International Journal o  f
Molecular Sciences
Review
PD-L1, a Potential Immunomodulator Linking Immunology
and Orthodontically Induced Inflammatory Root Resorption
(OIIRR): Friend or Foe?
Jiawen Yong 1,2,3,* , Sabine Gröger 1, Julia von Bremen 1, Joerg Meyle 2 and Sabine Ruf 1
1 Department of Orthodontics, Faculty of Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany
2 Department of Periodontology, Faculty of Medicine, Justus Liebig University Giessen,
35392 Giessen, Germany
3 Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial
Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province,
Cancer Center of Zhejiang University, Hangzhou 310003, China
* Correspondence: jiawen.yong@dentist.med.uni-giessen.de or yongjiawen.ggl@gmail.com;
Tel.: +49-641-99-46131
Abstract: Orthodontically induced inflammatory root resorption (OIIRR) is considered an undesired
and inevitable complication induced by orthodontic forces. This inflammatory mechanism is regu-
lated by immune cells that precede orthodontic tooth movement (OTM) and can influence the severity
of OIIRR. The process of OIIRR is based on an immune response. On some occasions, the immune
system attacks the dentition by inflammatory processes during orthodontic treatment. Studies on the
involvement of the PD-1/PD-L1 immune checkpoint have demonstrated its role in evading immune
responses, aiming to identify possible novel therapeutic approaches for periodontitis. In the field of
orthodontics, the important question arises of whether PD-L1 has a role in the development of OIIRR
Citation: Yong, J.; Gröger, S.; von to amplify the amount of resorption. We hypothesize that blocking of the PD-L1 immune checkpoint
Bremen, J.; Meyle, J.; Ruf, S. PD-L1, a could be a suitable procedure to reduce the process of OIIRR during orthodontic tooth movement.
Potential Immunomodulator Linking This review attempts to shed light on the regulation of immune mechanisms and inflammatory
Immunology and Orthodontically responses that could influence the pathogenesis of OIIRR and to acquire knowledge about the role of
Induced Inflammatory Root PD-L1 in the immunomodulation involved in OIIRR. Possible clinical outcomes will be discussed in
Resorption (OIIRR): Friend or Foe? relation to PD-L1 expression and immunologic changes throughout the resorption process.
Int. J. Mol. Sci. 2022, 23, 11405.
https://doi.org/10.3390/ Keywords: orthodontic tooth movement; orthodontic force; OIIRR; PD-L1; immunorthodontics;
ijms231911405 immunology; cementoblasts; cementum
Academic Editor: Naoe Taira Nihira
Received: 17 August 2022
Accepted: 23 September 2022 1. Introduction
Published: 27 September 2022
Orthodontic tooth movement (OTM) is induced by mechanical orthodontic forces
Publisher’s Note: MDPI stays neutral (compressive and tensile strain) and stimulated by the profound remodeling that occurs
with regard to jurisdictional claims in in the alveolar bone and periodontal ligament (PDL) [1]. On the tension side opposite to
published maps and institutional affil- the direction of OTM, anabolic processes dominate, while on the pressure side, resorptive
iations. processes prevail [2]. The orthodontic forces cause capillary vasodilatation inside the
periodontal microenvironments, in turn causing migration and extravasation of immune
cells accompanied by the expression of various cytokines. Hence, orthodontic forces may
Copyright: © 2022 by the authors. result in an altered homeostasis in different types of PDL cells as well as the host’s immune
Licensee MDPI, Basel, Switzerland. response [3].
This article is an open access article Within the periodontium, the dentine of the root is covered with a thin layer of
distributed under the terms and cementum. During OTM, local over-compression of the PDL may induce a hyalinization of
conditions of the Creative Commons the cementum, resulting in simultaneous cementum resorption in line with the removal of
Attribution (CC BY) license (https:// hyalinized tissue. This pathological process that causes substance loss from mineralized
creativecommons.org/licenses/by/ cementum and dentine is termed “orthodontically induced inflammatory root resorption”
4.0/). (OIIRR) [4]. OIIRR occurs seldomly and unexpectedly when orthodontic forces are applied
Int. J. Mol. Sci. 2022, 23, 11405. https://doi.org/10.3390/ijms231911405 https://www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2022, 23, 11405 2 of 13
and is being considered as an unavoidable and unpredictably pathologic consequence of
orthodontic treatment [5]. OIIRR is induced by a complicated combination of mechanical
and immunological factors, which comprehend the role of immunologic components,
including specialized immune cells [6].
