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Open access peer-reviewed chapter

Mesenchymal Stem/Stromal Cells in Allergic Disease Management

Written By

Leisheng Zhang, Zhongchao Han and Xiaowei Gao

Submitted: 24 May 2022 Reviewed: 08 June 2022 Published: 28 June 2022

DOI: 10.5772/intechopen.105763

Allergic Disease IntechOpen
Allergic Disease New Developments in Diagnosis and Therapy Edited by Öner Özdemir

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Allergic Disease - New Developments in Diagnosis and Therapy

Edited by Öner Özdemir

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Abstract

Allergic diseases are a clump of disorders caused by protective or harmful immune responses to specific exogenous stimulations. To date, the worldwide prevalence of allergic diseases has caused considerable perplex to patients and guardians physically and mentally. Despite the significant advances in preclinical investigation and clinical practice, yet the effective treatment strategies for allergic diseases are far from satisfaction. State-of-the-art renewal has highlighted the involvement of mesenchymal stem/stromal cell (MSC)-based cytotherapy for various allergic disease management including atopic dermatitis, pediatric asthma, allergic rhinitis, and urticaria, which largely attributes to the unique immunomodulatory properties and mode of action via autocrine and paracrine, direct- or trans-differentiation. In this chapter, we mainly focus on the latest updates of MSC-based investigations upon allergic disease administration as well as the concomitant prospective and challenges, which will provide overwhelming new references for MSC-based cytotherapy in regenerative medicine.

Keywords

  • mesenchymal stem/stromal cells
  • allergic diseases
  • exosome
  • immunomodulation
  • allergic rhinitis
  • cytotherapy

1. Introduction

Allergic diseases, including atopic dermatitis, pediatric asthma, allergic rhinitis, and urticaria, have been recognized as one of the most prevalent chronic diseases and affected more than 300 million individuals all over the world and thus, have garnered public health attention worldwide over the past decades [1]. To date, a variety of factors (e.g., IL-6, IL-8, IL-25, IL-33, INF-γ) and noxious stimuli (e.g., microbiota, helminths, human milk immunological composition) in the environment have been involved in the occurrence or progression of allergic diseases [2, 3]. Of note, immunomodulation has been acknowledged as the core strategy for allergic and autoimmune diseases.

Despite the diversity in the pathogenic mechanism of governing the progression, a variety of key elements involved in allergic diseases have been identified such as immune cells (e.g., mast cells, T cells), antibodies, cytokines, epigenetic and genetic determinants [1, 4, 5]. For instance, of the aforementioned pathogenic factors, mast cells with inflammatory mediator expression have been recognized playing a key role in various allergic reactions and autoimmune processes [6, 7].

For decades, integrated prevention and intervention strategies have been developed for the remission of allergic diseases. For example, the European Academy of Allergy and Clinical Immunology (EAACI) guidelines for allergen immunotherapy (AIT) have been reported in preparations for the administration of allergic disease by Dhami and colleagues [8]. Meanwhile, JAK/STAT inhibitors, together with relevant small-molecule cytokine antagonists such as CRTH2 inhibitors and PDE4 inhibitors, have been tested in a spectrum of allergic diseases [9]. Additionally, current advances have also suggested the probiotics and prebiotics in the treatment or prevention of allergic diseases during the prenatal period [10, 11, 12]. For example, Tang et al. reviewed that prebiotic-supplemented formulas might be an effective alternative for preventing atopic eczema in infants with high probability of developing allergic disease [10, 13].

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2. The overview of MSCs

Mesenchymal stem/stromal cells (MSCs) are cell populations with unique hematopoietic-supporting and immunoregulatory properties, which are currently recognized as the uppermost counterparts for regenerative medicine in the field [14]. Since the first isolation from bone marrow, MSCs with various origins have been identified including adult tissues and perinatal tissues such as adipose-tissue-derived MSCs (AD-MSCs), dental-pulp-derived MSCs (DPSCs) [15], fetal-liver-derived MSCs (FL-MSCs), amniotic-membrane-derived MSCs (AMSCs), amniotic-fluid-derived MSCs (AF-MSCs), umbilical-cord-derived MSCs (UC-MSCs) [16, 17], placenta-derived MSCs (P-MSCs) [18], supernumerary teeth-derived apical papillary stem cells (SCAP-Ss) [15]. Meanwhile, current progress also highlighted the large-scale generation of MSCs from human pluripotent stem cells (hPSCs) including human embryonic stem cells (hESCs) and human induced PSCs (hiPSCs) as well [19, 20, 21].

