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Transplantation
of donor-derived allogeneic hematopoietic cells causes increased survival in
patients suffering from various blood cancers and other hematologic and
immunologic diseases. However, this health benefit is limited to certain
patients. One major complication is graft-versus-host disease (GVHD) that
occurs when donor-derived immune cells recognize host cells/tissues as foreign
and perpetrate subsequent destruction. Cytokines are a major class of effector
molecules that are involved in GVHD pathogenesis. Proinflammatory cytokines
released by activated immune cells including T cells lead to the onset of GVHD.
T cell depletion (TCD) is an effective approach for GVHD prevention. Several
immune suppressive drugs are also used to treat GVHD. However, these
prophylactic and treatment strategies often lead to an immune compromised state
that increases the risk for infection and cancer relapse. Considering the
adverse effects of TCD and overall immune suppression, more selective
managements such as approaches targeting proinflammatory cytokines have emerged
as a promising strategy to control GVHD. Therefore, this work is dedicated to
review recent development in the studies of cytokines and their future
implication in GVHD therapy.
Keywords: Hematopoietic cell transplantation,
Graft-versus-host disease, T cells, Cytokines
INTRODUCTION
Graft-versus-host
disease (GVHD) is serious complication after allogeneic hematopoietic cell
transplantation (Allo-HCT). During anallo-HCT procedure, hematopoietic cells
harvested from an allogeneic donor are transplanted into a patient who suffers
a certain type of hematologic malignancy or other hematologic or immunologic
disease. After transplantation, however, donor derived immune cells may
recognize normal host cells/tissues as foreign and subsequently cause tissue
damages leading to onset of GVHD. The common symptoms of acute GVHD include
weight loss, alopecia (hair loss on scalp and elsewhere on body), skin lesions,
gastro-intestinal (GI) tract and liver complications that may lead to death
[1]. Among various cellular immune components, T cells are crucially important
in the pathogenesis of GVHD. Donor T cells undergo activation, proliferation
and migration into target organs as a cascade of molecular events involving
interaction between T cell receptors (TCR) and major histocompatibility complex
(MHC) bound allo-antigens, co-stimulatory signaling and cytokine signaling.
Cytokines are immune effectors as well as regulators of various immunologic
conditions including inflammation and hypersensitivity reactions [2,3]. Many
studies have demonstrated that cytokines are involved in various inflammatory
and regulatory activities during GVHD [4,5]. Following encounters between donor
T cells and host antigen presenting cells (APCs) presenting allo-antigens,
allo-reactive donor T cells are activated and undergo vigorous proliferation
and then migrate to the target organs and tissues. These events are accompanied
with enhanced secretion of proinflammatory cytokines that contribute to severe
acute GVHD. That is why a rapid onset of acute GVHD is considered as a result
of “cytokine storm” [6]. The manifestation and severity of GVHD ascribe to naïve
T cells maturing and differentiating into different lineages and phenotypes
including regulatory T cells (Treg), Th1, Th2, and Th17 cells (Figure 1). This differentiation is
associated with the presence of local cytokines that activate transcription
factors and determine supremacy of certain phenotypes [7]. Th1 cells secret
several cytokines namely interleukin-2 (IL-2), IL-10, interferon-gamma (IFN-γ),
tumor necrosis factor-alpha (TNF-α), and TNF-β. Th2 cells secret cytokines like
IL-3, IL-4, IL-5, IL-10, IL-13, IL-17E and IL-31. Th17 is known to secrets
IL-17 mainly [7]. In GVHD, donor naïve CD4+ T cells recognize allo-antigens
presented on the host’s APCs and differentiated into Th1, Th2, and Th17 cells
depending upon local cytokine milieus. In MHC-mismatched models of GVHD, T
helper (Th) cells differentiated into Th1 subtypes that mediate tissue damage
in GI tract and liver. In the absence of IFN-γ, Th cells differentiated into
Th2 and Th17 subsets and caused damage in lung and skin. If there is neither
IL-4 nor IFN-γ the dominating subset is Th17 cells that lead to tissue damage
in skin. If both the IFN-γ and IL-17 are absent, the dominating subset is Th2
cells that cause idiopathic pneumonia in GVHD patients [8]. Furthermore, in the
presence of IL-12 Th cells differentiate into Th1 phenotype and cause release
of IFN-γ and IL-2 cytokines [9]. In summary, the literature has described
cytokines as effector molecules as well as regulatory factors in GVHD
pathogenesis. This review aims to corroborate the past and current knowledge
regarding the functions of cytokines in GVHD pathogenesis with special emphasis
on potential therapeutic managements.