During OTM, specific immunocompetent cells migrate to the periodontal ligament.
Among the PDL resident cells, immune cells such as neutrophiles, antigen-presenting cells
(APCs: dendritic cells and macrophages) [7], natural killer (NK) cells, and T and B lympho-
cytes (B and T cells) [8] may contribute to changed levels of various immune factors in the
periodontium [9]. Apart from immune cells, PDL cells, including cementoblasts, function
as primary mechanosensors that translate mechanical stimuli into cellular signals [10].
Cementum has been proven to be capable of protecting the tooth roots from OIIRR [11].
The cementum is composed of acellular extrinsic fiber cementum (AEFC), cellular intrinsic
fiber cementum (CIFC), cellular mixed stratified cementum (CMSC), acellular afibrillar
cementum (AAC), and intermediate cementum [12]. The acellular and cellular cementum
are synthesized by cementoblasts that possess the ability to repair resorption pits with
new formed cementum [4,13] and, meanwhile, play an immunomodulatory role in the
periodontal microenvironment during orthodontic treatment [14,15]. The root dentine is
protected by the Hertwig’s epithelial root sheath (HERS); intermediate cementum; and,
after the fragmentation of the sheath, by the cementum (cementoblasts). The combination
of these biological structures protects the dentine from immunologic recognition during
the development of orthodontic root resorption. In the case of an exposure of dentine
structures, an antoimmune reaction—also known as an immunologic response against the
organism’s “self” components—will be triggered [16].
The programmed cell death-ligand 1 (PD-L1) is a type-I transmembrane protein with
an extracellular domain at its N-terminus that functions as an immune checkpoint. It
suppresses the immune response by interacting with the programmed death cell receptor
(PD)-1 that is found to be expressed in T cells [17], B cells, NK cells, dendritic cells (DCs),
and monocytes [18]. The PD-1 (receptor)/PD-L1 (ligand) co-inhibitory pathway regulates
T cell activity, which plays important roles in immune responses and autoimmunity. It
was reported that high levels of PD-L1 are expressed in many tumor cells [19]. In vivo, its
expression was demonstrated in the tissue of oral squamous carcinoma cells [20], human
colon carcinoma cells [21], and human prostate cancer cells [22]. PD-L1 exerts immunosup-
pressive effects on the immune response of the host; thus, its expression strongly may limit
anti-tumor treatment efficacy [23]. Additionally, a very recent systematic review has also
demonstrated that the PD-1/PD-L1 pathway is involved in the pathology and treatment of
periodontitis [24]. However, the possible roles of PD-L1 expression and its interaction with
immune cells in OIIRR have not been fully elucidated.
In this article, we review current evidence regarding immunology in OIIRR and
discuss the potential immunomodulatory properties of PD-L1 in the context of OIIRR.
Furthermore, the possible clinical implication of PD-L1 in OIIRR prevention and therapy
will be addressed.
2. OIIRR
OIIRR occurs on almost all tooth roots exposed to orthodontic forces. It takes place
in approximately 80% of orthodontically treated patients [25] and is inevitable during
OTM [2]. Many researchers have convincingly demonstrated in different animal studies
that the resorption of root cementum is unpreventable [26]. While in most individuals, the
amount if root resorption is minimal and does not have any clinical consequences, in some
cases, it may be severe and lead to premature tooth loss.
2.1. Pathophysiology of OIIRR
In 2002, Brezniak et al. proposed the more descriptive and accurate term of orthodontic
force-induced root resorption in light of the actual histologic process and termed it OIIRR [4].
The pathogenesis of OIIRR has received a lot of attention in the past decade, especially
Int. J. Mol. Sci. 2022, 23, 11405 3 of 13
in the view of the immune system responses [27]. The apical root third (1/3) is covered
mainly with cellular cementum, which consists of cementocytes in lacunae and living
cementoblasts with the supporting vasculature, thus forming a non-mineralized cementoid
layer [28] and making this area vulnerable to forces and cell-injury-related reactions [29].
On the other hand, blood vessels occupy approximately 47% of the space within the PDL
in the apical region, in comparison with 4% at the cervical area of the root [30], which
makes the blood supply of this apical third of the PDL better than in the rest of the
root surface. Therefore, when forces damage the protective layer, it leads to exposure of
dentine and, affected by resorption, the corresponding apical 1/3 parts of the root are
more easily “digested” and the newly available space is filled with bone components [26].
