Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1447-1456
Published online before print April 20, 2006,
doi: 10.1161/01.ATV.0000222906.78307.7b
(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1447.)
© 2006 American Heart Association, Inc.
T Cell Costimulation in the Development of Cardiac Allograft Vasculopathy
Potential Targets for Therapeutic Interventions
Mitsuaki Isobe;
Hisanori Kosuge;
Jun-ichi Suzuki
From the Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Correspondence to Mitsuaki Isobe, MD, Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo 113-8519, Japan. E-mail isobemi.cvm{at}tmd.ac.jp
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Abstract
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Cardiac allograft vasculopathy (CAV) is a form of coronary arterial
stenosis and a leading cause of death in patients who survive
beyond the first year after heart transplantation. Histopathologically,
this lesion is concentric diffuse intimal hyperplasia of the
arterial wall that is accompanied by extensive infiltration
of inflammatory cells, including T cells. Many studies have
explored the potential risk factors related to this arterial
lesion and its pathogenesis. Continuous minor endothelial cell
damage evokes inflammatory processes including T cell activation.
Costimulatory molecules play crucial roles in this T cell activation.
Many costimulatory pathways have been described, and some are
involved in the pathogenesis of CAV, atherogenesis, and subsequent
plaque formation. In this review, we summarize the present knowledge
of the role of these pathways in CAV development and the possibility
of manipulating these pathways as a means to treat heart allograft
vascular disease and atherosclerosis.
Cardiac allograft vasculopathy (CAV) is a serious complication after heart transplantation. Continuous minor endothelial cell damage and subsequent T cell activation evoke inflammatory processes. Many costimulatory pathways for T cell activation are involved. The role of these pathways in CAV development and atherogenesis are discussed in this brief review.
Key Words: transplantation rejection T cellmediated immunity arteriosclerosis atherosclerosis smooth-muscle cell
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Introduction
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Cardiac transplantation provides long-term survival for patients
with end-stage heart disease. The percentage of patients surviving
to 1 year after heart transplantation continues to increase;
however, the percentage of patients surviving beyond 1 year
has not changed significantly over the past 20 years.
1 Long-term
functional deterioration of allografts is caused by chronic
rejection. The pathologic features of chronic rejection include
reduced vessel size and parenchymal fibrosis. Development of
cardiac allograft vasculopathy (CAV) has been a major cause
of morbidity and mortality following heart transplantation.
1 The mechanism of CAV is not known despite extensive basic and
clinical studies; however, inflammation and immunity are known
to be associated with the pathogenesis of CAV. CAV lesions contain
immune competent cells; among these cells, activated T lymphocytes
are the most conspicuous. Therefore, T cell-mediated immunity
and subsequent inflammation appear to be an important feature
of initiation and progression of CAV. There are similarity and
difference among CAV, atherosclerosis, and restenosis after
balloon angioplasty as shown in
Table 1. The pathophysiology
of CAV should be recognized in a spectrum of wide range of arterial
lesions.
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Risk Factors for and Treatment of Graft Vasculopathy
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One of the major risk factors for CAV is the episodic frequency
and severity of acute rejection. Donorrecipient differences
in major histocompatibility complexes and ineffective immunosuppression
increase the risk.
2,3 Nonimmunologic factors are also known
to confer risk. In cases of kidney transplantation, cadaveric
donor kidneys are more likely to have stenotic arterial lesions
than living-related donor kidneys, suggesting the importance
of ischemia/reperfusion injury in the pathophysiology of allograft
vasculopathy.
4 Both clinical and experimental studies have indicated
that cytomegalovirus infection promotes CAV.
5 Factors influencing
endothelial function, such as hyperlipidemia, diabetes, hypertension,
and high donor age, are also known to increase the risk of CAV
3,6 (
Figure 1).

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Figure 1. Schematic representation of our model for the pathogenesis of cardiac allograft vasculopathy (CAV) illustrating the central role of immune activation. CMV indicates cytomegalovirus.
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Treatment of CAV is controversial. Although a variety of pharmacological interventions has been applied,711 their effects are limited and these agents have not achieved popularity. Catheter-based coronary interventions have been reported,12 but the results are not satisfactory because the coronary lesions are not segmental; they are diffuse. To save a patients life, cardiac re-transplantation is sometimes performed, but the survival rate is worse than that for first-time transplantation.