2.1 Biofunctions of MSCs

As mentioned above, MSCs are heterogeneous populations with advantaged properties, which thus have been largely recognized as the dominating stromal cells in the hematopoietic microenvironment and the splendid “seed” cells for cellular therapy [22]. Not until the year of 2006, the International Society for Cellular Therapy (ISCT) released minimal guidelines for MSC definition including the fibroblast-like plastic-adherent cells, high percentage of subsets with mesenchymal-associated biomarker expression (CD73, CD90, CD105), whereas minimal expression of hematopoietic-associated (CD31, CD34) or immune-related (HLA-DR) surface markers and multi-lineage differentiation potential toward adipocytes, osteoblasts, and chondrocytes [23]. Of the biofunctions, immunomodulation is of great importance for the translational purposes of MSCs and the derivatives in tissue engineering and regenerative medicine via simultaneously inhibiting and stimulating the immune system and secreting immunosuppressors [24].

To date, MSCs have been extensively explored in multiple intractable and recurrent diseases such as acute-on-chronic liver failure (ACLF) [25], acute myocardial infarction (AMI) [26], acute myelogenous leukemia (AML) [27], refractory wounds [28], atopic dermatitis (AD), Crohn’s disease (CD) [18], graft-versus-host disease (GvHD) [16], coronavirus disease 2019 (COVID-19)-associated acute lung injury and acute respiratory distress syndrome (ALI/ARDS) [29, 30].

2.2 Regulatory mechanisms of MSCs

Generally, MSCs function mainly via serving as constructive microenvironment for hematogenesis, secretion (autocrine, paracrine), immunomodulation, and differentiation [31, 32, 33, 34]. For instance, the orchestration of multiple pathways (e.g., TGF-β, PPAR-γ2, and the Smad3-SOX9-CREB/p300 axis) in MSCs is critical for in vitro differentiation toward the mesodermal lineages [35, 36]. Instead, López-García and Castro-Manrreza verified the TNF-α and IFN-γ in mediating the immunoregulatory capacity of MSCs in the modulation of the immune response [37]. Interestingly, Montesinos and colleagues verified the regulatory effect of TNF-α and IFN-γ for the enhanced expression of ICAM-1 and microvesicle release of BM-MSCs when exposed to an inflammatory environment [38]. As to bone-marrow-derived MSCs (BM-MSCs), Zhang et al. demonstrated the hyperactivation of JAK–STAT signaling in AML patients compared with those in healthy donors [27].

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3. MSCs for allergic disease management

As an intractable autoimmune disease with complex pathogenesis, allergic diseases have caused heavy economic and psychological burden to the patients and their families, and in particular, those with relapse and resistance against drugs. For the purpose, autogenous and allogeneic MSCs with unique bidirectional immunomodulatory property have caught the attention of pioneering investigators in the field. To date, MSCs have been involved in various subtypes of allergic disease management with considerable efficacy such as allergic rhinitis, allergic dermatitis, allergic asthma, and urticaria.

3.1 MSCs for allergic rhinitis management

Allergic rhinitis (AR), a well-described disease entity with extra-nasal manifestations, is considered as a major and increasing chronic inflammatory disease in the respiratory tract [39, 40, 41]. The pathogenesis of AR is associated with inflammatory mediators (e.g., IgE) and sensitized mast cells in the submucosa of the upper aerodigestive tract, which is also involved in various upper airway diseases including otitis media, chronic laryngitis, oral allergy syndrome, and obstructive sleep apnea [40, 42, 43, 44]. Clinically, although with certain disadvantages such as repeated attacks and adverse reaction, a series of desensitizing drugs including nasal glucocorticoids and antihistamines, together with acupuncture, are currently in use for allergic rhinitis treatment [39, 45, 46, 47].

