International Immunopharmacology 133 (2024) 112020

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International Immunopharmacology
journal homepage: www.elsevier.com/locate/intimp

Review

Potential therapeutic options for celiac Disease: An update on Current

evidence from Gluten-Free diet to cell therapy
Effat Noori a, *, Nader Hashemi b, Delsuz Rezaee c, d, Reza Maleki e, Forough Shams b, *,
Bahram Kazemi b, f, Mojgan Bandepour b, f, Fardin Rahimi a
a
Department of Biotechnology, Faculty of Medicine, Shahed University, Tehran, Iran
b
Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
c
School of Allied Medical Sciences, Ilam University of Medical Sciences, Ilam, Iran
d
Department of Medical Biotechnology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
e
Adelaide Medical School, The University of Adelaide, Adelaide, SA 5005, Australia
f
Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

A R T I C L E I N F O A B S T R A C T

Keywords: Celiac disease (CD) is a chronic autoimmune enteropathy and multifactorial disease caused by inappropriate
Celiac disease immune responses to gluten in the small intestine. Weight loss, anemia, osteoporosis, arthritis, and hepatitis are
Enzyme therapy among the extraintestinal manifestations of active CD. Currently, a strict lifelong gluten-free diet (GFD) is the
Non-dietary treatments
only safe, effective, and available treatment. Despite the social burden, high expenses, and challenges of
Gluten-free diet (GFD)
following a GFD, 2 to 5 percent of patients do not demonstrate clinical or pathophysiological improvement.
Cell therapy
Nanoparticle Therefore, we need novel and alternative therapeutic approaches for patients. Innovative approaches encompass
a broad spectrum of strategies, including enzymatic degradation of gluten, inhibition of intestinal permeability,
modulation of the immune response, inhibition of the transglutaminase 2 (TG2) enzyme, blocking antigen
presentation by HLA-DQ2/8, and induction of tolerance. Hence, this review is focused on comprehensive ther­
apeutic strategies ranging from dietary approaches to novel methods such as antigen-based immunotherapy, cell
and gene therapy, and the usage of nanoparticles for CD treatment.

1. Introduction deficiencies [1], infertility [6], osteoporosis, and neurological disorders

[1]. Typical manifestations of CD encompass abdominal discomfort,
Celiac disease (CD) is a chronic immune-mediated disorder in diarrhea, nausea, nutrient absorption issues, and stunted growth during
genetically susceptible individuals, triggered by ingesting gluten found childhood. It also extends its effects beyond the gastrointestinal tract to
in wheat, barley, rye, and their derivatives [1,2]. Due to its high proline involve the skin, liver, joints, brain, heart, and additional organs [6,7].
residue content, gluten is resistant to complete proteolytic degradation CD affects 1–3 % of the general population [8–11] and currently, the
in the human gastrointestinal tract, leading to the aberrant activation of only therapeutic option is a GFD, which poses challenges due to its high
the immune system, villous atrophy, crypt hyperplasia, and infiltration cost and limited availability of suitable products [6,12]. However, pa­
of inflammatory cells within both the small intestinal epithelium and the tients may assess a life-long GFD and related lifestyle modification to be
lamina propria in those with a genetic vulnerability [3,4]. In addition to difficult, owing to its unavailability, higher costs, and poor satisfacto­
genetics and gluten consumption, CD development is also influenced by riness [13]. As mentioned, hyper- vigilance to GFD subordination can
abnormal immune responses, imbalanced gut microbiota, and compro­ also influence the quality of life, exactly the disease itself. This has in
mised intestinal tight junction integrity [5]. Simultaneously with the turn created and not fulfilled the need for substitutions. Owing to
revelation of dietary gluten as the causative agent six decades ago, our numerous constraints including burdensome strict lifelong diet, inade­
knowledge about the pathophysiology of CD has augmented substan­ quate mucosal healing, and the inability of all patients to comply with
tially. CD is characterized by small-intestinal mucosal damage and this diet, alternative or supplemental therapies for CD beyond GFD are
malnutrition, which causes anemia, vitamin and trace element necessary [12,14]. The pursuit of novel therapeutic avenues is crucial to

* Corresponding authors.
E-mail addresses: [email protected] (E. Noori), [email protected] (F. Shams).

https://doi.org/10.1016/j.intimp.2024.112020
Received 23 January 2024; Received in revised form 1 April 2024; Accepted 3 April 2024
Available online 11 April 2024
1567-5769/© 2024 Elsevier B.V. All rights reserved.
E. Noori et al. International Immunopharmacology 133 (2024) 112020

address the unmet needs of CD patients especially who do not respond to continuously symptomatic despite a GFD, in whom supplement thera­
conventional treatments. By exploring and developing alternative stra­ pies may be required. For these reasons, there is a growing interest in
tegies beyond the GFD, the goal is to enhance treatment outcomes, non-dietary treatment options. As many crucial mechanisms of disease
alleviate patient burden, and improve the overall quality of life for in­ pathogenesis have been distinguished, CD is discussed as an attractive
dividuals living with celiac disease. Innovative approaches in the field of disease for therapeutic development. Novel therapies can theoretically
gluten-related disorders have expanded to encompass a wide range of intervene with these mechanisms at various steps of disease pathogen­
strategies aimed at improving the quality of life for those affected. These esis [16]. Hence, providing innovative non-dietary alternative therapies
approaches include enzymatic degradation of gluten, inhibition of in­ that are both safe and effective is crucial and urgently required [17].
testinal permeability, modulation of the immune response, inhibition of This review provides complete therapeutic strategies from dietary to
the TG2 enzyme, blocking antigen presentation by HLA-DQ2/8, and novel approaches such as antigen-based immunotherapy, cell and gene
induction of tolerance [15]. Moreover, there may be patients who stay therapy, and the usage of nanoparticles for CD treatment.

Fig. 1. Pathophysiology of celiac disease (CD). Three important factors: 1) Dietary, 2) Stress signal, and 3) Microbial can induce innate immunity and permeability
activators. Proteolysis-resistant gluten peptides can be transported across lamina propria. Glutens are deamidated by TG2 to present by APCs of HLA-DQ2/8 mol­
ecules. This presentation activates gluten-specific T cells that recognize the DC-bound peptides and are activated, leading to the expansion of proinflammatory gluten-
specific T cells. Also, it produces high levels of pro-inflammatory cytokines, with a Th1 cytokine pattern. Activated CD4+ T cells stimulate the activation and clonal
expansion of B cells, which differentiate into plasma cells and produce antibodies. Opportunistic pathogens such as Pseudomonas aeruginosa (P.aeruginosa) produce
pro-inflammatory proteases (elastase) with induce gluten-independent innate immune response through protease-activated receptor-2 (PAR-2). Direct events
initiated by viral and bacterial pathogens include activation of PAR-2-mediated pathways, epithelial disruption, imprinting of a proinflammatory signature in DCs,
and activating IELs, a marker of CD. Activation of cytotoxic IELs contributes to mucosal atrophy by annihilating ECs. Although T cell activation in CD is developed by
gluten, the specific factors that activate IELs and stimulate increased permeability, as well as the underlying pathways, are largely unclear. Additional immune
proinflammatory and epithelial effects have been required. Also, innate peptides act through unknown mechanisms as a stress signal toward enterocytes, inducing
expression of MIC and IL-15. IL-15 increases the permeation of IEL into the epithelium, and arms them with the NK receptor NKG2D. IL-15 may also affect the Th1
response. IELs bearing NKG2D target MIC-expressing enterocytes for killing via apoptosis, villous flattening, and causing destruction of the epithelial layer [26].

