation. Arteriosclerosis, 1984; 4: 323–40
3. Faggiotto A, Ross R: Studies of hypercholesterolemia in the
nonhuman primate. II. Fatty streak conversion to fibrous plaque.
Arteriosclerosis, 1984; 4: 341–56
U
4. Gu L, Okada Y, Clinton SK et al: Absence of monocyte chem-
oattractant protein-1 reduces atherosclerosis in low density lipoprotein
receptor-deficient mice. Mol Cell, 1998; 2: 275–81
5. Aiello RJ, Bourassa PA, Lindsey S et al: Monocyte chemoattract-
ant protein-1 accelerates atherosclerosis in apolipoprotein E-deficient
LY L
mice. Arterioscler Thromb Vasc Biol, 1999; 19: 1518–25
6. Charo IF, Peters W: Chemokine receptor 2 (CCR2) in athero-
This copy is for personal use only - distribution prohibited.
sclerosis, infectious diseases, and regulation of T-cell polarization.
Microcirculation, 2003; 10: 259–64
N A
7. Smith JD, Trogan E, Ginsberg M et al: Decreased atherosclero-
sis in mice deficient in both macrophage colony-stimulating factor (op)
and apolipoprotein E. Proc Natl Acad Sci USA, 1995; 92: 8264–68
O N
8. Schober A, Bernhagen J, Thiele M et al: Stabilization of athero-
sclerotic plaques by blockade of macrophage migration inhibitory fac-
tor after vascular injury in apolipoprotein E-deficient mice. Circulation,
2004; 109: 380–85
SO
9. Lucas AD, Greaves DR: Atherosclerosis: role of chemokines and
macrophages. Expert Rev Mol Med, 2001; 2001: 1–18
10. Babaev VR, Gleaves LA, Carter KJ et al: Reduced atherosclerotic lesions
in mice deficient for total or macrophage-specific expression of scaven-
ger receptor-A. Arterioscler Thromb Vasc Biol, 2000; 20: 2593–99
11. Febbraio M, Podrez EA, Smith JD et al: Targeted disruption of the class
B scavenger receptor CD36 protects against atherosclerotic lesion de-
R
velopment in mice. J Clin Invest, 2000; 105: 1049–56
12. Zhang W, Yancey PG, Su YR et al: Inactivation of macrophage scaven-
ger receptor class B type I promotes atherosclerotic lesion development
in apolipoprotein E-deficient mice. Circulation, 2003; 108: 2258–63
This copy is for personal use only - distribution prohibited.
PE
13. Emeson EE, Shen ML, Bell CG et al: Inhibition of atherosclerosis in
CD4 T-cell-ablated and nude (nu/nu) C57BL/6 hyperlipidemic mice.
Am J Pathol, 1996; 149: 675–85
14. Hansson GK: Immune mechanisms in atherosclerosis. Arterioscler
Thromb Vasc Biol, 2001; 21: 1876–90
15. Zhou X, Nicoletti A, Elhage R et al: Transfer of CD4(+) T cells aggra-
vates atherosclerosis in immunodeficient apolipoprotein E knockout
mice. Circulation, 2000; 102: 2919–22
16. Mosmann TR, Sad S: The expanding universe of T-cell subsets: Th1,
Th2 and more. Immunol Today, 1996; 17: 138–46
17. Laurat E, Poirier B, Tupin E et al: In vivo downregulation of T helper
cell 1 immune responses reduces atherogenesis in apolipoprotein E-
knockout mice. Circulation, 2001; 104: 197–202
18. Groux H: An overview of regulatory T cells. Microbes Infect, 2001; 3:
883–89
19. Roncarolo MG, Bacchetta R, Bordignon C et al: Type 1 T regulatory
cells. Immunol Rev, 2001; 182: 68–79
20. Mcguirk P, Mills KH: Pathogen-specific regulatory T cells provoke a shift
in the Th1/Th2 paradigm in immunity to infectious diseases. Trends
py is for personal use only - distribution prohibited.