Th1 Cytokines in GVHD
Among
various Th1 cytokines, IL-2 is one of the most studied cytokines for its role
in activation, proliferation and expansion of T cells in GVHD. Several studies
indicate a potential role of IL-2 in GVHD [10-14]. The role of IL-2 in GVHD is
very diverse that includes amplification of allogeneic immune response,
activation of T cells and NK cells, stimulating secretion of TNF-α by
macrophages and inflammatory damages to the skin and gut [15]. Considering the
importance of IL-2, high dose and low dose of IL-2 therapy are used to diminish
GVHD [11,12]. Administration of high dose IL-2 for several days beginning on
the day of allo-HCT attenuates GVHD mortality in lethally irradiated mice [11].
Low dose therapy with IL-2 has also been reported, that expands Treg population
in vivo and is associated with a lower incidence of GVHD [12]. Low dose of IL-2
restores CD4+Foxp3+Treg homeostasis without causing any
adverse effect on the graft-versus-leukemia/lymphoma (GVL) response [13]. On
the other hand, prevalence of chronic GVHD is characterized by constitutive phosphorylation
of Stat5 in conventional CD4+ T cells (Tcons) associated with elevated amounts
of IL-7 and IL-15 and relative functional deficiency of IL-2. The IL-2 therapy
resulted in the selective increase of Stat5 phosphorylation in Treg and a
decrease of phosphorylated Stat5 in Tcons [14]. However, there are certain
limitations of IL-2 therapy in GVHD. For examples, in experimental GVHD model,
IL-2 administration to donor mice induces a dose-dependent expansion of Treg
cells in the graft but is insufficient to suppress GVHD [16]. In xenogeneic
model of GVHD where human peripheral blood mononuclear cell transplanted into
immunodeficient mice, although, low-dose IL-2 administration caused increase in
Treg cells but was unable to control pro-inflammatory cytokines production by
pathogenic Tcons [16]. Taken together, studies are divided into pro- and
anti-IL2 therapy in GVHD.
Another
member of Th1 secreted cytokines, IL-10 (also known as human cytokine synthesis
inhibitory factor) is a regulatory cytokine that play an important role
in GVHD. IL-10 can modulate CD4+ T cells functions by down-regulation of
another Th1 cytokine IL-2 [17]. IL-10 does not contribute to GVHD mediated by
effector T cells. In contrast, IL-10 creates tolerogenic environment to allo-antigens
independent of IL-2 or CD28 stimulation [18]. A study, using IL-10 deficient
donor or host mice in a MHC-mismatched model of acute GVHD, reported increased
GVHD if either donor or host B cells were unable to produce IL-10 [19]. The induction of IL-10 release in host B
cells attenuates acute GVHD in experimental model [20]. Furthermore, donor bone
marrow graft and Treg-derived IL-10 are important for the donor Treg-mediated
suppression of GVHD [21]. High frequency of donor cells producing IL-10 in response
to host allo-antigen stimulation has been correlated with the absence of acute
GVHD post allo-HCT. Conversely, low frequency of IL-10 response is strongly
associated with more severe GVHD [22].
Another
major Th1 cytokine, IL-12, produced mainly by dendritic cells and macrophages,
is a heterodimeric cytokine that mediated cellular immunity [23]. The dimeric
components of IL-12 are a heavy chain subunit p40 and a light chain subunit p35
that are critical for the functions of active IL-12 [23]. Interestingly, IL-12
shares a common p40 subunit with another cytokine IL-23. This subunit is
important for driving Th1 differentiation and stabilization of Th17 phenotype.
Result showed that both donor- and host-derived p40 is important for the
induction of acute GVHD. The therapeutic efficacy of anti-p40 was evident by
its ability to reduce acute GVHD [24].