However, in the cervical area, the root is covered by acellular cementum and a resorption-
resistant layer made of predentine, dentine, and mineralized repair tissue [31], forming
a protective local lining of the cervical area on the root surface. Moreover, osteoclasts
are not capable of binding to a non-mineralized surface [32], indicating that resorption
cervically is rare. Radiographically, this results in tooth root shortening. Common sites of
OIIRR are found close to the hyalinized zone on the pressure area of the tooth root [33]
when strong forces are subjected for a sustained period of time. Based on mice and rat
studies, Brudvik et al. (1993) observed a consistent pattern of OIIRR. This started with
the rapid development of an ischemic necrosis (hyalinization) of the compressed PDL.
Root resorption then started in the circumference of this necrotic (hyalinized) area. Only
after several days did resorption occur in the central parts of the hyalinized zone [33].
The authors suggested that OIIRR is an elimination process of the hyaline zone. These
resorptive phenomena are followed by compromised blood vessels and a low oxygen
supply [34], with PDL cells dying as a result of hypoxia in the nearby hyaline zone and
the resulting cell-free area developing a glassy histological appearance. During removal
of the hyaline tissue, the surrounding outer surface of the root, which is composed of
the cementoblast layer covering the cementoid, can be further destroyed [35], thereby
exposing the dense mineralized cementum beneath to the forces. Odontoclasts/osteoclasts
are then activated and attach to the mineral matrix, forming a sealing zone and adopting
a polarized morphology that initiates mineral resorption of cementum and dentine [36].
This resorption process continues until there is no hyalinized tissue present and/or the
level of orthodontic force application diminishes. Then, the hyalinized tissue is resorbed
by an influx of phagocytic cells and osteoclasts, which are recruited to the necrotic tissues
(indirect resorption). As a result of these resorptive cells’ indiscriminate action against
both necrotic and root hard tissue, cementum and occasionally dentine are resorbed by the
recruited macrophages, odontoclasts, and osteoclasts [4]. Resorption eventually developed
across the entire root surface as time progressed. In certain tooth roots, resorptive activity
even continued after the force removal [37].
The cause and risks of OIIRR are complex, but it is believed that sterile inflammatory
processes include different components: mechanical forces (magnitudes), types of mechani-
cal forces (continuous, interrupted, or intermitted), direction and duration of force, tooth
root morphology, distance of root apical movement, surrounding matrix, PDL, cementum,
and certain biological messengers [26,38]. The severity of OIIRR is classified into three
levels: (1) cementum or surface resorption with remodeling; (2) dentine resorption with
repair (deep resorption); and (3) circumferential apical root resorption [4]. In humans, the
OIIRR-associated risk factors such as exact force magnitude may be dependent on the indi-
vidual variations in humans (Harris et al., 2006), and thus have not been determined until
now. It has been widely known that the heavy rotational forces produced significantly more
root resorption than light rotational forces and the compression area shows significantly
higher root resorption than other areas in the human study [39].
2.2. Resorptive and Immune Cells in OIIRR
The key resorptive cells involved in OIIRR of cementum include mono-nucleated
macrophage-like cells, osteoclasts, dentinoclasts, and odontoclasts, the latter of which are
Int. J. Mol. Sci. 2022, 23, 11405 4 of 13
extremely similar in the morphologic and functional aspects to those of osteoclasts, albeit
slightly smaller [40] (Figure 1).
Figure 1. Schematic representation of the healthy tooth root and OIIRR and the core components of
the immune and resorptive cells during OTM. Root resorption lacunae were marked mainly in the
apical region as well as on the pressure side of the orthodontically moved tooth root.
Endocytotic vesicles containing liberated apatite crystals are found in odontoclasts,
implying that demineralization in the resorptive microenvironments is not completely
comparable with osteoclasts [41]. Activated osteoclasts are derived from the bone-marrow-
derived circulating monocyte/macrophage lineage [42]. Activated odontoclasts are dif-
ferentiated from circulating monocytes that express tartarate-resistant acid phosphatase
(TRAP) [43].
