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Promising Immunomodulatory
Effects of Bacterial Lysates in
Allergic Diseases
Agnieszka Kaczynska
1
, Martyna Klosinska
1
, Kamil Janeczek
1
*, MichałZarobkiewicz
2
and Andrzej Emeryk
1
1
Department of Pulmonary Diseases and Children Rheumatology, Medical University of Lublin, Lublin, Poland,
2
Department
of Clinical Immunology, Medical University of Lublin, Lublin, Poland
In light of an escalating prevalence of allergic disorders, it is crucial to fully comprehend
their pathophysiology and etiology. Such knowledge would play a pivotal role in the search
for new therapeutic approaches concerning not only diseases’symptoms, but also their
underlying causes. The hygiene hypothesis indicates a high correlation between limited
exposure to pathogens in early childhood and the risk of developing allergic disorders.
Bearing in mind the significance of respiratory and digestive systems’mucous
membrane’sfirst-line exposure to pathogens as well as its implications on the host’s
immune response, a therapy targeted at aforesaid membranes could guarantee promising
and extensive treatment outcomes. Recent years yielded valuable information about
bacterial lysates (BLs) known for having immunomodulatory properties. They consist of
antigen mixtures obtained through lysis of bacteria which are the most common etiologic
agents of respiratory tract infections. They interact with dendritic cells located in the
mucous membranes of the upper respiratory tract and the gastrointestinal tract by toll-like
receptors. The dendritic cells present acquired antigens resulting in innate immune
response development on the release of chemokines, both stimulating monocytes and
NK cells maturation and promoting polymorphonuclear neutrophil migration. Moreover,
they influence the adaptive immune system by stimulating an increase of specific
antibodies against administered bacterial antigens. The significance of BLs includes not
only an anti-inflammatory effect on local infections but also restoration of Th1/Th2 balance,
as demonstrated mainly in animal models. They decrease Th2-related cytokine levels (IL-
4, IL-13) and increase Th1-related cytokine levels (IFN-g). The reestablishment of the
balance of the immune response leads to lowering atopic reactions incidence which, in
addition to reduced risk of inflammation, provides the alleviation and improvement of
clinical manifestations of allergic disorders. In this review, we hereby describe
mechanisms of BLs action, considering their significant immunomodulatory role in
innate immunity. The correlation between local, innate, and adaptive immune responses
and their impact on the clinical course of allergic disorders are discussed as well. To
conclude our review, we present up-to-date literature regarding the outcomes of BLs
implemented in atopic dermatitis, allergic rhinitis, and asthma prevention and treatment,
especially in children.
Keywords: adaptive immunity, bacterial lysate, asthma, allergic rhinitis, atopic dermatitis, innate immunity
Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 9071491
Edited by:
Milena Sokolowska,
University of Zurich, Switzerland
Reviewed by:
Gerdien Tramper,
Franciscus Gasthuis & Vlietland,
Netherlands
Heidi Makrinioti,
Chelsea and Westminster Hospital
NHS Foundation Trust,
United Kingdom
*Correspondence:
Kamil Janeczek
kamil.janeczek@umlub.pl
Specialty section:
This article was submitted to
Molecular Innate Immunity,
a section of the journal
Frontiers in Immunology
Received: 29 March 2022
Accepted: 30 May 2022
Published: 22 June 2022
Citation:
Kaczynska A, Klosinska M,
Janeczek K, Zarobkiewicz M and
Emeryk A (2022) Promising
Immunomodulatory Effects of Bacterial
Lysates in Allergic Diseases.
Front. Immunol. 13:907149.
doi: 10.3389/fimmu.2022.907149
REVIEW
published: 22 June 2022
doi: 10.3389/fimmu.2022.907149
INTRODUCTION
Recent decades followed the endurance of tremendous changes
in the environment, economic and social developments
alongside worldwide urbanization (1). Unfortunately, that led
to an increased prevalence of allergic disorders estimated at 20%
of the population, especially children (2). Possible collocations
are also noticed regarding atopic sensitization and
hyperresponsiveness in the upper airway (3). The ‘atopic
march’refers to an observed incidence of atopic dermatitis
(AD) and food allergies in infancy, gradually progressing into
allergic rhinitis (AR) and allergic asthma later in childhood (4).
Asthma development is observed in 30% of children with AD (5).