Immunol, 2002; 23: 450–55
21. Groux H, O’garra A, Bigler M et al: A CD4+ T-cell subset inhibits an-
tigen-specific T-cell responses and prevents colitis. Nature, 1997; 389:
737–42
22. Doetze A, Satoguina J, Burchard G et al: Antigen-specific cellular hy-
poresponsiveness in a chronic human helminth infection is mediated
by T(h)3/T(r)1-type cytokines IL-10 and transforming growth factor-
beta but not by a T(h)1 to T(h)2 shift. Int Immunol, 2000; 12: 623–30
Ohashi R et al – Atherosclerosis: immunopathogenesis and immunotherapy
23. Cavani A, Nasorri F, Prezzi C et al: Human CD4+ T lymphocytes with
remarkable regulatory functions on dendritic cells and nickel-specific
Th1 immune responses. J Invest Dermatol, 2000; 114: 295–302
24. Levings MK, Sangregorio R, Galbiati F et al: IFN-alpha and IL-10 in-
duce the differentiation of human type 1 T regulatory cells. J Immunol,
2001; 166: 5530–39
25. Macdonald AJ, Duffy M, Brady MT et al: CD4 T helper type 1 and reg-
ulatory T cells induced against the same epitopes on the core protein
in hepatitis C virus-infected persons. J Infect Dis, 2002; 185: 720–27
26. Mcguirk P, Mccann C, Mills KH: Pathogen-specific T regulatory 1 cells
induced in the respiratory tract by a bacterial molecule that stimulates
interleukin 10 production by dendritic cells: a novel strategy for eva-
sion of protective T helper type 1 responses by Bordetella pertussis. J
Exp Med, 2002; 195: 221–31
SE
27. Mallat Z, Gojova A, Brun V et al: Induction of a regulatory T cell type
1 response reduces the development of atherosclerosis in apolipopro-
tein E-knockout mice. Circulation, 2003; 108: 1232–37
28. Ludewig B, Freigang S, Jaggi M et al: Linking immune-mediated arteri-
al inflammation and cholesterol-induced atherosclerosis in a transgen-
RA
ic mouse model. Proc Natl Acad Sci USA, 2000; 97: 12752–57
29. Geng YJ, Henderson Le, Levesque EB et al: Fas is expressed in human
atherosclerotic intima and promotes apoptosis of cytokine-primed hu-
man vascular smooth muscle cells. Arterioscler Thromb Vasc Biol, 1997;
17: 2200–8
30. Seitz CS, Kleindienst R, Xu Q et al: Coexpression of heat-shock protein
60 and intercellular-adhesion molecule-1 is related to increased adhe-
sion of monocytes and T cells to aortic endothelium of rats in response
to endotoxin. Lab Invest, 1996; 74: 241–52
31. Kleindienst R, Xu Q, Willeit J et al: Immunology of atherosclerosis.
Demonstration of heat shock protein 60 expression and T lymphocytes
bearing alpha/beta or gamma/delta receptor in human atherosclerot-
ic lesions. Am J Pathol, 1993; 142: 1927–37
32. Melian A, Geng YJ, Sukhova GK et al: CD1 expression in human athero-
sclerosis. A potential mechanism for T cell activation by foam cells. Am
J Pathol, 1999; 155: 775–86
33. Steinman RM, Cohn ZA. Identification of a novel cell type in periph-
eral lymphoid organs of mice I: Morphology, quantitation, tissue dis-
tribution. J Exp Med, 1973; 137: 1142–62
34. Bobryshev YV, Lord RS: Ultrastructural recognition of cells with den-
dritic cell morphology in human aortic intima. Contacting interactions
of Vascular Dendritic Cells in athero-resistant and athero-prone areas
of the normal aorta. Arch Histol Cytol, 1995; 58: 307–22
35. Bobryshev YV, Lord RS: Mapping of vascular dendritic cells in athero-
sclerotic arteries suggests their involvement in local immune-inflamma-
tory reactions. Cardiovasc Res, 1998; 37: 799–810
36. Bobryshev YV, Lord RS, Rainer S et al: Vascular dendritic cells and
atherosclerosis. Pathol Res Pract, 1996; 192: 462–67
37. Bobryshev YV: Dendritic cells and their involvement in atherosclerosis.
Curr Opin Lipidol, 2000; 11: 511–17
38. Haberland ME, Fong D, Cheng L: Malondialdehyde-altered protein oc-
curs in atheroma of Watanabe heritable hyperlipidemic rabbits. Science,
1988; 241: 215–18
39. Palinski W, Rosenfeld ME, Yla-Herttuala S et al: Low density lipopro-
tein undergoes oxidative modification in vivo. Proc Natl Acad Sci USA,
1989; 86: 1372–76
40. Boyd HC, Gown AM, Wolfbauer G et al: Direct evidence for a protein
recognized by a monoclonal antibody against oxidatively modified LDL
in atherosclerotic lesions from a Watanabe heritable hyperlipidemic
rabbit. Am J Pathol, 1989; 135: 815–25
41. Bergmark C, Wu R, De Faire U et al: Patients with early-onset periph-
eral vascular disease have increased levels of autoantibodies against ox-
idized LDL. Arterioscler Thromb Vasc Biol, 1995; 15: 441–45
42. Maggi E, Chiesa R, Melissano G et al: LDL oxidation in patients with
severe carotid atherosclerosis. A study of in vitro and in vivo oxidation
markers. Arterioscler Thromb, 1994; 14: 1892–99
43. Lehtimaki T, Lehtinen S, Solakivi T et al: Autoantibodies against oxidized
low density lipoprotein in patients with angiographically verified coro-
nary artery disease. Arterioscler Thromb Vasc Biol, 1999; 19: 23–27
44. Bui MN, Sack MN, Moutsatsos G et al: Autoantibody titers to oxidized
low-density lipoprotein in patients with coronary atherosclerosis. Am
Heart J, 1996; 131: 663–67
45. Salonen JT, Yla-Herttuala S, Yamamoto R et al: Autoantibody against
oxidised LDL and progression of carotid atherosclerosis. Lancet, 1992;
339: 883–87
RA259
Electronic PDF security powered by IndexCopernicus.com
This copy is for personal use only - distrib
Review Article
46. Wu R, Nityanand S, Berglund L et al: Antibodies against cardiolipin
and oxidatively modified LDL in 50-year-old men predict myocardial
infarction. Arterioscler Thromb Vasc Biol, 1997; 17: 3159–63
47. Palinski W, Miller E, Witztum JL: Immunization of low density lipopro-
tein (LDL) receptor-deficient rabbits with homologous malondialde-
hyde-modified LDL reduces atherogenesis. Proc Natl Acad Sci USA,
1995; 92: 821–25
This copy is for personal use only - distribution prohibited.