Pro-inflammatory
cytokine IFN-γ is mainly produced by activated T-cells, NKT cells and NK
cells. IFN-γ inhibits GVHD in lethally irradiated mice receiving allo-HCT but
promotes lethality in un-irradiated and sub-lethally irradiated recipients
[25]. The extent of conditioning markedly affects the role of IFN-γ in GVHD
lesions mediated by CD4+ T cells. For example, in a GVHD model using sub-lethal
total body irradiation (TBI), the absence of IFN-γ is playing a protective role
in GVHD, while in lethal TBI condition, loss of IFN-γ is associated with
increased pathogenesis [26]. However, there is experimental evidence that IFN-γ
may not be required in GVHD pathogenesis but can facilitate the GVL effects
[27]. Further studies are required to explore IFN-γ involvement in GVHD for
more in depth insight on its use as a therapeutic target.
Another
cytokine from Th1 family that plays important role in the GVHD is TNF-α. It is
directly involved in tissue damages by inducing apoptosis or necrosis of target
cells and synergizes with cytotoxic T lymphocytes and NK cells [28]. Therefore,
use of TNF-α antagonist has shown promising results in GVHD management. For
example, Korngold et al., have investigated that the inhibition of TNF-α during
HCT can diminish inflammatory GVHD reactions without hindering effective GVL
response [28]. However, a recent study reported that TNF-α priming can enhance
CD4+ Foxp3+ regulatory cell suppressive function to
attenuates GVHD [29]. Also, another study indicated that GVHD control depends
to production of TNF-α by T cells and expression of TNFR2 on regulatory T cells
[30].
In
summary, the roles of Th1 cytokines in GVHD pathogenesis are diverse yet not
completely defined. Management of Th1 cytokines for GVHD prophylaxis and
treatment appears promising, but optimization is still an issue that needs
further effort.
Th2 Cytokines in GVHD
Th2
cytokines can attenuate Th1 cytokines such as TNF-α and interrupt Th1 cytokine
cascade post allo-HCT and therefore was once thought to lead to the suppression
of GVHD pathogenesis [31]. Recently, transplantation of myeloid derived
suppressor cells (MDSCs) has been reported to skew allogeneic T cell response
toward Th2 cells and enhanced Th2-specific cytokines that caused suppressed
GVHD [32]. However, other studies have suggested various cytokines of Th2
family are associated with GVHD. For example, IL-3 is a growth promoting
cytokine involved in the differentiation and apoptosis of various hematopoietic
cell types [33]. Up-regulated level of IL-3 is reported in a significant
subgroup of patients suffering from extensive chronic GVHD [34]. Similarly,
high-dosage of IL-3 accelerates GVHD and impairs survival of the host [35].
Another Th2 cytokine, IL-4 is a pleiotropic cytokine produced by activated T
cells [36]. The IL-4 receptor (IL-4R) also binds to IL-13, that contribute to
several overlapping functions of IL-4 and IL-13 [37]. IL-4 plays an important
role in the regulation or pathogenesis of allogeneic responses [38]. Th2 cell
therapy can rapidly ameliorate severe GVHD by creating hindrance in IL-4 and
IL-10 functions, IL-2 consumption and APC modulation [39]. IL-5 is another
member of Th2 cytokine family originally defined as a T-cell-derived cytokine
that triggers activated B cells for terminal differentiation into
antibody-secreting plasma cellsat least in mice [40]. Elevated level of serum
IL-5 is reported in acute GVHD [41]. The cytokines IL-5, IFN-γ, and TNF-α have
been used as biomarkers of acute GVHD [42]. IL-13 is mainly involved in the
allergic inflammation and other ailments including GVHD [3]. Therefore,
association between IL-13 levels and acute GVHD may be exploited as a strong
predictor of this disease. In summary, it is now clear that acute GVHD is not a
purely Th1-type cytokine-driven response, but Th2-type cytokine such as IL-13
has also been involved in the pathogenesis of acute GVHD [42]. Therefore, the
roles of these Th2 cytokines need further mechanistic clarification in GVHD
pathogenesis and management to achieve optimum exploitation.
Th17 Cytokines in GVHD
Th17
cells are known to release cytokines including IL-17and IL-22 [43]. Th17 cells
synergize with naive T cells to induce lethal GVHD. In vitro polarized Th17
cells can induce higher GVHD leading to the severe skin and pulmonary
conditions [44]. Th17 cells have an inverse relationship with Treg cells In
GVHD. The dynamic changes of Th17 and Treg cells along with the level of Th17
cytokines are associated with the onset and resolution of acute GVHD [43].