Recently, Zheng et al. investigated the outcomes of 70 patients with allergic rhinitis with the administration of azelastine hydrochloride and montelukast sodium and found that clinical symptom score (e.g., nasal itching, runny nose, and nasal congestion) and serum levels of proinflammatory factors (e.g., hsCRP, IL-6, and IL-8) revealed preferable improvement compared with those 67 patients with azelastine hydrochloride alone [48]. Simultaneously, Xiong et al. recently reported the ameliorative effect of Chinese herbs (e.g., Guominjian) upon AR by utilizing the anti-inflammatory, anti-allergic, and immunomodulatory effects [49]. However, the spectrum of AR and the complex immunopathology further affect the efficacy of antiallergic drugs including antihistamines and mast cell stabilizers and thus, limit the treatment with the concomitant corticosteroid. Moreover, the recurrence of AR has been considered difficult to handle by current drug therapy.

Of note, pioneering clinicians have turned to MSC-based remedy for further improvement in the management of AR based on the immunomodulatory properties. For example, two interventional studies (NCT05167552, NCT05151133) have been registered according to the Clinicaltrials.gov website, and a total number of 78 participants are being enrolled for further treatment with various doses (low dose, 0.5 × 106 cells/kg; moderate dose, 1.0 × 106 cells/kg; high dose, 2.0 × 106 cells/kg) of hUC-MSC infusion (Table 1).

ConditionsNCT no.StatusPhasesEnrollLocation
Allergic rhinitisNCT05167552Not yet recruitingP1, P260—
NCT05151133RecruitingP118China
Allergic dermatitisNCT02888704CompletedP113Korea
NCT03252340Active, not recruiting11Korea
NCT04179760RecruitingP1, P292Korea
NCT04137562RecruitingP2118Korea
UrticariaNCT02824393CompletedEarly P110Turkey

Table 1.

MSC-based clinical trials upon atopic diseases.

3.2 MSCs for atopic dermatitis management

Atopic dermatitis (AD), also regarded as atopic eczema, is a relapsing inflammatory skin condition and a chronic heterogeneous skin lesion worldwide among childhood, infancy, and even adulthood, and in particular, among those families with a history of allergic diseases [50, 51, 52]. To date, a variety of pathogenic factors associated with the environmental, immunologic, and genetic elements have been identified for the intrinsic and extrinsic subtypes of AD such as food allergies, respiratory diseases, autoimmune disorders, and inflammatory skin infections [50, 53]. For example, the well-established ingredients including dysbiosis of skin microbiota, epidermal barrier disruption, overactivation of the helper T cell subsets (e.g., Th1, Th2, Th17, Th22), together with increased immunoglobulin E (IgE) and eosinophils in blood, have been demonstrated in association with the pathogenesis of AD [54, 55]. Of the disease progression, the impaired skin barrier is considered as the initial step during the development of AD, which is adequate to cause further allergic sensitization and skin inflammation [56]. Simultaneously, AD is deemed to the initiation phase of relevant atopic disorders such as food allergy and allergic asthma and rhinitis, which is continuous for ages and maintains the relapsing-remitting status in numerous patients [57].

Therewith, despite the current pharmacological and nonpharmacological treatment modalities in relieving misery in patients with moderate to severe AD, the efficacy or persistence is still unsatisfactory on account of the indeterminacy and complexity of the underlying pathogenesis [1, 52]. Strikingly, Kim et al. reported the safety and certain improvements of AD inpatients with an overall response rate of 55% at week 12 with a high dose of hUC-MSC (5 × 107) administration through local subcutaneous injection [58]. Similarly, our group further reported the real cure of an elderly patient rather than partial remission by conducting a single round of intravenous injection of hUC-MSCs without recrudesce during the 14-month’s follow-up. Overall, the aforementioned proof-of-concept studies ulteriorly highlighted the feasibility upon AD patients with refractory AD-associated symptoms.

3.3 MSCs for allergic asthma management

Allergic asthma, known as a “syndrome” with over 300 million individuals worldwide, which also has become a dominating burden in Westernized societies [59].

Generally, allergic asthma is caused by a complex interplay between environmental stimulus and genetic and factors [60, 61]. As a chronic airway inflammatory disease, patients with allergic asthma reveal multifaceted clinical manifestations such as intermittent attacks of airway hyper-reactivity, breathlessness, coughing, and wheezing. As to adult asthma, an initial exposure to allergen triggers Th2 cell-dependent immune response that regulates the production of IgE and cytokines in the lungs [60]. Distinguishing from the characteristics of ILC2s in chronic allergic diseases, IgE sensitization has been considered acting as a crucial role in the progression of allergic diseases [60, 62, 63]. Collectively, the environmental and genetic factors orchestrate the complexity and challenges of allergic asthma posed for the further development of novel remedies for effective treatment and prevention of allergic asthma.