48. Ameli S, Hultgardh-Nilsson A, Regnstrom J et al: Effect of immuniza-
tion with homologous LDL and oxidized LDL on early atherosclerosis
in hypercholesterolemic rabbits. Arterioscler Thromb Vasc
Biol, 1996; 16: 1074–79
49. Zhou X, Caligiuri G, Hamsten A et al: LDL immunization induces T-
cell-dependent antibody formation and protection against atheroscle-
rosis. Arterioscler Thromb Vasc Biol, 2001; 21: 108–14
50. Stemme S, Faber B, Holm J et al: T lymphocytes from human athero-
sclerotic plaques recognize oxidized low density lipoprotein. Proc Natl
Acad Sci USA, 1995; 92: 3893–97
51. Caligiuri G, Nicoletti A, Zhou X et al: Effects of sex and age on athero-
sclerosis and autoimmunity in apoE-deficient mice. Atherosclerosis,
1999; 145: 301–8
52. Nicoletti A, Paulsson G, Caligiuri G et al: Induction of neonatal toler-
U
ance to oxidized lipoprotein reduces atherosclerosis in ApoE knock-
out mice. Mol Med, 2000; 6: 283–90
53. Frostegard J, Wu R, Giscombe R et al: Induction of T-cell activation by ox-
idized low density lipoprotein. Arterioscler Thromb, 1992; 12: 461–67
54. Wick G, Schett G, Amberger A et al: Is atherosclerosis an immunolog-
LY L
ically mediated disease? Immunol Today, 1995; 16: 27–33
This copy is for personal use only - distribution prohibited.
55.Frostegard J, Lemne C, Andersson B et al: Association of serum antibodies
to heat-shock protein 65 with borderline hypertension. Hypertension,
1997; 29: 40–44
N A
56. Pockley AG, Wu R, Lemne C et al: Circulating heat shock protein 60
is associated with early cardiovascular disease. Hypertension, 2000; 36:
303–7
O N
57. Xu Q, Dietrich H, Steiner HJ et al: Induction of arteriosclerosis in nor-
mocholesterolemic rabbits by immunization with heat shock protein
65. Arterioscler Thromb, 1992; 12: 789–99
SO
58. Maron R, Sukhova G, Faria AM et al: Mucosal administration of heat
shock protein-65 decreases atherosclerosis and inflammation in aortic
arch of low-density lipoprotein receptor-deficient mice. Circulation,
2002; 106: 1708–15
59. Chmiela M, Kowalewicz-Kulbat M, Miszczak A et al: A link between
Helicobacter pylori and/or Chlamydia spp. infections and atheroscle-
rosis. FEMS Immunol Med Microbiol, 2003; 36: 187–92
60. Blasi F, Denti F, Erba M et al: Detection of Chlamydia pneumoniae but
R
not Helicobacter pylori in atherosclerotic plaques of aortic aneurysms.
J Clin Microbiol, 1996; 34: 2766–69
61. Juvonen J, Juvonen T, Laurila A et al: Immunohistochemical detection
This copy is for personal use only - distribution prohibited.
PE
of Chlamydia pneumoniae in abdominal aortic aneurysms. Ann NY
Acad Sci, 1996; 800: 236–38
62. Fong IW, Chiu B, Viira E et al: Rabbit model for Chlamydia pneumo-
niae infection. J Clin Microbiol, 1997; 35: 48–52
63. Benagiano M, Azzurri A, Ciervo A et al: T helper type 1 lymphocytes
drive inflammation in human atherosclerotic lesions. Proc Natl Acad
Sci USA, 2003; 100: 6658–63
64. Dummer S, Lee A, Breinig MK et al: Investigation of cytomegalovirus
infection as a risk factor for coronary atherosclerosis in the explanted
hearts of patients undergoing heart transplantation. J Med Virol, 1994;
44: 305–9
py is for personal use only - distribution prohibited.