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2. The state of CD in the world architecture remains normal in grades 0 and 1, but shows hyperplasia in
grades 2–4, villi are intact in grades 0, 1, and 2, but become blunted in
Epidemiological studies have documented a consistent rise in the grades 3 and 4. These structural characteristics help specialists in the
prevalence of autoimmune diseases (ADs) globally over the past three diagnosis and treatment of this disorder [5,35–37]. Marsh–Oberhuber
decades [18]. Infections and dietary patterns emerge as significant classification and mucosal changes of the intestine associated with CD
environmental drivers behind the global upsurge in AD, with CD being were illustrated in Fig. 2.
particularly prevalent among the ADs that are on the rise [19,20].
Several factors have been identified as contributors to the increase AD 4. Gluten and GFD
including migration and population growth, changes in dietary patterns,
increased food processing, and the utilization of industrial food addi­ Gluten, which accounts for 80 % of the total protein content of
tives [18,19]. Studies have shown that industrial food additives and wheat, barley, and rye, is composed of glutenins and gliadin peptides
processing promote intestinal permeability [19,21,22] by compromising [19,38–41]. The unique properties of gluten enhance the quality of
the integrity of tight junctions, which in turn triggers local and systemic baked products including bread, cakes, pastries, and biscuits [14].
immune responses leading to AD [19]. Furthermore, adherence to hy­ Gluten, which contains large quantities of proline (15 %) and glutamine
giene standards and lifestyle changes have been linked to a rise in (35 %) in its composition, [40,42] is the most significant environmental
autoimmune disorders, including CD, in developed countries during past driver of CD development [19]. Remarkably high amounts of these
years [5,23]. A potential factor in the increased risk of CD is the alter­ amino acids lead to resistance to enzymatic proteolysis in the gut
ation in wheat consumption patterns [24], characterized by an upsurge [38,43]. The gliadin peptide is composed of four fractions α, β, γ, and ω
in the manufacturing of processed foods and the widespread presence of the former is more toxic than others [44]. The antigenic impact of
gluten in these products [25]. gluten, associated with gliadins [38,43], leads to reduced F-actin levels,
initiation of apoptosis, secretion of zonulin, and weakened tight junction
3. Immunopathology and histopathology features of the CD integrity in the gastrointestinal mucosa, thereby enhancing epithelial
permeability [19,45,46].
Based on CD pathophysiology, factors such as 1) dietary, 2) stress For foods and products to qualify as gluten-free, they must inherently
signal, and 3) microbial can induce innate immunity and permeability lack gluten and remain uncontaminated throughout all stages of prep­
activators are involved in this problem (Fig. 1) [26]. In dietary, aration and manufacturing [47]. According to the European Union (EU),
proteolysis-resistant gluten peptides could be transported across lamina substances are considered gluten-free if they contain less than 20 mg of
propria and deamidated by TG2 for presentation by antigen-presenting gluten per kilogram of the product [44]. Hischenhuber et al., showed
cells (APCs) with HLA-DQ2/8 molecules [27]. The role of CD4+ helper T that gluten intake between 10 and 100 mg/day in celiac patients is safe
cells in CD was determined through the isolation of proinflammatory [48]. Moreover, Akobeng et al., reported that daily gluten consumption
gluten-specific CD4+ T cells from the intestinal tissues of CD patients < 10 mg could not cause histological damage [49]. In another study,
[26]. Th1 phenotype in pathogenic T cells is characterized by the gen­ Gibert et al., demonstrated that a product was considered gluten-free
eration of tumor necrosis factor (TNF-α) and interferon gamma (IFN-γ), with a gluten content of less than 20 parts per million [50].
which are associated with HLA-DQ2- and/or DQ8 [28]. The generation
of antibodies against tissue transglutaminase (tTG) and deamidated 5. Therapeutic approaches for CD treatment
gliadin peptide (DGP) strongly depends on the presence of CD-
associated HLA types as well as gluten. tTG-specific B cells internalize The only treatment for celiac disease is a rigorous lifelong GFD, since
tTG in complex with gluten peptides and represent gluten-derived there is no effective pharmaceutical treatment available [36,51,52].
peptides to gluten-specific T cells, thereby effectively enhancing the T Studies have shown that susceptibility to gluten toxicity among celiac
cell response [29]. Therefore, the pathogenic mechanism of CD initiates patients is variable and strict adherence to GFD is difficult and complex
when deaminated gluten binds to HLA-DQ2 and HLA-DQ8, prompting in practice [53–56]. Following a GFD, small intestinal mucosal damage
gluten-reactive immune cells (CD4+ T cells) to release IFN-γ and anti­ typically heals within 1–2 years, and gluten-induced symptoms often
bodies against gluten and autoantigens, thereby initiating an autoim­ subside within a few weeks [57]. However, multiple barriers impede the
mune response (tTG targeting autoantibodies) that results in intestinal efficacy of this therapy, including: the widespread use of gluten in
inflammation (crypt hyperplasia and villous atrophy) [13,30,31]. Acti­ processed and homemade foods, as well as in pharmaceutical products,
vation of intraepithelial lymphocytes (IELs) serves as a marker of CD and even trace amounts of gluten is immunogenic for susceptible individuals
contributes to mucosal atrophy through the destruction of epithelial [25,44], evidence that many celiac patients do not respond to a GFD
cells (ECs). However, the mechanisms underlying IEL activation, which [58–60], and the high cost of accessing a GFD [36,51]. Additionally,
stimulates increased mucosal permeability, remain largely unclear. celiac patients on GFD may experience psychological, metabolic,
Furthermore, direct actions initiated by bacterial and viral pathogens nutritional, cardiovascular, and gastrointestinal issues, significantly
lead to a series of events including disruption of epithelial integrity, impacting their quality of life [5]. The response rate to GFD is influenced
activation of PAR-2-mediated pathways, induction of a proinflammatory by factors such as the age of diagnosis, frequent consultation by a
signature in DCs, and the activation of IELs [32]. physician and a nutritionist, and good awareness in the family [61].
Histological findings of biopsy in CD are stratified into five grades, Approximately 7–30 % of celiac patients, even with complete strict GFD,
enabling reference centers to detail histologic features, confirm di­ fail to achieve clinical or histologic improvement [30]. Also, late-
agnoses, and evaluate disease severity [33–35]. In this classification diagnosed or untreated patients may face a heightened risk of compli­
system, grade 3 is subdivided into three stages based on the severity of cations, such as osteoporosis, enteropathy-associated intestinal T cells,
villous erosion. Type 3a manifests with mild villous flattening, while lymphoma, collagenous sprue, refractory sprue, ulcerative jejunoileitis,
type 3b exhibits a substantial villous flattening, and type 3c is charac­ non-Hodgkin lymphoma, small bowel adenocarcinoma, reproductive
terized by a flat mucosa. Moreover, all three categories demonstrate an disorders, and prevalence of autoimmune diseases [36,44]. Given these
elevation in crypt height, along with an increase in IEL counts surpassing factors, there is a high rate of dissatisfaction among patients consuming
40 IEL per 100 ECs. The key factors assessed in biopsy examinations GFD [51,62], necessitating alternative non-dietary approaches for the
include the degree of villous atrophy, increased IELs, and crypt archi­ treatment of refractory sprue [25,51,63]. Although new therapeutic
tecture [33]. The characteristic histologic features across grades can be approaches may not replace GFD, they can potentially prevent and even
summarized as follows: in grade 0, the number of IELs is normal, limit the complications of CD [53].The emerging therapeutic options for
whereas higher grades exhibit elevated IEL counts (≥30/100 ECs), crypt CD can be widely classified into the following categories: (1) modulation