Speculations surrounding atopic diseases center around adaptive
immune response disturbances with consideration of Th1/Th2
imbalance as well as the hygiene hypothesis, underlying the
crucial role of innate immunity (6). Therapeutic options regard
lifestyle changes, such as food interventions and environmental
prevention, but also focus on finding an appropriate
pharmacological treatment (7–9). Current guidelines
recommend multiple medications that alleviate allergy
symptoms and improve quality of life. However, treatment has
several limitations and is burdened with side effects; thus,
introducing new therapeutic approaches remains crucial.
Bacterial lysates (BLs) seem to be an effective and safe way of
allergy prevention and treatment. They consist of inactivated
respiratory tract bacteria obtained by mechanical or chemical
lysis. Their significant mechanism of action enables them to
modulate the immune response by activating innate immunity
and, as the data suggest, by restoring Th1/Th2 balance (10,11).
This publication aimed to summarize and explain the
immunomodulatory effects of BLs in the prevention and
treatment of patients (mainly children) with AD, AR, and
asthma. Furthermore, the clinical outcomes of this treatment
were discussed as well.
This narrative review consists of a presentation and analysis of
literature and previously published studies obtained from PubMed,
Scopus, and Google Scholar databases. In all the databases, we used
the combination of the following keywords: ‘atopic dermatitis’,
‘allergic rhinitis’,‘asthma’,‘bacterial lysate’,‘bacterial extract’,
‘innate immunity’,‘adaptive immunity’,‘mechanism of action’,
‘immunomodulation’and ‘immunomodulatory properties’.
IMMUNOLOGICAL, GENETIC, AND
EPIGENETIC FACTORS OF
ALLERGY DEVELOPMENT
During years of evolution, the immune system has developed
numerous mechanisms necessary to eliminate harmful
environmental factors. Pathogens, allergens, and pollutants are
recognized and neutralized every day. Both innate and adaptive
immune responses work closely to prevent infections. However,
sometimes the reaction becomes too intense. This phenomenon,
called hypersensitivity, is a cause of multiple diseases such as
allergies, autoimmune disorders, and transplant rejections. This
review will focus mainly on the immediate type of
hypersensitivity as it is typical for allergies. It is characterized
by the increased level of IgE antibodies specific to allergens
(asIgE) as well as the disturbance of Th1/Th2 immune response
balance, which combined with chronic inflammation in the
mucosa leads to burdensome allergic symptoms (12).
Many years of observations indicate numerous factors that
affect the risk of allergy development. These include genetic
factors, exposure to allergens in childhood, food consumed by
the child during early life, infectious and toxic agents (13).
Thehygienehypothesisseemstobethemostreliable
explanation for the rising allergy incidence. It is closely linked
with the decrease of infectious disease burden due to vaccines,
antibiotics, and hygiene measures. It has been proven that
prenatal or early-life immunostimulatory signals significantly
impact the development of the immune system (14,15). The
‘old friends’hypothesis points out the beneficial role of symbiotic
bacteria and parasites in dendritic cells’maturation and
maintenance of Th1/Th2 balance (16). This hypothesis
suggests that a key to treating allergic disorders may be a
controlled presentation of antigens that could replace
mentioned early-life exposure (17,18).
Clinical findings show a strong correlation between various
genetic factors and the severity and treatment of allergic diseases.
The risk of asthma or AR development is increased in children
whose parents, especially mothers, suffer from these disorders
(19). Particular genes directly impact the immune response, both
humoral and cellular. For instance, IL-13+2044G/A, IL-4-590C/T
polymorphisms are associated with an increased risk of
childhood asthma development (20).
Exposure to air pollutants is another important risk factor. It
may explain the increased incidence of allergic diseases among
children who live in industrial areas or whose relatives smoke
(21). Pollutants (e.g. diesel emission particles) act as adjuvants
and stimulate the production of cytokines that promote Th2 type
response (22). Moreover, they cause oxidative stress that lowers
corticosteroids responsiveness and reduces symptoms
control (23).
It is presumed that immunomodulatory preparations that
could possibly restore the natural balance in the immune
response can conceivably be a game-changer in allergic
diseases. BLs seem to be a good candidate for such treatment
as they are characterized by a significant ability to modulate the
immune response in a plethora of ways. What distinguishes them
from conventional drugs used in the treatment of allergic
diseases is that they can affect both innate and adaptive
immune responses.