The immunological system response accompanied with inflammatory responses dur-
ing OTM and OIIRR relies on the cooperative activities between innate and adaptive immu-
nity [27]. Monocytes are precursors of DCs, osteoclasts, and macrophages [44]. Monocytes
would be recruited to the site of irritation by locally produced pro-inflammatory cytokines,
and they afterwards differentiate into macrophages or dendritic cells [45]. Odontoclasts
and dentinoclasts share a common origin, but the latter specifically resorb dentine [46].
Macrophages are scavenger cells whose function is to eliminate necrotic tissues [4] de-
pending on the phenotypes of the macrophages that could be activated by endotoxins
and cytokines from T cells. Activated macrophages can eliminate pathogens, produce
pro-inflammatory cytokines, and present the antigens to T cells [47]. T lymphocyte cells
are a crucial mediator of an adaptive immune response for OTM to initiate cellular immu-
nity [27].
In addition, multinucleated TRAP-positive giant cells participate in hyalinized tissue
removal and the adjacent root structure resorption [33]. TRAP-positive cells are able to
differentiate into fully developed odontoclasts or osteoclasts in response to a mechanical
stimulus in a matter of hours [48].
2.3. Cementum Repair in OIIRR
Decompression alters the resorption process and repair of the cementum process is
initiated once the applied orthodontic forces have been discontinued [49,50]. Physiolog-
ically speaking, cementoblasts begin the biological process of repairing these resorptive
defects within a few days. The resorption lacunae are initially covered in a layer of acellular
cementum deposition. However, over several weeks or months, these lacunae are mostly
replenished with cellular cementum [51]. Jaeger et al. (2008) [51] showed that, in the in vitro
rodent model, the reparation processes of cementum did not initiate until the orthodontic
force was released. It is also notable that the cervical and apical portions of the root appear
to usually lead to cellular cementum repair. Nearly half of the resorption lesions were being
repaired after five weeks without the orthodontic forces, and almost 90% after 10 weeks.
Similar results were also reported in human studies.
Int. J. Mol. Sci. 2022, 23, 11405 5 of 13
This process usually takes at least 6–8 weeks to become radiographically visible [29].
However, this process is only superficial and can thus not replace a resorbed apical part
of a root. Apical root resorptions of less than one-third of the root length usually do not
have clinical consequences. Irreparable damage to the root surface and loss of more than
1/3 of the original root length occur in 1–5% of clinical cases [52]. This kind of severe root
resorption can manifest itself clinically as increased tooth mobility and even occasional
tooth loss.
In response to orthodontic forces, an inflammatory process is involved in the occur-
rence of cementum-repairing activities [26]. Inflammatory mediators such as prostaglandins
(PGs) or interleukins (ILs) were found to be higher in the periodontium.
3. Immunological Aspects in OIIRR
The underlying immune process of OIIRR is still not completely understood. The
hyaline necrosis of the periodontium causes damage to the cementum, thus the dentine
matrix is exposed [53]. Once these periodontal structures are exposed to the immune
system, a cascade of immunological processes is activated for the lymphocytes to recognize
and prime other cell types to differentiate for the elimination of the “nonself” components.
Based on clinical studies [16,53], anti-dentine antibodies are detectable in patients with
traumatized root resorption. Thus, the susceptibility to OIIRR is likely to be linked to
autoimmune response against dentine matrix proteins.
3.1. Possible Immunological Responses to OIIRR
In the initial phase of orthodontic force application (within 3 days), the first infiltrating
immune cells that reside in mouse PDL mainly consist of neutrophils, monocytes, lym-
phocytes, and APCs [44,54]. Besides removing tissue debris, neutrophils also produce
chemotactic mediators to recruit monocytes and macrophages [44]. The local acute-phase
inflammation induced by orthodontic forces evokes a characteristic immune response
owing to the presence of immune cells and the release of cytokines [44].
Two distinct in vitro phenotypes of macrophages exist: the classically activated phe-
notype (M1, known as “killer” macrophages) and the alternatively activated phenotype
(M2, known as “healer” macrophages) [55]. Both are reported to play critical roles during
OTM [56]. The macrophage M1 and the M2 polarization status exhibit a remarkable plas-
ticity with different inflammatory conditions in the orthodontic microenvironment [57].