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Fig. 2. Classification of celiac disease based on Marsh-Oberhuber. In MARSH type 0, microscopic enteritis and normal villi were shown with a pathological
enhancement of T lymphocytes, shortening of microvilli, variation of enterocytes, and increased α/β/γ/δ T cell receptors. MARSH I is characterized by normal villous
architecture with or without crypt hyperplasia, microscopic enteritis with no atrophy, and increased IEL count ≥ 25 IELs/100 enterocytes. Marsh II is defined by
microscopic enteritis, increased IEL count (>20 IEL/100 enterocytes and crypt hyperplasia), enlarged crypts, and the influx of inflammatory cells. In Marsh IIIa,
features include villus effacement and crypt hyperplasia, shortened blunt villi, IEL infiltration, and hyperplastic crypts. Marsh IIIb is distinguished by recognizable
atrophic villi, the presence of inflammatory cells, and enlarged crypts. Marsh IIIc is recognized by severe atrophic, the total absence of villi, hyperplastic, and
infiltrative lesions. The mucosa appears completely flat with no observable villi and IELs/100 enterocytes is ≥ 25 [216].

of the immunostimulatory effects of toxic gluten peptides, (2) elimina­ bureaucratic hurdles related to genetically modified organisms (GMOs);
tion of toxic gluten peptides before reaching the intestine, (3) induction (vi) the complexity and high cost of manipulating hexaploid wheat ge­
of gluten tolerance, (4) modulation of intestinal permeability, and (5) netics; and (vii) the risk of contamination [14,25,133,138].
restoration of gut microbiota balance (Fig. 3). Therapeutic strategies for
CD patients, along with their mechanisms of action, are comprehen­ 5.1.2. Enzyme therapy
sively detailed in Table 1. Humans lack the enzyme necessary to break the proline-glutamine
bond in gluten [139], leading to incomplete digestion and the forma­
tion of various peptides. These peptides can trigger harmful immune
5.1. Elimination of toxic gluten peptides before reaching the intestine reactions in individuals with a genetic predisposition [36]. Studies
showed that gluten proteins are partially hydrolyzed by gut enzymes
5.1.1. Food production and wheat genetic manipulation [68,140]. Gluten proteins are rich in proline (P) and glutamine (Q)
Grains containing gluten have been modified using genetic engi­ residues, forming repetitive PQ sequences that render them resistant to
neering strategies including small interfering RNA (siRNA) technology degradation by mammalian digestive enzymes located in the gastroin­
and selective breeding of early wheat specie [130]. These strategies aim testinal tract [141–143]. Specific proteases, present in bacteria, fungi,
to develop gluten-free strains and remove harmful proteins for those plants, and insects, have been recommended to treat gluten proteins
genetically predisposed [14,36]. Recent studies have demonstrated that either before or during food consumption [25,36,133]. Degrading
employing ribonucleic acid interference (RNAi) technology can effec­ gliadin before it reaches the mucosa emerges as a significant alternative
tively reduce the expression of gliadins in hexaploid wheat [14,25]. In treatment to GFD, highlighting the potential for broader dietary man­
contrast to RNA interference (RNAi), CRISPR/Cas9 technology facili­ agement strategies in CD [30].
tates more stable and heritable modifications [131,132]. CRISPR/Cas9
provides a more effective suppression of gliadin expression than RNAi 5.1.2.1. Microbial and plant enzymes. Enzymes of bacteria and fungi can
technology and has the capability to substitute celiac-toxic fragments detoxify of gluten components before reaching the small intestine
with non-toxic ones [133]. Gluten consists least 50 different immuno­ epithelium. This approach can be considered as a substitute or supple­
genic peptides (10–40 amino acids length) which two 26- and 33-mer ment to GFD [14]. Prolyl-endopeptidase (PEPs) is proline-specific
peptides derived of gliadin are noteworthy for their strong induction enzyme capable of cleaving gluten peptides and eliminating the pe­
of destructive T cell responses in CD [134–137]. Gluten are produced by ripheral blood T cell response in celiac patients [36]. As demonstrated
genes located at different genetic locations in the wheat genome, making by Shan et al., PEPs can reduce the harmful effects of gluten by hydro­
genetic manipulation challenging [25]. Additionally, further challenges lyzing the peptide bond on the carboxyl side of proline residues, sug­
in modifying wheat gluten content include: (i) reduced or lost baking gesting their potential as a therapeutic option for CD [144]. This enzyme
qualities; (ii) limited information of all immunogenic peptides in wheat; expresses in different microbial including Aspergillus niger, Fla­
(iii) the lack of updated RNAi constructs for newly discovered toxic vobacterium meningosepticum, Sphingomas capsulata, and Myxococcus
epitopes; (iv) genetic instability in modified wheat lines; (v)

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Fig. 3. Emerging therapeutic approaches for CD treatment. (A) Therapeutic approaches for non-dietary CD treatment consist of genetic modification, microbial
modification, and masking of antigenic gluten capacity to decrease gluten toxicity by protein sequestration. (B) Refractory celiac disease (RCD) is a complex
autoimmune disorder that is unresponsive to at least 12 months of treatment with a strict GFD. Anti-IL15 antibodies have been proposed for the treatment of RCD I.
IELs in RCD I constitute polyclonal expansions of T cells displaying a normal phenotype (surface CD3 + and CD8 + ). In RCD II, IL15 derived from ECs and other
cytokines secreted by lamina propria CD4+ T-helper type 1 cells (e.g., IL2, IL21, and TNF-α) have been shown to induce maturation arrest, proliferation, and
expansion of the aberrant IELs. This is achieved through granzyme B–dependent cleavage of intracellular NOTCH1 and activation of the JAK-STAT signaling pathway
(C) Dietary approaches to CD treatment include of GFD, oral TG2-blockers, oral drugs preventing epithelial pass of gluten, and oral administration of glutenases. (D)
Nexvax 2 is a peptide-based therapeutic vaccine that targets gluten-specific T cells. This process is mediated via dendritic cells displaying multiple epitopes from the
disease driving antigen. (E) In immunotherapy, the latter type of epitopes are known as immunodominant gluten epitopes. In CD patients expressing HLA-DQ2.5, five
gluten epitopes (DQ2.5-glia-a1, DQ2.5-glia-a2, DQ2.5-glia-u1, DQ2.5-glia-u2, and DQ2.5-hor3) are among the known immunodominant epitopes. Nanoparticles
combined with immunotherapy, particularly for the encapsulation of gluten protein extract (TAK-101) and tolerance induction, are notable. Nanoparticles loaded
with TAK-101 and inhibitors of TG2 have shown promise in reducing gluten-induced mucosal injury, being unique in this respect.