BACTERIAL LYSATES
Methods of Preparation
Bacterial lysates are immunomodulatory preparations consisting
of inactivated antigens derived from respiratory tract pathogens
(24,25). Bacterial species most commonly responsible for these
infections are Streptococcus pneumoniae, Haemophilus
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influenzae, Moraxella catarrhalis, Streptococcus pyogenes,
Streptococcus viridans, Staphylococcus aureus, Klebsiella
pneumoniae and Klebsiella ozaenae (26).
The bacterial extracts are obtained in two ways, chemical or
mechanical, which accordingly indicates different biological
effects. Polyvalent chemical bacterial lysates (PCBLs) undergo
alkaline lysis, during which the bacterial cell membrane is
discomposed because of high pH in the range of 11.5-12.5
(27). Additionally, protein denaturation results in reduced
immunogenicity after administration (28). Polyvalent
mechanical bacterial lysates (PMBLs) endure lysis by either
ultra-sonication or high pressure homogenization (27). This
method is said to be more efficient as, within its course, the
structures of bacterial antigens are not disrupted, which
guarantees a better immune response (29).
Basic Mechanisms of Action
Most of the evidence for the mechanism of action of BLs comes
from animal and in-vitro studies. The mechanism of action
presented by BLs is based upon a natural immune response
provoked by pathogens, as it leads to stimulation of lymphoid
tissue located in the mucosa, both locally and generally (30).
Subsequently, through toll-like receptors (TLRs), BLs activate
dendritic cells (DCs), being at the core of the innate and adaptive
mucosal immunity (10,31–33). As a result of that,
proinflammatory cytokines are released, which consequently
mobilize effector cells (27,34,35). The immunomodulatory
effects of BLs reach not only cellular, but also humoral
immunity (36). They promote antiviral cytokines production,
macrophages, and NK cells activation in addiction to eosinophils
mitigation (37,38). Moreover, by their action, the Th2-
associated immune response is weakened, with the effect of
Th1/Th2 balance restoration (39–42).
Application in Clinical Practice
The use of bacterial extracts implies significant
immunomodulatory effects, and its safety has been confirmed
through extensive research (43–45). For the past 100 years, the
preparations have been successfully used to prevent recurrent
respiratory tract infections (RTIs) (34,36). Recent years have
yielded information about the pivotal role of BLs’ability to
restore Th1/Th2 balance which allows prevention and treatment
of various allergic diseases, such as asthma, AR, or AD (46–51).
Studies confirming the effectiveness of BLs in the prevention and
treatment of allergic diseases are discussed in more detail in
paragraph: clinical effects of BLs therapy.
Route and Regimens of Administration in
Allergic Diseases
BLs can be administered orally, sublingually, and intranasally in
a capsule, tablet, or spray form (29). The administration choice
should be made considering each route’sslightlydifferent
metabolic and immunomodulatory effects (36). Nevertheless,
the sublingual administration appears to be the most
promising and safest alternative, as it provides robust and
long-lasting immunity. This can possibly be attributed to the
high concentration of dendritic cells in sublingual mucosa (52).
OM-85, which represents one of PCBLs, is advised to be taken
orally with some fluid. It is available in two dosage forms.
Capsules or sachets designated for children contain 3.5 mg of
preparation, whereas adults should take 7 mg (53,54). On the
other hand, PMBLs, e.g. Ismigen is taken sublingually on an
empty stomach. Irrespective of age it is administered in a 7 mg
sublingual tablet (46). However, another PMBL, namely MV130
is a suspension prepared to be sprayed sublingually once per day
(55). In asthma therapy, the intranasal spray form of BLs appears
to be a promising option, which allows for a significant dose
reduction compared to other routes of administration (56).
The treatment plan of using BLs in the therapy of allergic
diseases is usually the same as that recommended in the
prevention of RTIs. However, as the data suggest, it can be
assumed that the period in which the therapy is started is
essential in the case of seasonal allergic diseases. For instance,
the treatment plan in seasonal AR (SAR) usually consists of
prescribing one PMBL tablet sublingually per day for 10 days
with 20 days of a break for three consecutive months, and the
treatment should preferably be started a few days before the
beginning of the pollen season (57). In a perennial AR (PAR),
the dosing regimen is the same as described above; however, it is
assumed that in this group of patients, repeating this regimen
twice per year may provide additional benefits (58). Table 1.
summarizes the BLs regimens for the prevention and treatment
of allergic diseases used in clinical trials.