IL-17 mediates its function via surface receptors on target cells [45].
Participation of IL-17 has been studied in the acute rejection of organ
transplants and GVHD [46]. Both CD4+ IL17-producing T cells and CD8+ IL17-
producing T cells secret the IL-17 cytokine. These subsets of T cells are
suspected to initiate Th1 response at early phase in GVHD [47]. In an allo-HCT
model using pan T cells, IL-17 is dispensable for GVHD and GVL activity.
However, IL-17 contributes to the early development of CD4+ T cell-mediated
GVHD by up-regulating production of proinflammatory cytokines [46]. Concurrent
to this study reports IL‑17‑producing
CD8+ T (Tc17) in the initiation of GVHD [48]. In addition to IL-17, other Th17
cytokines are also targeted by researchers to explore their role in GVHD.
Interleukin-22 protects intestinal stem cells from immune-mediated tissue
damage and regulates sensitivity to GVHD [49]. Treatment
with IL-22 in vivo after allo-HCT enhanced the recovery of intestinal
stem cells, increased epithelial regeneration and reduced intestinal pathology
and mortality from GVHD [50]. In addition, IL-22 producing RORγt+ ILC3 subset
was reported to be involved in the prevention of intestinal GVHD via
strengthening the intestinal mucosal barrier [51]. Furthermore, one of the
other important cytokines that is produced by Th17 and T follicular helper
cells is IL-21 [7]. Also, splenic neutrophils can express IL-21 during acute
GVHD [52]. IL-21 was shown to play a
critical role in GVHD development through increasing B cell activation and
proliferation, alloantibody generation and disrupting Treg homeostasis
[53,54]. It was also shown that direct
or indirect (through Rho associated kinase 2) inhibition of IL-21 ameloraited
GVHD symptoms [55]. Taken together,
these studies show that the diverse roles of Th17 cytokines in GVHD are highly
important, yet more in depth explorations are still required to define the
precise contributions of various Th17 cytokines in GVHD.
Other Cytokines, Chemokines and T Cell
Populations in GVHD
Apart
from Th1, Th2 and Th17 cytokines, various other cytokines also play important
roles in GVHD directly or indirectly. For example, TGF-β-dependent CD103
expression is involved in regulating destruction of gut epithelium by CD8+ T
cells during GVHD pathogenesis [56]. The anti-inflammatory cytokine IL-35 can
suppress acute GVHD in patients post allo-HCT. This cytokine targets
phosphorylation of STAT1 and STAT4 which is generally inhibited in mice in
acute GVHD. Treatment of IL-35 leads to up-regulated phosphorylation of STAT1
and STAT4 and amelioration of acute GVHD. These observations advocate the
potential therapeutic efficacy of IL-35 in GVHD [57]. Homeostatic interleukin
IL-7 regulates T cell survival and proliferation in vivo and is also known as a thymotropic cytokine along with SCF
[58,59]. A recent study suggests that elevated IL-7 but not SCF is associated
with development of GVHD [59]. Another proinflammatory cytokine, IL-15, induces
T cell proliferation and demonstrates IL-2-like properties [60]. Both IL-7 and
IL-15 have been associated with the peripheral T cells regeneration in mice and
humans [61]. Considering the importance of IL-7 and IL-15 in immune functions,
these cytokines have been targeted for the treatment of acute GVHD [61]. In
addition, increased levels of cytokines and chemokines including B cell
activating factor (BAFF), IL-33, CXCL10 and CXCL11 are reported in GVHD
pathogenesis [62]. The role of chemokine CCR7 in GVHD is especially affiliated
with gastrointestinal (GI) tract complications. CCR7 significantly regulates
elevated allo-antigens presentation in mesenteric lymph nodes of GI tract [63].
Furthermore, the binding of IL-33 to receptor “suppression of tumorigenicity 2
(ST2)”presents intriguingly both pro-inflammatory and anti-inflammatory
effects. The increased levels of soluble ST2 are a biomarker for
steroid-refractory GVHD and mortality. Blockade of IL-33 and ST2 interaction
induces marked reduction in GVHD lethality [64]. Another recent study suggests
a role of IL-26 in the pathogenesis of transplant-related obliterative
bronchiolitisas IL-26+CD26+CD4+ T cells in
part induces chronic GVHD of the lungs [1].