This allows such a polarization switch to participate in the regulation of inflammation
and cellular homeostasis. On this point, an increased M1 versus M2 ratio was detected in
the initial phase of OTM [58], which seems to be related to OIIRR and is accompanied by
pro-inflammatory cytokine secretion [59]. M1 macrophages increase inflammation, while
M2 macrophages inhibit inflammation [60]. Besides macrophages, Yamasaki et al. (1982)
reported a significantly decreased mast cell count after application of orthodontic forces,
suggesting a possible participation of mast cells in the initial stage of OTM [61].
Under prolonged duration of orthodontic force application, OIIRR was found to be
concomitant with an increased infiltration of CD68+ and iNOS+ M1 macrophages [56]. The
severity of OIIRR can partly be impaired because the ratio of M1 versus M2 macrophages
was found to be decreased [57]. The macrophages and the monocytes that participate
in OTM differentiate further into osteoclasts, a process that causes a rapid increase in
osteoclasts’ proportion in the PDL during this stage.
The NK cells participate in the innate immune regulation by activating signaling
pathways related to OIIRR [14]. The up-regulation of tumor necrosis factor (TNF)-α and
interferon (IFN)-γ, cytokines secreted predominantly by NK and T cells, further support
the regulatory roles of NK cells in OIIRR.
The DCs are normal resident cells in the PDL and mainly play roles as APCs to react
with T and B cells. Upon orthodontic force application, increased numbers of CD11b+ DCs
were expressed around the hyalinized tissue between dentine and cellular cementum [58],
indicating their involvement in the process of OIIRR.
Int. J. Mol. Sci. 2022, 23, 11405 6 of 13
The involvement of T cells [62] was also demonstrated by the occurrence of an in-
creased percentage of CD4+ T cells [63]. Low levels of γβ-T cells are reported to be involved
in OTM by a production of IL-17α, indicating their participation and quick response to
the mechanical stimuli. The up-regulation of classical αβ-T lymphocytes was reported,
as well as a significantly attenuated tooth displacement after their depletion [54], further
confirming the role and participation of T cells in OTM [14].
B cells are already primed for orthodontic forces [44]. In conjunction with this,
Kook et al. (2011) reported a sustaining increase in the number of CD220+ B lympho-
cytes in PDL [63] in response to orthodontic forces, which supports this point. However,
the exact roles of these immune cells for OIIRR are still ambiguous.
3.2. The Molecular Immunological Change in OIIRR
Cytokines and chemokines are substances released by immune cells for the commu-
nication of signals between immune and non-immune cells [64] (Figure 2). It has been
shown that IL-1α and IL-1β have potent capacities to increase root resorption [65]. Notably,
significant elevations in immune factor levels in the periodontium in the case of OIIRR
were documented, such as pro–inflammatory cytokines (TNF-α and IFN-γ; IL-1β and -6;
IL-2, -3, -4, -7, -9, -1, -15, and -17; IL-17α) [66], chemokines (monocyte chemotactic protein
(CCL)-2 [67], CCL-5, -3, and CCR-1; CCR3) [68], and pattern recognition receptors (PRRs)
(Toll-like receptor (TLR)-2, -4, -7, and -8 [44]; CNTF receptors [69]).
Figure 2. Regulation of the inflammatory factors and immunological activities by orthodontic forces.
4. PD-L1 and OIIRR
Concerning the progress of OIIRR, recent studies have tried to associate its initializa-
tion with a specific antigen present in the PDL that might alter the immunologic response,
PD-L1 [24]. It is well-known that PD-L1 plays a crucial role in maintaining inhibitory sig-
nals to PD-1-expressing T cells, which leads to an impairment of the immune response [70].
Besides oral squamous carcinoma cells [20,21,71,72], recent studies showed that, upon
stimulation with Porphyromonas gingivalis (P. gingivalis) and its components, PD-L1 was
up-regulated in cells belonging to the oral masticatory mucosae such as primary human
gingival keratinocytes [71] and human oral epithelial cells [72], with a regulated expres-
sion on both basal keratinocytes and prickle cells [73]. PD-L1 has also been investigated
to be widely expressed on OIIRR-associated periodontal tissue cell types, such as hu-
man osteoblasts [74], human osteoclasts [75], human PDL cells [76], and human gingival
fibroblasts [77].