xanthus that are able to hydrolyze gliadin peptides in vitro and in vivo [64,65,67]. Studies have indicated that ALV003 can be used without
conditions [14]. The in vitro and a clinical trial studies from either PEPs causing any significant side effects to prevent the gliadin-induced T cell
enzyme derived of A. niger [76] or F. meningosepticum [145] showed response in CD and resistance to the stomach digestive condition
these enzymes reduced gluten-induced response of celiac patients [73]. [12,14,67,100,149,151]. AN-PEP (prolyl endoprotease) exhibits resis­
Gluten degrading peptidases derived of this microorganisms have tance and efficacy in intestinal conditions. Studies have established the
endopeptidase activity that cleaves after XP and significantly degrades safety profile of AN-PEP and its capability to alleviate clinical symptoms
most gluten in the stomach before it enters the duodenum in patients with CD [100,149]. Martial Rey et al., showed that digestion
[14,146–148]. with nepenthesin (non-canonical aspartic proteases plus prolyl endo­
In addition to microbial enzymes, cysteine proteinase EP–B2 in protease of Nepenthes spp) generates small peptides that reduce the
germinating cereal has been shown to degrade gluten [149]. Analysis of immunogenic regions of gliadin [12]. No intestinal inflammation was
cereal protein content via RP-HPLC during germination demonstrated observed in NOD/DQ8 mice that were administered this enzyme after
that prolamins are efficiently degraded into non-toxic fragments [7]. gliadin treatment. These findings indicate that this strategy has potential
The activity and stability of this enzyme have been confirmed in vitro, as for success and warrants further development and optimization [12,14].
well as in the gastrointestinal tracts of rhesus macaques and rats [149]. The limitation of gluten-specific proteases lies in their susceptibility
According to in vitro investigations, enzymes from germinating barley to proteolysis by digestive enzymes in the gut, especially during the
are more efficient at detoxifying gluten than those from oats and wheat. ingestion of food. In this regard, three major issues must be addressed for
In contrast to the synthesis of recombinant PEPs, the extraction of pro­ in vivo application: 1) the safe quantity of gluten that can be ingested
tease from germinating cereals is more straightforward, safe, and pro­ through this approach, 2) the required amount of gluten-targeted pro­
vides an enzyme of extremely high activity [7,150]. tease, and 3) whether proteases are effective in the acidic conditions of
Three potential drug candidates with endopeptidase activity have the stomach [12,133,149].
been identified: Latiglutenase (ALV003), AN-PEP (Aspergillus niger
prolyl-endoprotease) [149], and ALV002 (Sphingomonas capsulata prolyl 5.1.3. Engineered peptidases
endopeptidase) [25]. ALV002 hydrolyzes gluten and reduces the The enzymatic computational design was used to engineer recom­
immunogenic potential of this protein [100]. ALV003 comprises a 1:1 binant peptidases like KumaMax (kuma010) and Kuma030. Wolf et al.,
mixture of barley EP–B2 and S. capsulate PEP (ALV001) which could be used the Rosetta Molecular Modeling Suite to design KumaMax and
more efficient than any enzyme alone for the treatment of celiac Kuma030 [70] based on the endopeptidase kumamolisin of

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Table 1
Different therapeutic approaches are used for CD.
Treatment approaches Mechanism of action Main feature Agents Status Main findings ref

Elimination of toxic Endopeptidase and Cysteine endoprotease ALV001 Under Degrades gluten proteins and [64–66]
gluten peptides PEPs2 investigation1 reduces the immu-
nogenic potential of gluten
Sphingomonas capsulata ALV002 Under Reducing the immunogenic [65]
PEP investigation potential of gluten
Latiglutenase ALV003 Phase II Prevent the gliadin-induced T [67]
(IMGX003) cell response
Elastase derived from (CEL-3B) Under Peptidase activity against the [68]
Homo sapiens investigation gliadin peptides increased in
patients with CD.
Cysteine endopeptidase B EP-B2 Under Administration of EP-B2 [69]
investigation prevented clinical relapse
in response to a dietary gluten
challenge
Serine Kuma030 Phase I Reduction of IFN production [70]
endoprotease KumaMax and T-cell proliferation.
Kuma010
Dipeptidyl peptidase- IV DPP-IV Under Successfully degrade small [71]
investigation amounts of gluten
Cysteine protease Triticain α Under Patients [72]
investigation had no worsening of symptom
scores and histopathology
Flavobacterium FM-PEP Under N.A3 [73]
meningosepticum investigation

Sphingomonas capsulata SC-PEP

Myxococcus xanthus MX-PEP
Aspergillus niger AN-PEP Phase II Clinical symptoms of celiac [74]
endopeptidase patients are reduced
Combination of STAN-1 Phase II Therapeutic role for [75,76]
microbial enzymes this agent remains unclear
4
Glutenase E40 Pre-clinical T lymphocytes cultured from [77]
duodenal biopsies of celiac
patients, showed a strongly
reduced or absent release of IFN-
g
Exopeptidases Combination of fungal AMY02 Pre-clinical Inhibits the immune generated [78]
exopeptidases T-cell activation
Probiotics Cocktail encompassing VSL#3 Clinical used Reduces the toxicity of gluten [79]
eight bacterial species
Bifidobacterium B. infantis NLS- Phase II Significantly improved CeD [80]
infantis SS symptoms
Bifidobacterium Bbr8 LMG P- Under In patients suffering from CD led [81]
breve 17501 investigation to decrease in pain perception
and a modification of the
intestinal microbiota
Polymeric binders Gluten-Sequestering BL-7010 Clinical trial Alter paracellular permeability, [82]
Engineered peptidases Polymers completed decrease the secretion of
Probiotics proinflammatory cytokines,
attenuate T cell activation and
atrophy villus
Neutralize gluten Oral egg yolk anti-gliadin AGY-010 Uhase I Decrease [83]
proteins polyclonal IgY antibodies symptoms, serology, and
intestinal permeability
Inhibition of Balance of proteases Serine proteases inhibitor Elafin Under Prevent gluten-induced [84]
proinflammatory and anti-proteases investigation pathology
proteases
Modulation of Tight-junction Larazotide acetate AT-1001 Phase III Prevents gliadin-induced [85]
intestinal modulation (INN-202) inflammatory response
permeability formation
Modulation of the Anti-cytokines and Blocks IL-2 and IL-15 Hu-Mik-b-1 Phase I Capable of suppressing IL-15 [86]
immunostimulatory gluten antibodies action by satu-
effects rating the IL-2/IL-15Rβ subunit
Targeting of IL-15/IL-21 BNZ-2 Under Prevents cytokine and gliadin- [87]
investigation induced release of IFN-γ
Blocking IL–15 AMG714 Phase II Blocks anti-apoptotic properties [88]
(PRV-015) of IL-15
Anti-IL-15 mAb CALY-002 Phase II Recommended for RCD5 [89]
patients
Pan-JAK inhibitor Tofacitinib Phase II Recommended for RCD patients [90]
A polyclonal anti-gluten AVX-176 Pre-clinical Inhibit activation of the innate [91,92]
antibody immune system and enzyme-
mediated peptide deamidation
(continued on next page)

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Table 1 (continued )
Treatment approaches Mechanism of action Main feature Agents Status Main findings ref