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Immunomodulatory Agents and CAV
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The effects of immunosuppressive drugs have been investigated
experimentally and clinically. Cyclosporine and tacrolimus bind
to the intracellular cytosolic immunophilins, cyclophilin and
FK binding protein 12, respectively, inhibiting calcineurin
phosphatase. This prevents transcription of cytokines such as
IL-2 and progression of the T cell cycle from G0 to G1.
13 Early
experimental studies demonstrated that cyclosporine inhibits
smooth muscle proliferation.
14,15 Clinically, triple-drug therapy
with cyclosporine, steroid, and azathioprine has been a standard
immunosuppressive treatment for >20 years and is effective
in suppressing acute rejection. However, this drug combination
has little effect on the development of CAV. Observation of
256 patients revealed a positive correlation between coronary
intimal thickness and low daily doses of cyclosporine dose,
16 but the clinical usefulness of cyclosporine in cases of chronic
cardiac allograft rejection remains controversial. The role
of tacrolimus in preventing CAV is also unclear.
17 A randomized
prospective trial in which 160 recipients were followed-up for
4 years failed to detect any statistical difference in the development
of CAV between patients given cyclosporine and those given tacrolimus.
18
Sirolimus (rapamycin) interferes with DNA and protein synthesis and arrests the cell cycle of T cells in G1 phase. A significant dose-dependent reduction in intimal thickening in rat cardiac allografts after sirolimus treatment was reported.19 This interesting result can be explained by the potent inhibitory effects of sirolimus on growth factor-mediated proliferation of smooth muscle cells. Administration of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) has been associated with a reduced incidence of severe rejection episodes and reduced progression of CAV in patients.9,20 Animal experiments showed that this effect was independent of cholesterol reduction21 and may be associated with inhibition of major histocompatibility complex class II antigens22 or leukocyte function associated-antigen (LFA)-1 expression.23 The precise mechanism is yet to be determined. Peroxisome proliferator-activated receptor
is expressed in macrophages, T cells, endothelial cells, and smooth muscle cells. Our recent observation revealed a potent effect of its agonist, pioglitazone, in the suppression of acute as well as chronic rejection of cardiac allografts in animal models.24
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Pathology of CAV
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In cases of CAV, the stenotic coronary artery in the allograft
shows concentric diffuse thickening of the intima (
Figure 2).
Experimental models of this condition have revealed that the
cellular component of the thickened neointima comprises smooth
muscle cells. These cells express the embryonic-type smooth
muscle myosin heavy chain.
25 This increase in expression of
the synthetic myosin heavy chain isozyme is accompanied by a
decrease in the contractile myosin isozyme (SM2). Recent studies
revealed that some of the proliferated smooth muscle cells in
the thickened neointima originate from smooth muscle cell progenitor
cells from the recipients bone marrow.
26,27 Whatever
the origin of the smooth muscle cells, cell cycle regulatory
genes are activated to promote their proliferation.
28,29 In
the early stages of CAV, there are macrophages that sometimes
contain lipid deposits, and these macrophages resemble the foam
cells found in atherosclerosis. There is a significant infiltration
of T lymphocytes of various subsets expressing CD4 and CD8.
These lymphocytes are found not only in the thickened intima
but also in the perivascular areas. Expression of vascular cell
adhesion molecule (VCAM)-1 and intercellular adhesion molecule
(ICAM)-1 is enhanced in endothelial cells in the area of CAV.
30 In animal models of CAV, expression of matrix metalloproteinase
(MMP)-2 is enhanced in smooth muscle cells in the thickened
neointima and media, and that of tissue inhibitors of MMP is
decreased.
31 In the later phases of clinical CAV, focal atherosclerotic
plaques develop in the coronary arteries. These plaques can
destabilize and rupture, like atheromatous plaques.
32

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Figure 2. Pathology of severe cardiac allograft vasculopathy affecting 3 major coronary arteries and small intramyocardial arterioles from an 8-year-old boy who received a heart allograft at age 1 year. Elastica van Gieson staining. A, Right coronary artery (RCA). B, Left circumflex artery (LCX). C, Left anterior descending artery (LAD). D, Small arterioles in the myocardium.