INNATE IMMUNE RESPONSE
The innate immune response is a first-line of host defense against
harmful factors. It encompasses all tissues in the human body
and involves hematopoietic as well as nonhematopoietic cells.
These include DCs, neutrophils, eosinophils, macrophages, mast
cells, and NK cells. Those cells express numerous receptors that
can recognize pathogens and activate the immune response
(Figure 1)(63).
Toll-Like Receptors Activation
Toll-like receptors are dimeric proteins expressed on DCs and
monocytes. They are essential for recognition and response to
diverse microbial epitopes. Individual TLR reacts to a limited
number of pathogen-associated molecular patterns (PAMPs).
However, the whole TLR family (in humans, it comprises TLR1-
TLR10) can recognize most of them (64). Identifying TLRs
subtypes activated by BLs is an area of research.
Coviello et al. demonstrated that the immunomodulatory
effect of BLs was dependent primarily on TLR4 signaling. In
mice supplemented with BLs, the inflammatory cytokine
production was promoted, and respiratory syncytial virus
resistance was improved. Moreover, the significant role of
TLR4 in B cell maturation and antibodies production was
noted (65). However, not only TLR4 signaling pathway is
crucial in DCs activation; TLR2 may also be involved in
cytokine production induced by PCBL. Furthermore, NF-kB,
one of the key transcription factors for macrophages and
lymphocytes, was activated via TLR2 and TLR4 (32). On the
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other hand, Parola et al., in an in-vitro study, showed that PCBL
does not activate the interferon regulatory factor (IRF) pathway,
suggesting that TLR4 may not be involved in BLs recognition
and signaling (31). Duggan et al. demonstrated that BLs in mice
affected the innate lung response via TLR2/6 and TLR9 and
improved resistance against infection. They concluded that the
synergistic interaction of TLR2/6 and TLR9 supports the
antimicrobial capacity of lung epithelium and may be the basis
of new therapeutic approaches, both in inflammatory and
allergic disorders (66). The majority of studies present mainly
BLs’impact on TLRs in non-allergic disorders; nevertheless, this
knowledge may be helpful in allergy treatment.
Dendritic Cells Activation and Maturation
Dendritic cells play a significant role in the immune system. They
act as a bridge between innate and adaptive responses and
comprise an essential subset of antigen-presenting cells
necessary for antigen-specific proper T and B cell responses.
Dendritic cells migrate to secondary lymphoid tissues,
stimulating CD4+ T cells to differentiate into subtypes that
TABLE 1 | Characteristics of included studies.
First author, year of
publication (ref)
Subjects
[n]
Mean age
[years]
Intervention Treatment regimen Clinical and immunological outcomes BL
compared to control
Asthma treatment
Razi et al., 2010 (48) 75 2 OM-85
(PCBL)
vs. placebo
1x/day for 10 days each month for 3
consecutive months
↓RTIs, rate and duration of wheezing attacks
Lu et al., 2015 (37) 60 8.8 OM-85
(PCBL)
vs.
ICS
2 courses: 1x/day for 10 days each month
for 3 consecutive months
↓RTIs, frequency of asthma attacks and use of
antibiotics
↑serum NK, IL-10, IFN-g/IL-4
↓serum IL-4
Han et al., 2016 (18) 136 2.2 OM-85
(PCBL)
vs.
ICS/aminophylline/
antibiotics
1x/day for 10 days each month for 3
consecutive months
↓frequency and duration of capillary bronchitis
and asthma
↓serum IL-4, IL-17
↑serum IL-10 and IFN-g
Emeryk et al., 2018 (46)
Bartkowiak-Emeryk
et al., 2021 (57)
152 9.6 Ismigen
(PMBL)
vs.
placebo
1x/day for 10 days each month for 3
consecutive months
↓frequency and duration of asthma
exacerbations, use of reliever medications
↑time to the next asthma exacerbation
↑serum T lymphocyte, CD4+CD25+FOXP3+,
CD8+, CD3−CD16+CD56+
↓serum CD69+ and CD25+ subset of CD3+
Roßberg et al., 2020
(59)
606 5 weeks Pro-Symbioflor
vs.
placebo
3x/day for 6 months no influence on the development of asthma, AR,
AD
Nieto et al., 2021 (60) 120 2 MV130
(PMBL)
vs.
placebo
1x/day for 6 months ↓rate and duration of wheezing attacks,
symptoms, and medication scores
Allergic rhinitis treatment
Banche et al., 2007 (50) 41 29.3 Ismigen
(PMBL)
vs.