Tri-specific inhibitor of IL- EQ101 Pre-clinical Inhibit cytokines lL-15 and lL- [93]
2, IL-9 and IL-15 21 that drive cytotoxic T cell
and optimal approach CD
Anti-HLA-DQ2.5/gluten DONQ52 Pre-clinical Target immune complex causing [94]
peptide bispecific antibody CD
Blocking of intestinal CCR9 and integrin α4β7 Natalizumab Under Effectiveness in Crohn’s disease [36,95]
homing inhibitor antibody (LDP-02) investigation in suggesting a possible
CD effectiveness also in celiac
Phase II trial in disease
Crohn disease
CCR9 CCX282-B Phase II Intestinal inflammation was [96]
antagonist Vercinon attenuated
(Traficet-EN)
Anti-α4β7 inhibitor PTG-100 Phase Ib Preventing gluten-induced Clinical Trials
inflammatory injury NCT04524221
Vedolizumab Phase II Useful for the treatment of [4]
subsets of celiac disease patients
Cathepsin S inhibitor Competitive inhibitor of RO5459072 Phase I Decrease in maturation of MHC- [97]
cathepsin S (rg7236) II bearing B cells and dendritic
cells
NK lymphocyte NKG2D receptor MICA Under Proposed as therapeutics in CD [98]
activation blocker antagonists molecules investigation
Blocking HLA- DQ2 or Types of gluten peptide Azidoprolines Under Decreasing T Cell immune [99]
HLA-DQ8 analogs investigation responses
From CeD patients
Immune effector Anti-CD3 Adalimumab Under Prevent inflammation suppress [100–103]
blockers Anti-CD20 Infliximab investigation gluten activated T cells; suppress
Anti-TNF Certolizumab B cells
Anti-IFN–γ Fontolizumab
Itolizumab
Immunomodulatory Inhibiting pyrimidine de Teriflunomide Phase II Inhibit the immune activation in [104]
novo synthesis celiac disease patients during a Clinical Trials
3 day gluten challenge NCT04806737
CD8 T regulatory cell CD8 Treg Modulators MTX-101 Pre-clinical Bispecific CD8 Treg modulator [105]
modulators for celiac targeting inhibitory KIRs (Killer
treatment immunoglobulin-like receptors)
and regulatory CD8 T cell
specific marker
Inducing immune Necator N. americanus Phase II Decreased INF-γ and IL-17 [106]
tolerance americanus response to gluten exposure
Antigen-specific Lactococcus lactis express a AG017 Pre-clinical Potential to reverse gluten [107]
investigational drug gliadin peptide + sensitivity
immunomodulating
cytokine
Antigen processing Inhibition of 2-[(2-oxopropyl) thio] L682777 Under Prevent the activation of T-cells [108]
enzymes disruptor transglutaminase imidazolium inhibitor investigation
Cell-impermeable and R281 Under Prevent the toxic effects of [109]
permeable TG2 inhibitors R283 investigation gliadin

TG2 inhibitors ZED1227 Phase II Inhibits intestinal TG2 in [110]

TG2 inhibitors TAK227 patients directly
ZED1098 Under Very high selectivity for TG2 [111–113]
ZED1219 investigation
ZED1227
Cystamine Under Blocks TG2 and reduce [114,115]
investigation responses to T cell in celiac
patient
Vaccination Induce immune Gluten-derived peptides Nexvax2 Phase I Develops immune tolerance to [32]
tolerance to gluten gluten and reduces intestinal
damage in CD
Oral tolerogenic ALL-001 Under N.A [16,116]
immunotherapy investigation
Nanoparticles Antigen-specific Gliadin encapsulated in TAK-101 Phase IIa Induce gluten-specific tolerance [117]
immune suppression nanoparticles
Immune-modifying TAK-062 Phase II Well tolerated and rapidly and [118]
nanoparticle effectively degrades large
amounts of gluten
PLGA6 -antigen PLGA Under Induce tolerance via anergy, [119,120]
nanoparticles investigation activate Ag-specific regulatory T
cells
Negatively charged TIMP-GLIA Phase I Develop immune tolerance to [120]
synthetic nanoparticles gluten
Poly DL-lactide- CNP-101 Phase II Induce gluten tolerance in CD [121,122]
coglycolide
(continued on next page)

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Table 1 (continued )
Treatment approaches Mechanism of action Main feature Agents Status Main findings ref

Immune tolerization Small polymer-coated TPM502 Phase II Inducing immune tolerance to [123]
SPIONS7 conjugated with protect against the effects of
disease-relevant peptide gluten by preventing an immune
reaction
Induce gluten-specific Combines erythrocytes and KAN-101 Phase IIb Acceptable safety profile in [124]
tolerance gluten moieties patients with coeliac disease
with no dose-limiting toxicities
and no maximum tolerated dose
Glucocorticoid therapy Steroids Inhibitors of T cell Budesonide Under Effective ther- [125]
activation and cytokine Prednisolone investigation apeutic option for patients with
secretion Fluticasone RCD type I
propionate
Gene and Cell Therapy Mesenchymal stem cells MSCs MSCs Under Inhibitory effect on the [126]
(MSCs) investigation proliferation of gliadin-specific
T cells
Repairing Totipotent and pluripotent TSCs/PSCs Under Repair gastrointestinal and [127,128]
gastrointestinal stem cells investigation inverse the symptoms of CD
SIRT6 modulator SIRT6 inhibitor Vidofludimus calcium IMU-856 Phase II Restore intestinal barrier [129]
function and regenerate bowel
epithelium
1
A drug that has not been approved for general use by the Food and Drug Administration but is under investigation.
2
Prolyl endopeptidases.
3
N.A Not Available.
4
Testing of drug in non-human subjects, to gather efficacy, toxicity, and pharmacokinetic information.
5
Refractory CD.
6
Poly (DL-lactide-co-glycolide.
7
Superparamagnetic iron oxide particle.

Alicyclobacillus –As [53,70]. They used computational redesign of the In addition, in vivo studies showed that B. longum modulates proin­
active site of Kuma010 enzyme. The resultant protease, Kuma030, flammatory and regulatory cytokines such as IL-10. Also, L. casei repairs
demonstrated the ability to degrade over 99 % of gliadin in vitro, leading the intestinal injury and decreases proinflammatory cytokines [6,154].
to a reduction in T cell response. Furthermore, the specificity and ac­ Hence, the functions of the gastrointestinal bacteria and their effect on
tivity of Kuma030 were enhanced toward the PQPQLP motif in gliadin the pathogenesis of CD are striking. They are efficient degrading gluten
[70]. Kuma030 efficiently degraded gluten in bread within 30 min peptides, downregulating the proinflammatory response [100], stabi­
under simulated gastric conditions, reducing the gluten content from lizing tight junctions and improving intestinal epithelial permeability
60,000 mg/kg to 20 mg/kg in a short timeframe. Nevertheless, safety [62] and promoting intestinal epithelial cell survival [62,100,156].
and effectiveness trials of this enzyme must be conducted prior to its
application to patients with CD [152]. Proline-specific endoproteases 5.1.5. Polymeric binders
(PEP) from Sphingomonas capsulata (SC-PEP) with potential glutenase Another mechanism to decrease gluten toxicity is sequestering this
activity have been developed. The function of SC-PEP was enhanced protein. Poly hydroxyethyl methacrylate-co-styrene sulfonate (P
through mutation, resulting in a 20 % higher turnover at acidic pH and a [HEMA-co-SS]) or BL-7010 is a non-absorbable polymeric binder with a
200-fold higher resistance to pepsin [13]. high affinity for sequestering gliadin peptides [157] (Fig. 3A). Toxicity
studies in rats have shown that BL-7010 exhibits no mutagenic effects,
5.1.4. Probiotics undergoes no systemic absorption, and does not interact with the tested
Recent advances in CD pathophysiology have prompted the devel­ vitamins and digestive enzymes [82]. In pH similar to the stomach and
opment of new therapies, including probiotics. Current evidence sug­ duodenum, the polymer could alter paracellular permeability, decrease
gests that alterations in the number and type of microbiome bacteria the secretion of proinflammatory cytokines, and attenuate T cell acti­
may be associated with the disruption of immune homeostasis and the vation and atrophy villus. Therefore, nonspecifically binding to other
development of chronic inflammatory disorders, such as CD important medications should be evaluated [14,100,149,157]. Ascorbyl
[4,5,51,100,153]. Probiotics including Lactobacillus fermentum and palmitate in combination with zinc chloride is another polymeric binder
Bifidobacterium lactis may accelerate intestinal healing and reduce that could reduce TG2 activity and gluten toxicity [133]. Further studies
symptoms in patients after starting a GFD [62,153]. VSL#3 (containing are necessary to evaluate the safety and efficacy of this polymer.
8 different bacteria strains) as a commercially available probiotic re­
duces the toxicity of gluten in the fermentation process [153]. Gastro­
intestinal microbiome including lactic acid and bifidobacteria could 5.2. Modulation of intestinal permeability
hydrolyze gluten toxic peptide completely [79,149]. These findings
suggested that probiotics may alleviate symptoms and be useful as an One of the factors involved in the development of CD is aberrant
adjunctive dietary treatment for celiac patients [100,149,153] (Fig. 3A). intestinal tight junctions. Agents decreasing intestinal permeability
Investigations have shown that Bifidobacterium species are decreased or down-regulate the innate immune response and induce tolerance to
nonexistent in fecal samples and duodenal biopsies of celiac patients gluten [30,133]. Abnormal expression of epithelial junction proteins
compared to controls [4]. Several studies have revealed that these leads to increased permeability of the epithelial cell in untreated CD
bacteria can reduce the proinflammatory response, decrease gliadin- [14]. Gluten crosses the small intestinal barrier through transcellular
induced intestinal permeability, and lower tTG-IgA and anti-DGP anti­ and paracellular pathways [149]. The gliadin peptides bind to the
body in untreated celiac patients [51,154]. Therefore, bifidobacteria chemokine receptor CXCR3 and initiate zonulin release. The zonulin
could be used as an auxiliary treatment for CD [7,14,30,155]. Lindfors et leads to TJ disassembly via the MyD88-dependent pathway and
al., reported B. lactis could protect and recover ECs damaged by gliadin. entrance of gliadin into the sub epithelial [14,19]. Clinical investigation
showed that expression of zonulin and CXCR3 increased in the intestines