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Similar chronic changes in renal allografts are known as chronic allograft nephropathy. Pathologically this condition includes tubular atrophy, interstitial fibrosis, and fibrous intimal thickening of the vessel lumen.33 Fibrous intimal thickening involves smooth muscle cell proliferation and increased lipid-rich matrix in the intima of the arterial lumen, changes that are quite similar to the pathological changes that characterize CAV.
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Hypothesis for the Mechanism Underlying Development of CAV: Involvement of T CellMediated Immunity
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The risk factors and pathohistological features of clinical
and experimental CAV strongly suggest that immune responses
are involved in development of CAV (
Figure 1). The initiation
of this process includes endothelial damage and dysfunction.
32,34 Ischemia/reperfusion injury, acute rejection episodes, and cytomegalovirus
infection can cause vascular inflammation (endotheliitis and
arteritis). Immunohistological studies showed both humoral and
cell-mediated immunity are involved in the development of CAV.
35,36 It has been reported that development of CAV is minimal in allografts
transplanted into B cell-deficient mice that cannot produce
immunoglobulins.
37 The infiltration by T lymphocytes in the
early stages of CAV suggests that these cells interact with
damaged graft endothelial cells and sustain the chronic immune
response to the injured vessel wall.
36 Many cytokines, chemokines,
and other humoral factors play important roles in these processes,
and during these processes, T lymphocytes are activated.
There are data that support the involvement of T lymphocytes and the interaction of T lymphocytes with human leukocyte antigen (HLA) in the progression of CAV. The indirect pathway of antigen recognition by T cells in CAV development has been described.38 In this pathway, T cells recognize processed peptides derived from the recipients antigen-presenting cells. In contrast, in the direct pathway, T cells recognize alloantigen directly without antigen presentation. In experimental models, isografted hearts seldom develop intimal hyperplasia, and the degree of major histocompatibility complex difference is crucial in the extent of CAV development in murine models of cardiac allografts. Depletion of CD4+ but not CD8+ T lymphocytes prevents development of CAV.35,39 One interesting experimental model is re-transplantation of allografts to the donor strain at an early stage after allografting. These allografts showed continuous progression of CAV even after retransplantation of the heart graft into the donor strain. These results suggest that initial allogeneic stimulation at an early stage after transplantation is crucial for the development of CAV.40,41 In murine models of cardiac allografts, it is possible to induce immunologic tolerance by treatment with anti-LFA-1 and antiICAM-1 monoclonal antibodies42,43 or anti-CD154 antibodies and CTLA4Ig.44 In these animals, T lymphocytes become anergic against alloantigens and cannot respond to allostimulation. Cardiac allografts in these animals are reported to be free from CAV.30,45 These data also suggest that activation of T lymphocytes is crucial in the development of CAV.
Once activated, T lymphocytes produce a variety of cytokines including IL-2 (IL-2), interferon-
(IFN
), and tumor necrosis factor-
(TNF-
).46,47 IL-2 promotes proliferation of T lymphocytes, and IFN
acts on endothelial cells and other potential antigen-presenting cells to express major histocompatibility complex class II antigens.48,49 Among these cytokines, IFN
appears to be particularly important. Mice deficient in IFN
or treated with antibody to IFN
do not develop CAV, even though these recipients can reject parenchymal tissues.50 IFN
can also induce arteriosclerotic changes in the absence of detectable T cells by acting on vascular smooth muscle cells to potentiate growth-factor-induced mitogenesis.51 However, administration of recombinant IFN
in experimental models of vascular injury inhibits cell proliferation, as does IFN
addition to vascular smooth muscle cell cultures unless serum-free conditions are used.52,53 A major effect of IFN
in eliciting vascular remodeling is to prime macrophages for activation. Therefore, development of CAV, but not parenchymal rejection, requires IFN
. These cytokines also activate donor endothelial cells and promote expression of adhesion molecules such as ICAM-142,54 and VCAM-1.55 These adhesion molecules facilitate recruitment of T lymphocytes and macrophages to the site of CAV. In the presence of these cytokines and adhesion molecules, a variety of growth factors which include platelet-derived growth factor,51,56 fibroblast growth factor (FGF), TGF, insulin-like growth factor, and others,47 are secreted from activated endothelial cells and infiltrating cells. However, a recent study shows that the only significant effect of platelet-derived growth factor on atherosclerotic lesions is to inhibit T cell activation in the lesions.57 These factors stimulate the proliferation and migration of smooth muscle cells to promote intimal thickening.58 Recent investigations using apolipoprotein E (apoE) or low-density lipoprotein receptor knockout mice demonstrated that abrogation of TGFß signaling increased the size of atheroma and reduced the content of smooth muscle cells and collagen in the lesion.59,60 Accumulation of extracellular matrix is involved in this process, and endothelial thrombogenic activity increases.61 Therefore, activation of T lymphocytes and interaction of T lymphocytes with endothelial cells and smooth muscle cells are involved in the initiation and development of CAV.