State-of-the-art updates have suggested the therapeutic effect of MSCs or MSC-derived exosomes (MSC-Exo) in the management of allergic asthma in preclinical and clinical investigations [64, 65, 66]. For instance, Boldrini-Leite et al. took advantage of the ovalbumin-induced allergic asthma mice model for the remodeling of the inflammatory process and pulmonary symptoms and confirmed the potential of BM-MSCs to modulate lung inflammatory processes and tissue repair. Recently, Huang et al. found that the mitochondrial dysfunction and asthma pathophysiology in the asthma animal model were efficiently rescued by MSC injection, and the levels of relevant gene expression were reversed as well such as interleukins (e.g., IL-4, IL-5, IL-13, IL-25, IL-33) and mitochondria genes (e.g., COX-1, COX-2, Cytb, ND-1) and inflammatory factors (e.g., INF-γ) [65]. Similarly, de Castro et al. demonstrated the efficacy of human adipose tissue–derived MSCs (hAD-MSCs) and the extracellular vesicles upon experimental allergic asthma by airway remodeling. In detail, C57BL/6 female mice with experimental allergic asthma manifested reduced eosinophils in lung tissue, collagen fiber content in lung parenchyma and airways, levels of Tgf-β in lung tissue, and CD3+CD4+ T lymphocyte counts in the thymus [67]. Interestingly, Abreu and colleagues verified the enhanced therapeutic effect of MSCs upon allergic asthma by pretreatment with eicosapentaenoic acid (EPA) [68]. Moreover, serum from asthmatic mice has been proved with potentiated efficacy of MSCs in experimental allergic asthma [69]. Taken together, MSCs of different origins alone or in combination with relevant remedies reveal rosy prospective in allergic asthma management.

3.4 MSCs for urticaria management

Urticaria, including the immunological and nonimmunological subtypes, is a series of common skin disorder occurring in 0.5–5% of the general population that affects individuals of all ages and results from many different stimuli, which compromise quality of life and affect individual performance physically and mentally [70, 71, 72, 73]. Generally, urticaria acts as a hypersensitivity reaction with mast cell activation due to the stimulation of T lymphocytes and/or antibodies. Instead, nonimmunological urticarias with mast cell activation are involved in immunomodulation (e.g., Toll-like, complement, proinflammatory factors) or toxicity of xenobiotics (e.g., haptens, drugs). Therewith, the variations in the pathophysiological mechanisms further result in the great heterogeneity of clinical symptoms and the variable remedies [72, 74].

Urticaria exhibits multifaceted clinical manifestations such as intensely pruritic wheals, edema of the interstitial or subcutaneous tissue. In details, distinguishing from the acute urticaria, chronic urticaria, including chronic spontaneous urticaria (CSU) and chronic inducible urticaria (e.g., cold urticaria), is regarded as a difficult-to-treat skin disease and results in the major impact on quality of life in patients according to the European guideline on the management of urticaria, which describes a multidisciplinary approach for urticaria administration [75, 76, 77].

Being obscure in fully elucidating the underlying etiopathogenesis as well as the limitation in urticaria management, pioneering scientists and clinicians turned to MSC-based cytotherapy for developing more efficient treatment options [73]. Of note, Özgül Özdemir and colleagues employed autologous AD-MSCs for the administration of 10 refractory CSU patients and noticed the immunomodulatory effect upon CD4+ T cell subsets and cytokine expression profiling. For instance, the Th2 subset and pro-inflammatory factors (e.g., TGF-β1, IDO, PGE2, anti-FcεRI) revealed a significant decrease in urticaria patients with MSC injection after 2 weeks [73]. Collectively, despite the minimal literatures in the field, the findings suggested that MSCs might be an alternative and effective strategy for treatment-resistant CSU patients in clinical practice [73].

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4. Clinical trials of MSC-based remedy for allergic diseases

In the recent years, MSC-based cytotherapy has attracted the attention of a certain number of biologists and clinicians in the field for allergic disease management. According to the Clinicaltrials.gov website of National Institutes of Health (NIH), a total number of seven clinical trials have been registered worldwide (up to May 24th, 2022) including four trials in Korea (NCT02888704, NCT03252340, NCT04179760, NCT04137562), one trial in China (NCT05151133), one trial in Turkey (NCT02824393), and one trial unknowable (NCT05167552) (Table 1).