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of celiac patients [19]. [14]. Over-expression of IL–15 is a perpetual feature in small intestinal
mucosa of celiac patients [82,169]. Multiple research studies have
5.2.1. Tight-junction (TJ) modulation documented that IL-15 functions as a central regulator of intestinal
TJs regulate paracellular transport and prevent the passing of immune homeostasis and CD8+ T cell-mediated tissue degradation in CD
harmful bacteria and dietary antigens [25]. Zonulin, a regulator protein [169–171]. Augmenting the expression of IL-15 increases induction,
for epithelial permeability, impairs the integrity of epithelial TJs activation, and survival IELs and enhances the expression of MICA on
[14,30,158,159]. In addition to chemical drugs gastrointestinal micro­ ECs. Activation of IELs via the binding of MICA to NKG2D leads to
biota, including lactic acid and bifidobacteria, could stabilize TJs and blunting and atrophy of intestinal villi, enterocyte apoptosis, and
modulate the epithelial barrier function [154]. dysfunction of the epithelial barrier [13,14,169]. Given the important
The gliandin peptides infiltrated the lamina propria through either role of IL-15 in the loss of tolerance to gluten, resulting in inflammation
transcellular or paracellular processes [14,149]. The luminal contents and intestinal atrophy, anti-IL-15 therapy is being developed as a novel
are isolated from the lamina propria and the internal environment of the potential therapeutic strategy for CD particularly those with a refractory
body by ECs. Intercellular TJ and the mucosal immune system are reg­ condition [14,89]. Antibodies targeting IL-15 are currently the only
ulators of the permeability of the intestinal epithelium [160,161]. treatments available for blocking activity of this cytokine. Among these
Studies have demonstrated that TJ dysfunction is associated with a antibodies, Hu-Mik-b-1 blocks both IL-2 and IL-15 by targeting the
number of autoimmune diseases, including CD [162–164]. Various shared IL-2/IL-15R subunit [149]. Another antibody, AMG714 (PRV-
factors, such as dietary peptides, influence the pathophysiological 015), inhibits the anti-apoptotic effects of IL-15 in IELs, thereby pre­
regulation of TJs. In addition to genetic predisposition and exposure to venting IEL accumulation in the small intestine [149]. The AMG714
gluten as a trigger, defective TJs play a crucial role in the development phase II clinical trials has been performed in patients with refractory CD
of CD. In vivo and ex vivo experiments highlighted that gliadin induced (RCD). Likewise, Tofacitinib and CALY-002, which block IL-15
the release of zonulin and increased permeability [19,165]. In a study signaling, are being recommended for RCD patients (Fig. 3B) [89,100].
conducted by Jauregi-Miguel A et al., it was demonstrated that altered
expression patterns of TJ genes affected permeability in patients with 5.3.2. Blocking of intestinal homing
active CD. Nine genes expression levels including PARD6A, ZAK, Lymphocytes localize to the gastrointestinal mucosa via α4β7and
MAGI1and TJP1 altered in patients with active disease. These genes CCR9 integrins and CCL25 and MADCAM1 ligands. Interestingly,
involved in permeability, apicobasal polarity, and cell proliferation MADCAM1 is increased in the duodenum of celiac patients and lym­
[165]. phocytes with CCR9 receptors were augmented in the peripheral blood.
Given these data, lymphocyte homing to the small intestine could be a
5.2.2. Blocking gliadin transcellular transport potential target in CD while some concerns exist in this approach
In addition to the paracellular route, gliadin passes through the including this method may weaken immune defense, predisposing pa­
epithelium via secretory IgA (sIgA) transcellular. The mechanism of this tients to various gastrointestinal infections [14]. The anti-integrin α4
transfer is associated with binding gliadin–sIgA complexes to transferrin antibody (Natalizumab) has revealed effectiveness in CD while the CCR9
receptor CD [165], which is upregulated in the intestinal ECs of patients inhibitor (CCX282-B) and integrin α4β7 blocking antibody (LDP-02) are
with active CD. The inhibition of this mechanism has been proposed as a still under investigation for CD [36].
new therapeutic option for CD [14,166]. Zonulin larazotide (AT-100), a
synthetic octapeptide, has been shown to correct and modulate intesti­ 5.3.3. Blocking HLA–DQ2 or HLA–DQ8
nal TJ defects. Phase I and II clinical trials revealed that larazotide ac­ Approximately 90 % of celiac patients possess the HLA-DQ2 haplo­
etate was safe and well-tolerated, reducing the severity of type [6,25]. After reaching the subepithelial layer and undergoing
gastrointestinal symptoms and gluten-induced immune reactivity deamidation by TG2, gluten peptides bind with high affinity to the HLA-
[36,152]. AT-1001, an inhibitor of zonulin, is among the most exten­ DQ2 or HLA-DQ8 molecules on APCs. This binding leads to the activa­
sively studied pharmacological agents used for patient treatment. The tion of T lymphocytes and a cascade of the immune response [25].
phase II clinical studies demonstrated that patients treated with AT- Another potential therapeutic approach involves blocking HLA-DQ2 or
1001 had improved symptoms compared to the control groups HLA-DQ8 to prevent the adaptive immune response [94,172,173]. For
[14,149,158,166]. While these findings are promising, the drawback in this purpose, various analogs of gluten peptides have been developed.
these research is the lack of information on histologic improvement and Owing to interfering responses depending on HLA class 2, more studies
its implications [100]. are required [14].