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T Lymphocyte Activation and Costimulatory Signals
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Optimal activation of T lymphocytes requires costimulatory signals
from antigen-presenting cells in addition to the interaction
of T cell receptor with major histocompatibility complex antigen
on antigen-presenting cells (
Figure 3). Signaling through the
T-cell receptor without an appropriate costimulation leads to
T cell anergy or apoptosis.
62 The costimulatory signal is not
antigen specific and is derived from cell surface molecules
on antigen-presenting cells and on T lymphocytes. Simultaneous
engagement of the T cell receptor and costimulatory receptorligand
interaction results in the activation of NF

B and leads to production
of IL-2 that allows expansion of a specific T lymphocyte clone,
and promotes survival of T cells.
63,64 The interaction between
the costimulatory molecules and antigen-presenting cells is
not a single event. Many costimulatory factors are involved
in various facets of T lymphocyte activation and inactivation.
65,66 CD28-mediated signaling has been investigated as a major costimulatory
signal for T cells; however, mice without CD28 signaling have
normal immune responses suggesting that other costimulatory
molecules can substitute for CD28.
67 Other molecules that have
been examined for costimulatory activity belong to the B7 family
or the TNF/TNF receptor (TNFR) family (
Tables 2 and 3
). The
B7 family includes CD28, cytotoxic T lymphocyte-associated antigen-4
(CTLA-4), inducible costimulator (ICOS), programmed death-1
(PD-1), and B and T lymphocytes attenuator. The TNF/TNFR group
includes CD40, OX40, herpes virus entry mediator (HVEM), 4-1BB
(CD137), CD27, CD30, and glucocorticoid-induced TNFR-related
gene.
65,66 These molecules provide positive secondary signals
for T cell activation or transduce negative signals that downregulate
T cell responses.
68,69 The functions of these signals are differentially
regulated depending on the disease and situation. Therefore,
stimulation and/or blockade of these molecules show promise
as therapeutic applications for control of pathological situations,
including cancer, infection, transplantation, autoimmunity,
and vascular diseases.

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Figure 3. Schematic representation of signaling pathways leading to T cell activation and roles of costimulatory molecules for regulation of these pathways. MHC indicates major histocompatibility complex; TCR, T cell receptor.
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Costimulatory Molecules and CAV
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Evidence for the effects of T cell activation in CAV and atherosclerosis
has been reported. A considerable effort has focused on CD28-B7
and/or CD40-CD154 mediated T cell costimulation. Also, a small
number of recent investigations are showing involvement of ICOS-ICOS
ligand, PD-1-PD-Ligand, and HVEM-LIGHT pathways in arterial
lesions.
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CD28-B7 Pathway
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The B71/B72:CD28/CTLA-4 pathway is the best characterized
T cell costimulatory pathway. CD28 transduces positive signal
for T cell activation and survival, whereas CTLA-4 delivers
a negative signal for T cell responses.
69 It was reported that
CD28-mediated signal is inhibited by CTLA-4Ig, a recombinant
fusion protein that contains the extracellular domain of human
CTLA-4 fused to a human IgG heavy chain. In a rat model of cardiac
transplantation, CTLA-4Ig reduced the frequency and severity
of CAV in comparison with cyclosporine A-treated rats. This
attenuation was accompanied by a reduction in IFN

, monocyte
chemoattractant protein, inducible nitric oxide synthase, galactose/
N-acetylgalactosamine
macrophage lectin, and TGFß.