placebo
1x/day for 10 days each month for 3
consecutive months
↓symptom severity
↓serum IL-4
Koatz et al., 2016 (61) 29 40.5 1
st
year: standard
optimized care
2
nd
year:
OM-85 (PCBL)
1x/day for 10 days each month for 3
consecutive months
↓symptom severity, number of exacerbations
↑serum and salivary secretory IgA
Meng et al., 2019 (11) 60 31.3 OM-85
(PCBL)
vs.
placebo
1x/day for 10 days each month for 3
consecutive months
↓TNSS, itching score, nasal rhinorrhea score,
sneezing score
↓nasal IL-4, IL-13, eosinophils concentrations
↑nasal INF-g
Janeczek et al., 2021
(41)
70 9.2 Ismigen
(PMBL)
vs.
placebo
1x/day for 10 days each month for 3
consecutive months
↓TNSS, nVAS
↑PNIF
↓number of eosinophils in nasal swabs
Atopic dermatitis treatment
Bodemer et al., 2017
(62)
170 2 OM-85
(PCBL)
vs.
placebo
1x/day for 9 months ↓number of new flares
AD, atopic dermatitis; ICS, inhaled corticosteroid; nVAS, visual analogue scale for nasal symptoms; PCBL, polyvalent chemical bacterial lysate; PMBL, polyvalent mechanical bacterial
lysate; PNIF, peak nasal inspiratory flow; RTIs, respiratory tract infections; TNSS, total nasal symptom score. ↓, decerase; ↑, increase.
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depend on the nature of the activation signal and released
cytokines (67,68). Moreover, they can produce numerous
mediators which activate B cells and promote antiviral
response (69).
However, DCs need to maturate to achieve those abilities
properly. Firstly, they have to be activated by binding a ligand by
a specific TLR. Secondly, they migrate to lymph nodes and
present the antigen to T cells and transmit activation signals
via receptors on the surface of T cells: TCR (T cell receptor),
CD28, and CD40L (70). Zelle-Rieser et al. suggest that BLs
induce the terminal maturation of CD83+ DCs and their
ability to stimulate T cells (71). Accordingly, other animal and
in-vitro studies show a dose-dependent increase in the surface
expression of MHC II, CD40, and CD86 on DCs populations due
to the BLs supplementation (72,73).
Numerous pathways lead mature DCs to affect innate
immune response by producing antiviral cytokines. As
mentioned before, BLs activate NF-kB and MAPK dependent
pathways, which leads to IFN-a, IFN-b, and IL-8 production by
DCs (31). Similarly, Dang et al. observed that PCBL can induce
DCs to IFN-bproduction in a TLR adaptors Trif- and MyD88-
dependent manner (74). In mice sensitized to ovalbumin and
supplemented with BLs, enhanced IFN-gproduction was
observed (42). Similar findings were made by Bowman et al.,
who noted the increase in IFN-glevels in rats who received orally
OM-85 (39). Respectively, serum level of IFN-gincreased while
IL-4 decreased in children with bronchiolitis treated with BLs.
However, the research demonstrated decreased levels of NF-kB;
thus, BLs’impact on this molecule remains unexplained (75).
Ruth et al. who examined the impact of two different BLs,
consisting of different bacterial antigens, demonstrated in their
in-vitro study that OM-85 induced the secretion of IFN-b. At the
same time, Pulmonarom did not achieve similar results, which
allows us to conclude that BLs’composition significantly impacts
the treatment outcome (76).
Antiviral Cytokines Release
Activated DCs produce a plethora of cytokines that stimulate
cells involved in the innate immune response. IFN-ghas a
pleiotropic action in allergic disorders. As a mediator typical
for type 1 of the innate immune response, it protects against
intracellular pathogens through mononuclear phagocytes
activation. Meng et al. demonstrated that the level of IFN-g
was substantially increased in the group of AR patients treated
with PCBL (11). The meta-analysis also confirms this based on
19 studies evaluating bacterial lysate treatment in allergic
patients, which showed a significant increase of IFN-gafter the
supplementation with BLs (77). Lu et al. demonstrated similar
effects; however, the authors concluded that the improvement in
the asthma course was stimulated by the decrease of Th2-type
cytokines rather than by the increase of IFN-g(37). On the other
hand, BLs can also reduce the levels of IFN-g, which results in
restricted mucosal inflammation. However, this phenomenon
was observed in mice with experimental chronic rhinosinusitis;
thus, comparing the results with the allergic ones may be
troublesome (78).