4.1. Immunomodulator PD-L1
The PD-L1-expressing keratinocytes promote the regulation of a CD4+ T cell-mediated
local inflammatory reaction. This suggests that they have protective properties against
excessive tissue damage [73]. The PD-L1 expression facilitates these keratinocytes to evade
Int. J. Mol. Sci. 2022, 23, 11405 7 of 13
immune elimination via the interaction of PD-L1 with PD-1 on T cells [78]. Oral PD-L1
expressing epithelial cells could facilitate T cell differentiation, which enables a suppressive
effect on T helper effector cells [79]. Both PD-1 and PD-L1 levels were found to be signifi-
cantly enhanced in CD4+ and CD8+ T lymphocytes from periodontitis patients compared
with healthy individuals [80]. Recently, it was also reported that apical periodontitis lesions
show more PD-1 positive and PD-L1 positive lymphocyte infiltrations in conjunction with
higher cytokine levels [81]. Moreover, it is of importance that mesenchymal stem cells
taken from dental pulp and PDL show an increase in PD-L1 and exhibit immunoregulatory
properties [82]. These novel findings suggest deeper investigations are necessary into the
effects of PD-L1 during OTM as well as OIIRR.
4.2. Regulation of PD-L1 in Orthodontic-Induced Microenvironments
Under physiological conditions, PD-L1 has been detected in different in vivo and
in vitro models in various periodontal cell types. It has been demonstrated to be up-
regulated upon immune activation conditions, such as inflammations [83]. In recent
studies, we identified for the first time that PD-L1 is induced and constantly expressed on
murine cementoblasts in response to compression and hypoxia, simulating orthodontic-
force-induced microenvironmental changes [84,85]. In detail, the recent data revealed
that the application of a compressive force at a magnitude of 2.4 gf/cm2 enhances the
PD-L1 expression in cementoblasts. P. gingivalis peptidoglycan also up-regulate the PD-
L1 expression in cementoblasts and may induce tolerogenic signaling to T cells. When
cementoblasts were subjected to a modified compression, they expressed stable PD-L1,
which in turn may facilitate their antigenic escape from immune surveillance. In addition, it
was revealed that HIF-1α plays an pivotal role in the PD-L1 modulation [84]. Another very
recent study conducted by our group showed that long-term exposure to hypoxic conditions
augmented PD-L1 expression on cementoblasts [85]. Based on these observations, it is
reasonable to hypothesize that this ligand could serve as a potential target for therapies
aimed at anti-OIIRR [86] (Figure 3).
Figure 3. Inside-out signaling in cementoblasts under orthodontic-force-induced microenvironments
including compression and hypoxia. HIF-1α is crucial in the regulation of inducible PD-L1 expression
in cementoblasts. However, the schematic illustration shows an unknown mechanism of binding
for the interaction between cementoblasts expressing the PD-L1 ligand and antigen-presenting cells
expressing the PD-1 receptor, which may inhibit immune response.
Int. J. Mol. Sci. 2022, 23, 11405 8 of 13
Regarding the regulation of the T cell immune response, the functional profile of PD-L1
in a human inflammatory environment has previously been reviewed. It is widely accepted
that T cells are required in immune response and that they play essential roles during
OTM and OIIRR [9]. Shelby et al. (2020) demonstrated that overexpressed PD-L1 engages
PD-1 and causes an inhibitory downstream signaling of the T cell receptor when present in
an orthodontic-force-induced microenvironment [87]. Under healthy conditions, the PD-
1/PD-L1 pathway regulates host immune homeostasis, while in inflammatory conditions,
interactions between PD-1 and its ligand PD-L1 inhibit T cell responses, protecting the lesion
from hyperactivated T cells in cancer [86]. Based on a recent study, PD-L1 overexpression in
gingival basal keratinocytes of K14/PD-L1 transgenic mice reduces alveolar bone resorption
and periodontal inflammation in a periodontitis model [88].
4.3. Potential Clinical Perspective of Targeting PD-L1 Treatment for OIIRR
As the literature states, a PD-L1 checkpoint is functional in tumor-associated macro-
phages [89] and is regarded as a major driver in numerous types of cancers, and anti-PD-
L1/PD-1 drugs qualify for the therapy of cancer [90].
As OIIRR is linked to interactions between an inflamed microenvironment and the
immune response of the host, we proposed for the first time that the host immune system
can be modulated to affect the tooth root resorption and repair process during OIIRR. One of
the possible mechanisms is to target the PD-L1 molecule. The PD-L1 inhibitors that target
PD-1 have been shown to improve the outcome of melanoma survival [91]. This introduces
the hypothesis that the up-regulated PD-L1 participates in immune evasion during OTM.