70 Similar results with
CTLA-4Ig
71,72 and anti-CD28 monoclonal antibody
73 have been
reported in chronic cardiac or renal allograft rejection in
small animals. These investigations are the initial reports
showing that T cell recognition of alloantigens is a central
event in initiation of chronic rejection and that T cell costimulation
could be a target to prevent chronic rejection. Interestingly,
blockade of this pathway by CTLA-4Ig late after transplantation
is also an effective means to attenuate CAV. Rat cardiac transplant
recipients treated with a short course of cyclosporine followed
by injection of CTLA-4Ig at 1 to 2 months after transplantation
showed reduced CAV, infiltration of mononuclear cell infiltration,
and parenchymal fibrosis.
74 This observation supports the idea
that continuous T cell recognition of alloantigens and T cell
activation are mediators of intimal hyperplastic changes in
chronic allograft rejection.
The importance of the CD28 pathway in atherogenesis has been shown in mice lacking both apoE and CD2875 and in humans.76 Double knockout mice lacking both B71/B72 and low-density lipoprotein receptors show significant reduction in early development of diet-induced atherosclerotic lesions.77
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CD40-CD154 Pathway
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CD40 is expressed on a variety of cell types including macrophages,
dendritic cells, B cells, and endothelial cells.
78 CD154 is
expressed on activated T cells and platelets. Blockade of this
pathway either alone or together with the B7-CD28 pathway inhibits
autoimmune diseases
79 and leads to long-term allograft survival
in small and large animal transplantation models.
44,80 There
is evidence that CAV is attenuated when this pathway is inhibited
in animal models of cardiac transplantation.
81,82 Clinical analysis
of CAV lesions in heart transplant recipients revealed that
CD154 was expressed by infiltrating lymphocytes and that CD40
was expressed by intimal endothelial cells, foam cells, macrophages,
and smooth muscle cells.
83 This overexpression of CD40 was accompanied
by ICAM-1 and VCAM-1 expression in endothelial cells.
The role of the CD40-CD154 pathway in CAV development is still controversial. CD154 monoclonal antibody therapy alone fails to prevent development of CAV in some models.84,85 CD154/ transplant recipients develop allospecific tolerance to the donor hearts, but these allografts show significant CAV by 8 to 12 weeks after transplantation.86 Thus, low-level alloresponses may trigger vascular responses that ultimately result in graft failure even in recipients in whom donor-specific tolerance is induced. Other investigators have reported that blockade of the CD40-CD154 pathway targets predominantly CD4+ T cells and does not prevent CD8+ T cell-mediated immune responses. However, even in the absence of CD8+ T cells, CD154 blockade did not prevent formation of CAV.87 Using this situation, the role of IL-4 in the CAV in absence of CD40-CD154 costimulation is shown in a model of murine abdominal aortic allografts.85,88
The role of the CD40-CD154 interaction in atherogenesis has been the focus of much research.8991 T lymphocytes within the atherosclerotic vessel wall express CD154 and functional CD40. Low-density lipoprotein receptor knockout mice treated with anti-CD154 antibody for 12 weeks showed profound reduction in the areas of atherosclerotic lesions.89 CD154 /apoE double-knockout mice exhibited a decrease in plaque area.90,92 This signaling pathway is involved in upregulation of expression of matrix metalloproteinases and procoagulant tissue factors and subsequent development of plaque rupture and thrombosis.9395 However, it should be noted that recent attempts to treat large animals96 and patients with anti-CD154 led to thrombotic side effects probably because of the dense expression of CD154 on platelets.
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ICOS/ICOS Ligand Pathway
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ICOS is a member of the CD28/CTLA-4 family and is expressed
on activated T cells. Stimulation of the ICOS pathway promotes
secretion of IFN

, IL-4, and IL-10. Inhibition of the ICOS pathway
with anti-ICOS antibody or the soluble form of ICOS (ICOSIg)
prolongs cardiac allograft survival in a murine model, and combined
treatment with anti-ICOS antibody and cyclosporine A
97 or ICOSIg
and CTLA-4Ig
98 prolongs cardiac allograft survival indefinitely
and prevents development of CAV. ICOS ligand, also known as
B7-related protein 1 (B7RP-1), is expressed constitutively on
B cells and in peripheral lymphoid tissues.