BLs have some impact on the members of the IL-12 family. It
consists of IL-12, IL-23, IL-27 and IL-35. IL-12 promotes Th1
FIGURE 1 | Immunomodulatory effects of bacterial lysates. BLs stimulate immune response via numerous pathways. They activate DCs via TLR2/6 and TLR9.
Mature DCs produce cytokines that stimulate Th1 lymphocytes, macrophages and NK cells. Furthermore, they promote CD4+ lymphocytes to differentiate into Th1
and Treg subtypes and activate B cells to secrete IgA and IgG1. Created with BioRender.com.
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differentiation and IFN-gproduction, while IL-23 enhances Th17
response; IL-27 and IL-35 are mostly involved in regulating the
number and function of T regulatory cells (both Treg and Tr1)
(79). Byl et al. suggest that OM-85 involves the induction of IL-
12 secretion by accessory cells (80). Similar findings were made
by Lanzilli et al., who demonstrated a favorable impact of PMBL
on IL-12 level in the in-vitro study (81). The aforementioned
meta-analysis showed that the levels of IL-12 were increased after
the treatment with BLs; however, only 2 out of 19 enrolled
studies examined this phenomenon (77). On the other hand, in
the in-vitro study by Parola et al., the expected positive impact of
PCBL on IL-12 and IL-23 levels was not reached (31).
IL-10 is an important regulatory cytokine required to control
allergic diseases. It can act directly on Th2 cells, regulating the
survival of these cells and the severity of Th2-mediated allergic
airway inflammation. Studies in asthmatic children have shown a
significant increase in serum IL-10 concentration after BLs
(18,37).
Human beta-defensin-1 (hbD-1) is one of the essential
antimicrobial peptides in epithelial tissues. It can promote DCs
maturation via TLRs and inhibit the infectivity of multiple
viruses (82). Liao et al. observed a significant increase in hbD-
1 levels after PCBL supplementation in children with asthma and
recurrent RTIs (83). Similar findings were made by Roth et al.,
who examined the impact of PCBL on bronchial epithelial cells
infected with rhinovirus (84).
Macrophages and NK Cells Activation
Macrophages are the most abundant immune cells that play a
pivotal role in environmental allergen-induced airway
inflammation in asthma and AR (85). What is important, they
are a heterogenous population and divide into two subtypes: M1
macrophages induced by IFN-gand M2 macrophages promoted
by IL-4 and IL-13. Noticeably, they mirror the Th1/Th2
polarization; thus, distinguishing between activated subtypes is
crucial while examining the impact of the BLs (86). Luan et al.
demonstrated a positive impact of PCBL on murine
macrophages activity via IFN-g,TNF-a,IL-1b,andIL-6,
which promoted the M1 subtype (32). PCBLs can act as a
macrophage activator, promoting NO production and the
translocation of NF-kB into the nucleus in murine bone
marrow-derived macrophages (42).
NK cells are a subset of lymphocytes that principally
participate in innate immunity by cytokine production,
cytotoxicity, and activation of other cells. Notably, just like
macrophages, they are divided into two subtypes that reflect
the Th1/Th2 balance (87). IL-12 and IL-18 promoted by BLs
stimulate NK1 polarization, which results in enhanced IFN-g
secretion and IgE production suppression (88). The study by
Bartkowiak-Emeryk et al. showed an increase of NK cells in
asthmatic children sublingually treated with PMBL (57).
Moreover, DCs exposed to PCBL released increased levels of
CCL2 and CCL3, chemokines important for chemoattraction of
monocytes and NK cells (31). Migration of NK cells to inflamed
tissue is vital for eliminating cells infected by viruses. This, in
turn, leads to a decrease in the ratio of RTIs and thus to a
reduction in the severity of the symptoms of allergic diseases.
ADAPTIVE IMMUNE RESPONSE
The adaptive immune response has a broader and more finely
tuned repertoire of recognition for antigens than the innate
response. It involves a particular interplay between antigen-
presenting cells (APCs) and T and B lymphocytes resulting in
effective pathogen-specificimmunologiceffectorpathways.
Moreover, it has a tremendous impact on the host immune
homeostasis and immunologic memory (89). Such a variety of
immune responses depends on the differentiation of naïve CD4+
T cells towards Th1, Th2, Th17, or Treg lymphocytes (90).