Binding of the PD-L1 ligand to its receptor PD-1 on T cells promotes the formation of an
immunosuppressive microenvironment, which leads to T cell exhaustion and apoptosis [92],
and may thus speed up the process of OIIRR. As a result, we hypothesize that PD-L1
overexpression facilitates an antigenic escape from immune surveillance, making the
ligand a potential anti-OIIRR target [86]. Based on the evidence that PD-L1 up-regulation
was found to be HIF-1α-dependent, we identified a network mechanism emphasizing the
role of PD-L1/HIF-1α in cementoblasts. Thus, a combined blockade of PD-L1/HIF-1α
could be of relevance for treating OIIRR in orthodontic therapy.
Future in vitro studies should be performed with primary human cementoblasts as
well as in animal models to verify the mechanisms. The link between PD-L1 expression and
orthodontic forces needs to be evaluated by comparing how the checkpoint is expressed on
T lymphocytes from patients with OIIRR to those from healthy people.
However, it should be noted that the use of PD-L1-targeted drugs to control OIIRR in
orthodontics poses too great a systemic risk in the future. Given the importance of PD-1 in
suppressing self-reactive T cell-mediated immune responses, immunosuppression caused
by the PD-1/PD-L1 immune checkpoint inhibitors can result in the infiltration of T cells
into organs all over the body, causing an immune response [93]. Some of the drug’s side
effects include interstitial lung injury [94], gastrointestinal perforation [95], myocarditis [96],
and fulminant type 1 diabetes [97]. As the increasing evidence of PD-1/PD-L1 inhibitors’
application potential in dentistry, especially in the periodontal field, it is crucial to evaluate
their systemic and local toxicologic profile, although its application is at the infant stage
in periodontal diseases, not to mention in orthodontics and OIIRR. For example, oral
lichen planus has been reported to be associated with anti-PD-1/PD-L1 therapy [98]. More
immune-mediated oral and systemic toxicity events should be tested to contribute to the
potential clinical perspectives of treatment for OIIRR observed with this drug.
To date, there has not been a published study about its use in orthodontics. Moreover,
the major question remains about the dosage of the drugs regarding their application in
dentistry. If clinicians do not account for these variations and collect data about adverse
events, we will never gain knowledge about the real incidences of treatment-related side
effects in relation to PD-1/PD-L1 inhibitors in dentistry.
Int. J. Mol. Sci. 2022, 23, 11405 9 of 13
Furthermore, especially in orthodontics, it is also essential to understand the economic
impact of this influential, but expensive therapy. Until now, the cost-effectiveness of
PD-1/PD-L1 immune checkpoint inhibitors has not yet been systematically evaluated.
5. Conclusions
Root resorption, especially OIIRR, is linked to the interactions between inflammation
and the host immune response. There is little evidence about how immune cells and non-
immune cells in the periodontium contribute to OIIRR and how they interact with PD-L1.
The establishment of the role of PD-L1 in an orthodontically induced microenvironment
represents a significant emerging step toward unraveling the recognition mechanisms for
immune cells and pathogenic components concerning inflammatory conditions during
OIIRR. Thus, transgenic/gene knockout technologies should be conducted to elucidate
cellular and molecular immunologic processes and mechanisms induced by orthodontic
forces. The precise pathway mechanisms and the immune reactions behind the role of
PD-L1 in OIIRR should be revealed in future work. With this knowledge, it is the goal to
provide novel therapeutic approaches to prevent or treat OIIRR.
Author Contributions: Conceptualization, J.Y., S.G., J.v.B., J.M. and S.R.; methodology, J.Y., J.v.B., J.M.
and S.G.; validation, J.Y., S.G., J.v.B. and S.R.; formal analysis, J.Y. and S.G.; investigation, J.Y., S.G.
and J.v.B.; resources, J.Y.; data curation, J.Y. and S.G.; writing—original draft preparation, J.Y., J.v.B.
and S.G.; writing—review and editing, J.Y., S.G., J.v.B. and S.R.; supervision, J.M. and S.R.; project
administration, S.G., J.v.B. and S.R. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The datasets used and/or analyzed during the current study are
available from the corresponding author on reasonable request.
Conflicts of Interest: The authors declare no conflict of interest.
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