Moreover, IL-1β and associated MyD88 signaling in dendritic cells and T
cells are involved in GVHD. After conditioning therapy, the microbial products
and uric acid can activate NLRP-3 in donor T cells to increase IL-1β expression
that subsequently enhances GVHD severity [65]. On the other hand, it has been
demonstrated that MyD88 deficiency in T-cell depleted donor BM leads to
attenuated GVHD symptoms [66].
In
addition to Th1, Th2 and Th17 cells that produce associated cytokines and
affect GVHD, there are several important T cell populations that also impact
GVHD via cytokines and other mechanisms.
Many studies have documented the roles of Treg cells in GVHD. Both natural and induced Treg cells are able
to restrain conventional T cell proliferation and attenuate GVHD with multiple
mechanisms including IL-2, IL-10 and TGF-β [67]. CD4+CD103+Fop3+natural
Treg can directly migrate to GVHD target organs decreasing disease severity
[68]. Notably, the Th17/Treg ratio is correlated with clinical and pathological
GVHD and therefore could be used as a biomarker of GVHD [69]. IL-2 treatment in combination with rapamycin
has been shown to mitigate acute GVHD lethality, which is associated with
increased expansion of donor-type CD4⁺Foxp3⁺
Treg cells and reduction of CD4⁺CD25⁻
conventional T cells [67]. In addition,
T follicular helper (Tfh) cells are responsible for naïve B cells differentiation
to memory B cells and immunoglobulin class switching. Tfh cells express BCL-6
as transcription factor and CXCR5 and PD-1 surface markers with high secretion
of IL-21 cytokine. Tfh cells mostly locate in germinal center but a subset of
Tfh cells have been detected in peripheral blood. Tfh cells are required for
generation and maintenance of germinal center and B cells function in chronic
GVHD. These circulating Tfh cells appear to cause aggravation of chronic GVHD
[70,71]. Furthermore, a more recent
study has described a new CD4+ memory T population with high
expression of CD11c and α4β7 in gut that plays a pivotal role in initiating
gastrointestinal GVHD via promoting Th1 response and cytokine production [72].
Taken
together, these studies indicate that a wide range of cytokines and T cell
populations are involved in the pathogenesis of GVHD. A thorough understanding
of the complex molecular and cellular networks will provide better insights for
more effective GVHD management.
Updates on Cytokine-Related GVHD Management
Strategies
Recent
years witnessed a significant growth in findings related to the role of various
cytokines in the pathogenesis and management of GVHD. Several new drugs have
been used to treat GVHD based on cytokine regulation. For example, zinc
supplementation was reported to be beneficial in the induction of tolerance
that amelioratesTh1-dominated allogeneic immune response [73]. A recent study
also advocates granzyme B (GzmB) based therapeutic approach because GzmB knockout
T cells are associated with the production of prominent quantity of
proinflammatory cytokines that exacerbated GVHD [74]. An in vitro study using dendritic cell (DC) culture indicated that
bortezomib can inhibit the proliferation of DCs and also blocked expression of
costimulatory molecules CD80 and CD86. This drug was also found to diminish
IL-12 and TNF-α release in DCs following treatment of LPS [75]. Another study
was carried out on valproic acid, a histone deacetylase inhibitor that also
possesses anti-inflammatory effects. In
MHC-mismatched transplantation mouse model, valproic acid down regulated
Th1 and Th17 cell responses and cytokine production in vitro and in vivo
[76]. The use cyclopentylamino carboxymethylthiazolylindole-7 (NecroX-7) is
found useful in controlling GVHD in preclinical models. NecroX-7 is an
inhibitor of chromatin protein high mobility group box 1 (HMGB1). NecroX-7
protects mice against lethal GVHD by reciprocal regulation of Treg/Th1 cells
[77]. Erlotinib, an EGFR tyrosine kinase inhibitor ameliorates sclerodermatous
GVHD. These beneficial effects were mediated by decrease in IFN-γ and IL-13
production and autoimmune B-cell activation [78]. Moreover, BET bromodomain
inhibition can suppress GVHD through NF-κB regulation and decrease production
of inflammatory cytokines such as IL-6, IL-12, TNF-α in DCs and IFN-γ, IL-2,
IL-4 and IL-17 in activated T cells [79]. Although initial outcomes of these
cytokine-related therapeutic regimens raise hopes for better treatment, further
study is warranted to achieve optimum benefits.