5.3. Modulation of the immunostimulatory effects 5.3.4. Targeting B cells and T cells
Fighting against infectious and harmful agents and avoiding re­
5.3.1. Blocking IL–15 sponses against self-cells are the two main roles of the normal immune
Studies have shown that 1L-15 through Akt and STAT3 (signal system [174]. The lack of a normal immune response led to the devas­
transducer and activator of transcription 3) enhanced IL-21 synthesis in tation of several host particular tissues or organs. Antigen-specific
IELs and lamina propria lymphocytes (LPLs) [4,167]. IL-21 also main­ immunotherapy has been considered as a promising strategy for
tains the synthesis of both IFN- γ and IL-17A [44,168]. Augment curing autoimmune diseases such as CD [175]. The advantage of this
expression of IL-15, increases induction, activation, and survival IELs treatment approach lies in its ability to inhibit self-reactive lymphocytes
and enhances the expression of MICA on ECs. Activation of IELs via the and suppress antigen-specific immunity, without compromising the
binding of MICA to NKG2D leads to blunting and atrophy of intestinal normal immune responses to infections and tumors [175]. Most auto­
villi, enterocyte apoptosis, and dysfunction of epithelial barrier immune diseases arise from dysregulated interactions between APCs
[13,14,169]. IL-15 can enhance IL-21 synthesis in IELs and LPLs by and both self-reactive and regulatory lymphocytes [176]. Therefore,
activating the Akt and STAT3 (signal transducer and activator of tran­ most therapeutic approaches against autoimmune disease target the
scription 3) signaling pathways [167]. IL-21 may promote the produc­ APC and T-cell interactions [177]. Effector T cells have an important
tion of other inflammatory mediators, including IFN-γ and IL-17A role in the pathogenesis of CD. The involvement of effector T cells is
[44,168]. Potential targets for immunotherapy in CD include chemo­ pivotal in the development of celiac disease CD. Th17 cells, a unique
kines and their receptors, which play a crucial role in pathogenesis of class of effector T cells identified through their IL-17A secretion, have
this disease. Upon contact with the epithelium, toxic gliadin peptides been linked to CD [178]. In addition, IFN-γ can be produced by gliadin-
induce the expression of IL-15 from cells existing in gastrointestinal tract specific CD4+ T cells, which subsequently stimulates the secretion of

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matrix metalloproteinases (MMPs) [179] and signal transducer and to the gliadin peptide [36,193]. However, unresolved issues and dis­
activator of transcription 1 (STAT1) [180,181]. These processes advantages exist regarding the potential of vaccines for CD. Do these
contribute to the amplification and perpetuation of the localized in­ vaccines cover gluten and other subdominant epitopes? [14]. Is it
flammatory response in the gut of individuals with CD [181]. Elimina­ possible for a prospective vaccine to overcome the ineffectiveness of
tion effector T cells by anti-CD3 might be considered as non-dietary effector T cells caused by the suppression by regulatory T cells? [194].
treatment while more studies are required [14,36]. Besides T cells, Given that parasitic helminth infections have the capacity to modify the
targeting selective B cells with anti-CD20 antibodies has been suggested host’s immune system, hookworm approaches can be employed as a
for treatment of CD. Targeting B cells has been considered a promising possible therapy for celiac patients [195]. Furthermore, the safety and
strategy in the treatment of CD since generation of IgA by plasma cells effectiveness of vaccinations for treating CD should be evaluated to
will be sustained in the gut mucosa, while the effectiveness of this enable all patients to easily reintroduce gluten into their diet.
approach has been questioned [14].
7. The effects of nanoparticles on CD
5.3.5. Modulation of the other strategies
Most therapeutic approaches against CD focus on targeting the
5.3.5.1. Inhibition of transglutaminase. TG2 is a multifunctional enzyme interaction between antigen APCs and T-cells, as well as tolerogenic
and the most diverse isoenzyme of the TG family, often located in sub- dendritic cells (Tol DCs), which are critical in inducing and maintaining
epithelial layer of lamina propria [14,138,176,182]. This enzyme cat­ immune tolerance [175]. However, this therapeutic approach faces
alyzes intermolecular bonds between gliadin peptides and types I, III, limitations such as significant costs, potential destruction during trans­
and VI interstitial collagen [14,183] Defect in TG2 activity has been fusion, and the risk of suppressing non-specific immune responses.
demonstrated in many diseases such as CD [176] (Fig. 3C). Activated Enhancing the efficacy of inducing antigen-specific tolerance necessi­
TG2 plays a critical role in CD pathogenesis via Ca2+- dependent post­ tates the use of nanoparticle-based drug delivery systems to load Tol DCs
translational modification of gluten peptides [176]. This modification with disease-specific antigens [117,175]. Achieving long-term remission
(deamidation) increases the affinity of gluten peptides to HLA-DQ2 or remains a significant challenge in the management of autoimmune
DQ8 receptors on APCs [5,100,176]. diseases, including CD. The majority of existing therapies lack specificity
TG2 can mediate inflammation by generating immunogenic neo- and inadvertently targeting immune cells. Additionally, the extensive
epitopes on gliadin peptides through cross-linking with extracellular immunosuppressive properties of these treatments frequently lead to
matrix molecules and aiding in the transportation of T-cells to inflamed adverse side effects [196]. However, new strategies like nanoparticle-
tissues [184]. Consequently, TG2 inhibition emerges as a promising based drug delivery systems are being developed to achieve antigen-
therapeutic strategy for CD, but due to multifunctional nature of this specific immune suppression without harming the normal immune
enzyme, further investigation is warranted [14,100]. TG2 inhibitors system [174]. Kelly et al., showed that induction of gliadin-specific
function by inhibiting the active site of an enzyme and are classified into immune tolerance can be a promising therapeutic approach for CD
three types, including irreversible inhibitors (Iodoacetamide and 3-halo- [117]. This therapeutic approach prevents the initiation of immune re­
4,5-dihydroisoxazoles), reversible inhibitors (Zn2+), and competitive sponses to gliadin and the development of the disorder. In this study,
amine inhibitors (putrescine and monodansylcadaverine) [30,185,186]. gliadin was encapsulated in negatively charged nanoparticles known as
Molberg et al., indicated that cystamine can reduce T cell responses in TAK-101. Phase 1 and phase 2a assessed primary and secondary end­
biopsies from celiac patients by inhibiting TG2 activity [187]. Also, in points including safety, tolerability, pharmacokinetics, changes in en­
situ studies demonstrated that the 2-[(2-oxopropyl) thio] imidazolium teropathy, and frequency of intestinal intraepithelial immune cells.
(L682777), a TG2 inhibitor, can prevent gluten peptides from cross­ Results indicated that TAK-101 has the potential to promote gluten-
linking with endogenous proteins and thus suppress T-cell activation specific tolerance and effectively treat CD (Fig. 3E) [16,117,197].
[30]. Additionally, in vitro and ex vivo investigations have revealed that Furthermore, poly (DL-lactide-co-glycolide) (PLGA)-antigen nano­
TG2 inhibitors called R283 and R281 reduce the harmful effects of particles have been shown to induce tolerance via anergy within Ag-
gliadin [109,188]. Moreover, a new generation of TG2 inhibitors, specific effector T cells and subsequently activate Ag-specific regulato­
ZED1227, developed to directly inhibit intestinal TG2 in patients, has ry T cells [117,198,199]. Another study by Freitag et al., demonstrated
already been tested in phase I clinical trials. There is a lack of evidence the safety and efficacy of PLGA nanoparticles encapsulating gliadin in
on the safety and effectiveness of TG2 inhibitors; hence, more in­ celiac mice. The data indicated that these nanoparticles can induce
vestigations are required [38,133]. tolerance to gliadin-specific inflammatory responses, suggesting a
promising treatment for CD [120].
6. The effect of vaccination on CD
8. Gene and cell therapy for CD
In addition to inhibiting harmful events in the pathogenesis of CD,
strategies such as suppressing the inflammatory immune response with Refractory celiac disease type II (RCD II), characterized by abnormal
hookworm or inducing tolerance through vaccinations are desirable T cells, carries a high risk (60 %-80 % within 5 years) of evolving into
(Fig. 3D). The discovery of gluten epitopes is necessary for developing Enteropathy-associated T-cell lymphoma (EATL) and often shows
vaccination strategy [14]. It should be highlighted that the peptide- resistance to treatments like azathioprine/prednisone, cyclosporine, and
based vaccination is only effective in celiac patients with HLA-DQ2 IL-10 therapy [200]. Infusion of mesenchymal stem cells (MSCs) is an
genotype [30]. Nexvax2, a vaccine derived from gluten peptides emerging therapeutic method providing potential therapy options for
[189,190], has successfully completed phase I clinical studies and safety CD [126]. Ciccocioppo et al., showed that the symptoms of a 51-year-old
assessments. Research indicates that administering small doses of woman with type II RCD improved after receiving several infusions of
gluten-derived peptides over time can prevent undesirable immune re­ autologous bone marrow-derived MSCs [201]. MSCs are multipotent
sponses. This approach promotes immune tolerance to gluten and stromal cells capable of self-renewal that can be isolated from adipose,
minimizes intestinal damage in celiac patients [14,30,191]. Tolerance to fetal, muscle connective tissue, placenta, and umbilical cord [202].
gluten can be induced through oral administration of genetically engi­ These cells could be differentiated into a variety of cells, such as myo­
neered Lactococcus lactis or via parasite infection [192]. Lactococcus cytes, osteoblasts, adipocytes, and chondrocytes [17,126,203]. The
lactis secreting the DQ8-restricted gliadin epitope can induce Foxp3 + protective effects of MSCs are mediated by molecules such as
regulatory T-lymphocytes, significantly suppressing immune responses indoleamine-2,3-deoxygenase, nitric oxide, prostaglandin E2 (PGE2),
and insulin-like growth factor (IGF) [126,204]. MSCs offer an