65,99 In vitro studies
revealed that ICOS ligand expression is induced on fibroblasts
treated with TNF-

and that it is expressed constitutively on
endothelial cells and is upregulated by treatment with IL-1ß
or TNF-

.
100 Although ICOS and CD28 signaling upregulate Th1
and Th2 cytokines, ICOS does not upregulate IL-2 production.
Therefore, ICOS stimulates T cell effector function but not
T cell clonal expansion.
65
Treatment of cardiac allografts with ICOSIg with blockade of the CD40 ligand/CD40 pathway attenuates development of CAV in mice.97 Our experiments revealed that ICOS ligand expression is induced on smooth muscle cells of thickened intima in CAV and treatment of recipient mice with either ICOSIg or anti-ICOS antibody suppresses development of CAV.101 Similar findings showing the importance of delayed blockade of this pathway have been reported by another laboratory.102 The authors speculate that delayed blockade of this pathway allows generation of regulatory mechanisms while inhibiting activation of effector/memory T cells. Because ICOS and ICOS ligand are not expressed in normal tissues and expression is induced during immune activation, this pathway may be a suitable target for prevention of CAV and other arterial lesions.
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HVEM-LIGHT Pathway
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LIGHT (homologous to
lymphotoxins, exhibits
inducible expression,
and competes with herpes simplex virus
glycoprotein D for
herpes
virus entry mediator [HVEM], a receptor expressed on
T lymphocytes)
was described as a member of the TNF superfamily.
103 LIGHT is
expressed in peripheral blood mononuclear cells, including T
and B cells, natural killer cells, monocytes, and granulocytes,
and binds to HVEM and lymphotoxin ß receptor (LTßR).
103,104 Although LTßR is not expressed by T or B cells, HVEM
is expressed by lymphocytes and endothelial cells. In vitro
studies revealed that the interaction of LIGHT with HVEM is
involved in T cell proliferation, cytokine production, and activation
of NF-

B.
105,106 In a murine cardiac transplantation model, LIGHT-deficient
recipient mice showed prolonged allograft survival.
107 Our recent
studies have shown that the LIGHT pathway is important in regulating
development of CAV in organ transplant recipients. Blockade
of the LIGHT pathway with HVEMIg significantly attenuates the
development of CAV.
108
Interactions between activated T cells and smooth muscle cells are complex. Previous in vitro studies showed that T cells promote smooth muscle cell proliferation via IFN
.109,110 However, other studies show that IFN
potently inhibits smooth muscle cell proliferation under standard cell culture conditions.52 Another study has demonstrated bidirectional effects of IFN
on smooth muscle cells depending on culture conditions.111 In addition, production of basic fibroblast growth factor and heparin-binding epidermal growth factor-like growth factor, which are potent growth stimuli for smooth muscle cells, in response to T cells is reported.112 We cocultured smooth muscle cells from a Bm12 donor and sensitized T cells from B/6 mice that reject cardiac allografts from Bm12 mice. Smooth muscle cells proliferated in response to IL-1ß stimulations, and this response was enhanced by coculture with the sensitized T cells. HVEMIg suppressed in vitro smooth muscle cell proliferation in response to activated T cells from rejected cardiac allografts, and this suppression is accompanied by reduced transcription of IFN
and IL-6.108
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Negative Regulators of T Cell Activation
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Costimulatory molecules that negatively regulate T cells have
been described. These inhibitory receptors include CTLA-4, PD-1,
and B and T lymphocytes attenuator, which are all expressed
on lymphocytes. PD-1 is a member of the CD28 family and was
identified in a T cell line undergoing programmed cell death;
113 however subsequent studies have shown that its expression is
associated with lymphocyte activation rather than cell death.
114 PD-1 activation leads to downregulation of immune responses,
and deficiency results in loss of peripheral tolerance to self
antigens.