Figure 2 explains the immunomodulatory impact of BLs on
restoring Th1/Th2 balance.
Th1 Type Immune Response Promotion
Th1 cells promote the type-1 pathway known as ‘cellular
immunity’characterized by fighting against viruses and other
intracellular pathogens, eliminating cancerous cells, and
stimulating delayed-type hypersensitivity skin reactions (91).
In response to an in-situ immunological stimulation, DCs
present antigens to naïve lymphocytes and produce IL-12 to
enhance their differentiation into specificTh1cells(90).
Furthermore, IFN-greleased by active NK cells, other CD4+,
and CD8+ lymphocytes shows the same effect (92). Therefore,
multiple animal studies and clinical trials examined the BLs’
impact on Th1 type immune response. In most of them, levels of
IL-12 and IFN-gwere measured to conclude about said changes
in Th1/Th2 balance. As mentioned in paragraph 4.3., BLs
significantly increase the release of IFN-gand IL-12; thus, their
positive impact on Th1 type immune response remains valid (11,
41,42,77,80,81).
Th2 Type Immune Response Inhibition
Th2 cells are lymphocytes whose high levels are specific for
allergic disorders. They produce IL-3, IL-4, IL-5, IL-9, and IL-13
and stimulate type 2 immunity, characterized by high antibody
titers and eosinophilia. This phenomenon is characteristic of AR
in the upper respiratory tract, asthma in the lower respiratory
tract, and atopic dermatitis in the skin; thus, restoring the said
type of immunity acts to be an effective way of their treatment
(93,94). IL-4 was significantly downregulated in animal models
after the treatment with BLs (39,42,95). Similar findings were
made in patients with allergic disorders, in whom the decrease in
IL-4 levels was accompanied by the improvements in the clinical
courses of these diseases (11,37,50). Accordingly, IL-13
concentration was reduced in both animals and humans (11,
95,96). IL-5 levels were measured only in murine models, and
studies demonstrated that BLs cause their significant decreases
(95,96).
Both PMBL and PCBL seem to be effective in lowering
eosinophil counts in blood and nasal and bronchoalveolar
lavage fluids. Janeczek et al. investigated the PMBL’s impact on
the clinical course of AR in children. They showed that
sublingual administration of the drug resulted in decreased
eosinophil count in nasal smears (41,57). PCBL tested in adult
patients and in murine models reduces eosinophil infiltration in
nasal mucosa and lungs (11,97). However, in the study by
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Rodrigues et al., PCBL did not reduce pulmonary eosinophilia;
thus, it may not inhibit the development of asthma in a mice
model. On the other hand, a significant reduction of IL-5 and IL-
13 in bronchoalveolar lavage fluid was noted (96). Bearing in
mind that most research proved that BLs reduce levels of IL-4,
IL-5, IL-13, and eosinophils, we can presume they have a positive
impact on Th2 type response decrease.
Tregs Activation
Regulatory T cells are subsets of CD4+ T cells that modulate the
immune response, maintain tolerance to self-antigens, and
prevent autoimmune diseases. They stem from CD4+ T cells
which acquired CD25 and FOXP3 molecules because of
weak self-antigen specificity (98). In a murine asthma model,
oral administration of PCBL induced an increase in the number
of CD4+CD25+FOXP3+ lymphocytes in intestinal lamina
propria and respiratory tract mucosa (99). Similar findings
showed a study that examined PMBL’s impact on Treg cells.
CD4+CD25+FOXP3+ lymphocytes significantly increased in
asthmatic children treated sublingually with Ismigen (57). The
mechanism of Treg cells’action is complicated and
multidirectional. Among others, they suppress the proliferation
and maturation of Th2 cells; thus, their activation seems to be
effective in allergy treatment.
B Cells Activation
B cells, along with T cells, are two major cell subsets involved in
adaptive immunity. Once activated, B cells maturate into
antibody-secreting plasma cells. Initially, plasma cells produce
IgM class antibodies, but eventually, they switch to IgA, IgG, or
IgE. This process in part depends on the cytokine milieu e.g. IL-4
and IL-13 promote the switch to IgE, while IL-10 and IFN-g
promote IgA and IgG1. As mentioned before, allergic disorders
are characterized by high IgE levels; thus, the direction in which
Ig-switch goes may lead either to allergy amelioration or
worsening (100). BLs seem to improve the immunoglobulin
profile in asthma and AR. Huber et al. demonstrated a
decrease of both total and asIgE in mice orally treated with
PCBL (42). Furthermore, in rat model of food allergy, animals
treated with BLs presented a significant decrease of asIgE (101).