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outstanding immunological capability and regulate numerous cells interactions, all contributing to its growing concern worldwide. It is
participating in the immune response. Furthermore, these cells can be noteworthy that the number of undiagnosed patients significantly ex­
transplanted across the HLA barrier without limitations. MSC infusions ceeds that of diagnosed individuals. In addition, the restrictions caused
have successfully treated immune-mediated diseases, including by high gluten exposure rates and dietary gluten limitation increase the
corticosteroid-refractory intestinal graft-versus-host disease and adult requirement to develop new therapies for CD. Currently, various non-
autoimmune enteropathy [205,206]. Regarding CD, MSCs have been dietary therapeutic approaches are being developed and tested in clin­
found to suppress the proliferation of gliadin-specific T cells and reduce ical research, offering potential medium- to long-term solutions for CD
the production of proinflammatory cytokines [201]. There are several patients. Developing novel medications that can replace or supplement a
rationales for employing MSCs in the treatment of RCD II including 1) GFD could be cost-effective, accessible, and without adverse effects.
developing a favorable microenvironment, called a quasi-niche in Latiglutenase, a leading candidate for adjunct therapy in CD treatment,
mesenteric lymph nodes and prime naïve immune cells toward a tol­ demonstrates high efficiency in gluten degradation. Further studies are
erogenic profile; 2) repairing intestinal lesions [17,207] by salvation required to determine if these enzymes can effectively neutralize an
enterocytes from apoptosis, maintaining epithelial barrier integrity, and entire gluten-containing meal. Larazotide acetate is the most advanced
protecting crypt stem cells; 3) reducing IL-15 and IL-15Ra expression, experimental drug to date, showing a decrease in both symptoms and
thus inhibiting the proliferation of natural killer cells and restoring anti-tTG antibody titers. Among drugs targeting the immune system,
absorptive function [201]; and 4) inhibiting B cell activation and pro­ those focusing on gluten-reactive CD4 T cells have undergone more
liferation, downregulating CD8, expanding T regulatory cells [208], and extensive investigation. Tolerance induction using nanoparticles loaded
thereby modulating lymphocyte and antigen-presenting cell responses with gluten (TAK-101) is striking for its potential to minimize gluten-
[207]. induced mucosal damage.
MSCs have the ability to modulate T and B cell activity in vitro, The promising immunotherapy AMG714, which blocks IL-15, re­
making them a promising new treatment option for autoimmune dis­ quires additional studies to identify precise targets for disease preven­
eases [208]. The therapeutic approach using MSCs, compared to he­ tion. Some restrictions exist on vaccine therapy, including its reliance on
matopoietic stem cell transplantation (HSCT), is safer and lacks recognized or previously assessed immunogenic epitopes and its effec­
associated risks such as conditioning therapy complications or Graft- tiveness being restricted to individuals with the specific HLA-DQ2 ge­
versus-host disease (GVHD) [201,208]. Moreover, using embryonic notype. Nevertheless, if successful, vaccine therapy holds the potential
stem cells in the naïve state has limitations, such as the tendency to form for extended benefits for patients. Additionally, innovative therapeutic
teratomas in implanted tissue [207]. methods like cell or gene therapy, which are presently being evaluated,
Young et al., suggested allogeneic adult-derived telomerase-positive may be beneficial for certain patient groups. It is noteworthy to high­
stem cells, such as pluripotent stem cells (PSCs), can be used for light that all of these treatments are investigative. More research on their
repairing gastrointestinal and immune systems in celiac patients [207]. efficacy and safety, involving larger populations and compelling clinical
PSCs have been shown to be useful in treating neurodegenerative, evidence, is needed before any can be ultimately recommended as a non-
myocardial infarction, and pulmonary disorders according to prior dietary CD treatment. The future holds promise for innovative thera­
clinical research [209,210]. Owing to their ability to inverse the peutic strategies expected to enhance the quality of life for patients
symptoms of CD and repair immune and gastrointestinal tissues, TSCs or suffering from CD.
PSCs are preferred over MSCs. Additionally, stem cells have the poten­
tial to provide successful treatments for currently incurable disorders CRediT authorship contribution statement
including RCD and enteropathy-associated T-cell lymphoma in the near
future [207]. Young et al., demonstrated that pluripotent stem cell Effat Noori: Writing – review & editing. Nader Hashemi: Writing –
transplantation can ameliorate clinical symptoms and modulate the original draft. Delsuz Rezaee: Resources. Reza Maleki: Investigation.
immune system in gluten-sensitive individuals [211,212]. Most studies Forough Shams: Writing – review & editing. Bahram Kazemi: Inves­
suggested that stem cell transplantation is more effective than conven­ tigation. Mojgan Bandepour: Investigation. Fardin Rahimi:
tional treatments for severe refractory autoimmune diseases [126,212]. Resources.
For instance, mesoderm derived human stem cells (hSCs) could produce
both lymphoid and myeloid lineages of blood cells and play an impor­
tant role in mucosal healing [126]. Allogenic hSCs transplantation Declaration of Competing Interest
normalizes cytokines profile and FOXP3+ T cell, thereby inducing im­
mune tolerance to oral antigens [213,214]. However, these treatments The authors declare that they have no known competing financial
have shown limitations including recurrence of symptoms and high risk interests or personal relationships that could have appeared to influence
of mortality [126]. Hence, hMSCs show great promise for the treatment the work reported in this paper.
of a variety of immune-related diseases with their intrinsic immuno­
modulatory properties. The successful isolation of hMSCs from various Data availability
tissues, coupled with promising findings from in vitro experiments and
pre-clinical trials, contributed to their usage in treating multiple No data was used for the research described in the article.
immune-related disorders, including CD [17]. The primary advantage of
MSCs, compared to other immunotherapy methods, lies in their ability References
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