Micro
RNAs (miRs) play important roles in regulation of various immune responses such
as infection, tumor, and autoimmunity [80]. Recently, the function of miR-17-92
cluster in allogeneic T cell response has been studied. Results suggest an
important role for miR-17-92 in donor T cells for GVHD induction. The miR-17-92
promotes CD4+ T cell functions, Th1 differentiation, but down-regulates Th2 and
inducible Treg functions [80]. In addition, miR-142 is implicated in hematopoietic
functions including T cell response. In
vivo deletion of miR-142 does not affect T cell development. But in vitro
and multiple models of GVHD targeting miR-142 leads to attenuated T cell
proliferation [81]. Recently, miR-155, known to regulate the innate immune
system, is studied for its role in DC functions during GVHD. Study suggests
that miR-155 deficiency in host system is associated with decreased
pro-inflammatory cytokines and attenuated GVHD pathogenesis [82]. Moreover, an
earlier study showed that expression of
miR146a increased in donor T cells after transplantation and deficiency
in Mir146a caused enhanced GVHD through TRAF6/TNF signaling pathway [83]. These
studies suggest that genetic manipulation by targeting miRs in GVHD therapy may
have beneficial impacts.
Uses
agonistic antibodies have shown proved efficacy in GVHD management. Recently,
αDR3, an antibody to death receptor 3 (DR3), has been investigated for its role
in the management of GVHD. DR3 is mainly present on Treg cells, lymphoid tissue
inducer cells and NKT cells [84]. Studies showed that agonistic antibody αDR3
expanded CD4+FoxP3+ Treg cells population in
vivo. Apart from the expansion of Treg cells, αDR3 also down-regulated
proinflammatory cytokines such as IFN-γ, IL-1β, and TNF-α. Notably this GVHD
alleviating effect was achieved by a single dose of αDR3 [84]. Another target
aimed to alleviate GVHD is the TNF-like weak inducer of apoptosis
(TWEAK)/fibroblast growth factor-inducible 14 (Fn14) axis. It was observed that
attenuation of TWEAK/Fn14 system alleviated disease development in several
models of colitis [85]. In GVHD, proinflammatory cytokine TNF play very
important role in intestinal cell death. TWEAK up-regulates TNF-induced cell
death. Therefore, proper understanding of Fn14 in TNF associated GVDH
pathogenesis will be useful. As such, an antibody-dependent cell-mediated
cytotoxicity (ADCC)-defective Fn14-blocking antibody has been utilized by
researchers to attenuate GVHD successfully [85]. These studies advocate
promising roles of monoclonal antibodies in GVHD management.
Cytokines
also find uses as biomarkers for GVHD. For example, tear cytokine profile was
found associated with systemic chronic GVHD. This finding is evident by the
presence of enhanced levels of IL-2, IL-10, IL-17α, IFN-γ, IL-6, and TNF-α tear
cytokines in chronic GVHD patients [86]. Recently, IL-6 and IL-9 have been
studied for their potential as biomarkers in GVHD [87]. In addition to
modulating T cells, recent study has also shown a potential role of cytokines
in modulation of NK cells. Adoptive transfer of IL-12, IL-15 and IL-18
pre-activated NK cells showed suppression of GVHD in a mouse model of
MHC-mismatched HCT [88].Together, adoptive transfer of cytokines pretreated immune
cells will pose a potential impact on the GVHD management.
CONCLUDING REMARK
In
summary, the role of cytokines in GVHD is indispensable. Several therapeutic
interventions based on targeting cytokines have already shown promising results
in GVHD amelioration. As Th1, Th2 and Th17 cytokines are associated with the
pathogenesis and management, exploitation of these immune mediators will
produce practical approaches to combat GVHD. Further studies are required to
understand the underlying mechanisms associated with the roles of cytokines in
GVHD in order to achieve optimum diagnostic and therapeutic benefits.
CONFLICT OF INTEREST
Authors
have declared that there is no conflict of interest.
ACKNOWLEDGEMENT
This work
was supported by NIH research grant # R01CA184728
(X.C.). We apologize to the authors whose studies are relevant to this subject
but are not cited due to space limitation.
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