65,115 In contrast to CTLA-4, which plays central roles
in lymphoid organs, PD-1 regulates inflammatory responses in
peripheral tissues. PD-L1 (ligand for PD-1) and PD-1 negatively
regulate CD8
+ T cell responses. The role of PD-1 in the development
of CAV is still controversial. PD-L1Ig promotes long-term graft
survival in CD28
/ recipients and markedly reduces
CAV when given in conjunction with anti-CD154 monoclonal antibody.
116 Expression of PD-L1 is also induced in endothelial cells and
smooth muscle cells in response to IFN

.
117 We observed that
administration of anti-PD-L1 monoclonal antibody into mice with
a cardiac allograft enhanced the progression of CAV.
118 IFN
expression by cardiac allografts was increased in response to
anti-PD-L1 monoclonal antibody treatment. An in vitro study
revealed that activated T cells from recipient mice bearing
rejecting allografts increased proliferation of smooth muscle
cells, and that anti-PD-L1 monoclonal antibody increased this
proliferation. Further studies are needed to clarify the differential
roles of this and other costimulatory pathways.
 |
Other Pathways
|
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There are many other costimulatory pathways important for T
cell activation. 4-1BB (CD137) is a costimulatory molecule of
T cells and a member of the TNFR family; 4-1BB is expressed
on activated T cells. In conjunction with a strong signal through
the T cell receptor, 4-1BB/4-1BB ligand interactions can provide
critical costimulatory signals either in the absence or presence
of CD28.
119 In a murine model of cardiac transplantation, administration
of anti4-1BB ligand antibody modestly prolonged allograft
survival.
120 Recent investigations have revealed the involvement
of OX40, which is expressed primarily on CD4
+ T cells, in the
development of atherosclerosis.
121 OX40 ligand is found to be
present on mouse atherosclerotic lesions; however, their role
in CAV has not been investigated.
122 Other costimulatory molecules
include glucocorticoid-induced TNFR-related gene and B and T
lymphocytes attenuator. Their important roles in T cell costimulation,
peripheral tolerance, inflammation, both pro- and anti-apoptotic
effects, and development of immune system have been described;
however, their effects on vascular immunology and CAV have not
been reported to date.
 |
Clinical Implications
|
|---|
These costimulatory pathways play a pivotal role not only in
T cell activation but also in regulating smooth muscle cell
proliferation. The contributions of these pathways to other
acute and chronic inflammatory cardiovascular diseases should
be the subject of future studies. Although these findings support
the idea that these pathways may be targets for clinical therapeutic
interventions for attenuating development of vascular lesions,
several issues should be addressed. Because there are many pathways
and because the individual roles of these pathways are unclear,
future studies should focus on the differential and collaborative
roles of these pathways in regulating T cell activation and
subsequent CAV development. The roles of these costimulatory
molecules in the human immune system have been a matter of investigation
because majority of the data have been obtained with murine
models. It is reasonable to assume that the processes of activation
and inactivation of T cells in humans are more redundant and
complex than those in mice.
Another future approach to use the T cell costimulatory pathways is tolerance induction to immunogens in arterial lesions. Blockade of some of these costimulatory pathways has been shown to induce tolerance to alloantigens. If the autoantigens in atherosclerosis and alloantigens in CAV were identified, blockade of specific pathways could serve as a novel therapeutic strategy to prevent or treat CAV.
In conclusion, increasing evidence suggests the importance of costimulatory pathways for T cell activation in vascular biology. As mentioned in this review, these pathways are involved in the pathogenesis of not only CAV but also atherogenesis and restenosis after vascular injury. In this respect, investigation of T cell costimulation in CAV could provide important insights into the pathophysiology of a wide range of vascular diseases and could aid in the development of novel therapeutic interventions for vascular diseases.
 |
Acknowledgments
|
|---|
The authors thank Professor Toshimitsu Uede of Hokkaido University
for providing us invaluable materials and his stimulating discussions
and Professor Jun Amano of Shinshu University for his collaboration.
We also appreciate the secretarial assistance of Mahoko Watarai.
Sources of Funding
Our investigation was supported by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO), a grant-in-aid from the Japanese Ministry of Education, Science, and Culture, and a grant-in-aid from the Japanese Ministry of Welfare.
Disclosures
None.
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Footnotes
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Original received October 31, 2005; final version accepted March
2, 2006.
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