RA260
Med Sci Monit, 2004; 10(11): RA255-260
65. Jacob HS: Newly recognized causes of atherosclerosis: the role of mi-
croorganisms and of vascular iron overload. J Lab Clin Med, 1994; 123:
808–16
66. Adler SP, Hur JK, Wang JB et al: Prior infection with cytomegalovirus
is not a major risk factor for angiographically demonstrated coronary
artery atherosclerosis. J Infect Dis, 1998; 177: 209–12
67. Raza-Ahmad A, Klassen GA, Murphy DA et al: Evidence of type 2 her-
pes simplex infection in human coronary arteries at the time of coro-
nary artery bypass surgery. Can J Cardiol, 1995; 11: 1025–29
68. Naghavi M, Barlas Z, Siadaty S et al: Association of influenza vaccina-
tion and reduced risk of recurrent myocardial infarction. Circulation,
2000; 102: 3039–45
69. Naghavi M, Wyde P, Litovsky S et al: Influenza infection exerts promi-
nent inflammatory and thrombotic effects on the atherosclerotic plaques
SE
of apolipoprotein E-deficient mice. Circulation, 2003; 107: 762–68
70. Karmann K, Hughes CC, Schechner J et al: CD40 on human endothe-
lial cells: inducibility by cytokines and functional regulation of adhe-
sion molecule expression. Proc Natl Acad Sci USA, 1995; 92: 4342–46
71. Mach F, Schonbeck U, Sukhova GK et al: Functional CD40 ligand is ex-
pressed on human vascular endothelial cells, smooth muscle cells, and
macrophages: implications for CD40-CD40 ligand signaling in athero-
sclerosis. Proc Natl Acad Sci USA, 1997; 94: 1931–36
72. Aukrust P, Muller F, Ueland T et al: Enhanced levels of soluble and mem-
brane-bound CD40 ligand in patients with unstable angina. Possible re-
flection of T lymphocyte and platelet involvement in the pathogenesis
of acute coronary syndromes. Circulation, 1999; 100: 614–20
73. Cipollone F, Mezzetti A, Porreca E et al: Association between enhanced
soluble CD40L and prothrombotic state in hypercholesterolemia: ef-
fects of statin therapy. Circulation, 2002; 106: 399–402
74. Schonbeck U, Varo N, Libby P et al: Soluble CD40L and cardiovascu-
lar risk in women. Circulation, 2001; 104: 2266–68
75. Mach F, Schonbeck U, Sukhova GK et al: Reduction of atherosclerosis
in mice by inhibition of CD40 signalling. Nature, 1998; 394: 200–3
76. Lutgens E, Gorelik L, Daemen MJ et al: Requirement for CD154 in the
progression of atherosclerosis. Nat Med, 1999; 5: 1313–16
77. Dwyer JM: Manipulating the immune system with immune globulin. N
Engl J Med, 1992; 326: 107–16
78. Kaveri SV, Dietrich G, Hurez V et al: Intravenous immunoglobulins
(IVIg) in the treatment of autoimmune diseases. Clin Exp Immunol,
1991; 86: 192–98
79. Kazatchkine MD, Dietrich G, Hurez V et al: V region-mediated selec-
tion of autoreactive repertoires by intravenous immunoglobulin (i.v.Ig).
Immunol Rev, 1994; 139: 79–107
80. Hentati B, Sato MN, Payelle-Brogard B et al: Beneficial effect of poly-
clonal immunoglobulins from malaria-infected BALB/c mice on the
lupus-like syndrome of (NZB x NZW)F1 mice. Eur J Immunol, 1994;
24: 8–15
81. Saoudi A, Hurez V, De Kozak Y et al: Human immunoglobulin prepa-
rations for intravenous use prevent experimental autoimmune uveo-
retinitis. Int Immunol, 1993; 5: 1559–67
82. Nicoletti A, Kaveri S, Caligiuri G et al: Immunoglobulin treatment re-
duces atherosclerosis in apo E knockout mice. J Clin Invest, 1998; 102:
910–18
83. Kwak B, Mulhaupt F, Myit S et al: Statins as a newly recognized type of
immunomodulator. Nat Med, 2000; 6: 1399–402
84. Kobashigawa JA, Katznelson S, Laks H, et al: Effect of pravastatin on out-
comes after cardiac transplantation. N Engl J Med, 1995; 333: 621–27
Electronic PDF security powered by IndexCopernicus.com