The interventional studies conducted by clinical investigators are designed to explore the safety and effectiveness of MSC-based treatment for relevant disease treatment including two trials for allergic rhinitis, four trials for allergic dermatitis, and one trial for urticaria (Table 1). Of the aforementioned clinical trials, two were not yet recruiting, three were recruiting, four were completed, and two were completed (Table 1). Meanwhile, we further noticed that all of the registered clinical trials were in the Phase 1 and Phase 2 stages (Table 1).

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5. Conclusions

MSCs and the concomitant derivatives have emerged as advantaged and alternative sources for allergic disease management. MSC- or MSC-exo/small secretory vesicles (sEVs)-based cytotherapy has supplied overwhelming new tissue engineering platforms to sequentially ameliorate disease manifestations and improve the clinical outcomes of patients with relevant allergic diseases. However, the lack of standardized methodology and evaluation criteria (e.g., safety, effectiveness, biodistribution) in the preparation of good manufacturing practices (GMP)-grade MSCs for clinical purposes hinders the development of MSC-based tissue engineering and regenerative medicine. Therefore, further understanding of the aforementioned aspects of MSCs will benefit clinical applications and the industrialization of MSC-based cytotherapy in future.

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Acknowledgments

The authors would like to thank the members in Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province & NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, and Institute of Biology & Hefei Institute of Physical Science, Chinese Academy of Sciences for their kind suggestions. This study was supported by grants from Science and technology projects of Guizhou Province (QKH-J-ZK[2021]-107), Natural Science Foundation of Jiangxi Province (20212BAB216073), the project Youth Fund funded by Shandong Provincial Natural Science Foundation (ZR2020QC097), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT320005), The 2021 Central-Guided Local Science and Technology Development Fund (ZYYDDFFZZJ-1), Gansu Key Laboratory of molecular diagnosis and precision treatment of surgical tumors (18JR2RA033), Key project funded by Department of Science and Technology of Shangrao City (2020AB002, 2020 K003, 2021F013), Jiangxi Provincial Key New Product Incubation Program Funded by Technical Innovation Guidance Program of Shangrao (2020G002), Natural Science Foundation of Gansu Province (21JR11RA186, 20JR10RA415), Key talent project of Gansu Province of the Organization Department of Gansu provincial Party committee (2020RCXM076), Fujian Provincial Ministerial Finance Special Project (2021XH018).

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Conflict of interest

The authors declare no conflict of interest.

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Notes/thanks/other declarations

Not applicable.

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Appendices and nomenclature

MSCs

mesenchymal stem/stromal cells

EAACI

the European Academy of Allergy and Clinical Immunology

AIT

allergen immunotherapy

AR

allergic rhinitis

AD

atopic dermatitis

IgE

immunoglobulin E

hAD-MSCs

human adipose tissue–derived MSCs

EPA

eicosapentaenoic acid

CSU

chronic spontaneous urticaria

UC-MSCs

Umbilical-cord-derived MSCs

P-MSCs

placenta-derived MSCs

AD-MSCs

adipose-tissue-derived MSCs

DPSCs

dental-pulp-derived MSCs

FL-MSCs

fetal-liver-derived MSCs

AMSCs

amniotic-membrane-derived MSCs

AF-MSCs

amniotic-fluid-derived MSCs

UC-MSCs

umbilical-cord-derived MSCs

P-MSCs

placenta-derived MSCs

hPSCs

human pluripotent stem cells

SCAP-Ss

supernumerary teeth-derived apical papillary stem cells

ISCT

the International Society for Cellular Therapy

hESCs

human embryonic stem cells

hiPSCs

human induced PSCs

MSC-exo

MSC-derived exosomes

sEVs

small secretory vesicles

GMP

good manufacturing practices

AML

acute myelogenous leukemia

CD

Crohn’s disease

GvHD

graft-versus-host disease

COVID-19

coronavirus disease 2019

ALI

acute lung injury

ARDS

acute respiratory distress syndrome

AMI

acute myocardial infarction

ACLF

acute-on-chronic liver failure

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Written By

Leisheng Zhang, Zhongchao Han and Xiaowei Gao

Submitted: 24 May 2022 Reviewed: 08 June 2022 Published: 28 June 2022

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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