On the other hand, asIgE levels did not decrease after the PMBL
therapy in children with SAR. However, in a placebo group, a
significant increase was observed; thus, the positive impact of the
mixture was achieved (41). IgA protects against microbes on
epithelial barriers as the main immunoglobulin associated with
mucosal membranes. Koatz et al. demonstrated a significant
increase in serum and salivary secretory IgA in patients with
asthma, AR, and chronic obstructive pulmonary disease after
PCBL supplementation (61). Furthermore, BLs seem to
positively impact IgA levels in children with bronchiolitis and
recurrent RTIs associated with immunoglobulins deficiency (75,
102). Similarly, IgG1 levels rise after the BLs supplementation,
even in patients with IgG deficiencies, and enable them to reach
the average age levels of these immunoglobulins (103).
THE ROUTE OF ADMINISTRATION OF BLS
AND IMMUNOLOGICAL EFFECTS
As described before, BLs can be administered in three ways, each
having specific implications on the immune system.
BLs can be administered orally (53). It is claimed that this
route of administration promotes a reorganization of the gut and
lung microbiota by maintaining immune homeostasis through
the gut-lung axis (104). The process starts with bacterial extracts
sampled by microfold cells, followed by gastrointestinal
absorption to Peyer patches that are part of gut lymphoid
tissue. This leads to antigen presentation to the mucosal DCs
(105). Consequently, the antigen-specific T and B lymphocytes
are stimulated; this process is partly modulated by cytokines:
TGF-band members of the tumor necrosis factor family (34,
FIGURE 2 | The Th1/Th2 balance restoration. Bacterial lysates act like immunomodulators and provide the maintenance of violated Th1/Th2 balance. By stimulating
dendritic cells, they activate the production of numerous cytokines that weaken Th2 type response and enhance Th1 type response. The said restoration leads to
allergy symptoms amelioration. Created with BioRender.com.
Kaczynska et al. Immunomodulatory Effects of Bacterial Lysates
Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 9071497
106). In the end, B-cell isotype switching to IgA occurs (107).
Because of described processes, the flow of the immune cells
begins (32,108). Activated DCs, lymphocytes, and lymphoblasts
begin their migration to the mesenteric lymph nodes, through
which they enter the blood system to eventually locate in distant
mucosa lymphoid tissue (107). This migration enhances the
defense against pathogens by stimulating pathogen cells and
increasing not only IgA concentrations, but also IgA-producing
plasma cells (53,109). Thus, BLs administered orally play a
pivotal role in the mucosal immune response.
Plasma cells can be found within nasal tissues; they secrete
antibodies, especially IgA (110). What is more, they can produce
antimicrobial peptides (AMPs), which protect the airway
epithelium from colonization (111). BLs administered
intranasally are found to induce the production of one specific
AMP, hbD-2. The process is linked to the stimulation of TLRs,
which interact with intranasal macrophages and DCs by the
bacterial molecule compounds of lysates (112,113). Moreover,
there is evidence that stimulation of intranasal tissues in mice by
BLs leads to interaction with several pattern recognition
receptors (PRRs) and engagagement of effector cells directly on
the epithelial surfaces, which plays a role as a ‘pre-alert scenario’
that prevents further respiratory infection and allows for
immediate elimination of pathogens (106,114). Animal studies
also show that airway administration of BLs can cause an acute
inflammatory response that lasts a minimum of 7 days (115).
It is believed that the sublingual route of BLs administration,
in particular those obtained with mechanical lysis, may result in
better clinical efficacy. It has been provided by a study by La
Mantia et al. on a group of 120 children with nasopharyngitis or
otitis media. Researchers demonstrated greater protective
efficacy of sublingual PMBL than oral PCBL (116). This route
of delivery is associated with systemic Th1 responses, increases in
IgG with decreases in IgE concentrations, as well as attenuation
of eosinophil recruitment (10,81). It is emphasized that the
sublingual administration provides a specific-humoral and cell-
mediated immunity that lasts up to 4 months after the last
immunization. A strong and sustained immune response to
pathogens is possible thanks to generation and stimulation
antigen-specific memory CD4+ and CD8+ cells (117,118).
Moreover, due to the high concentration of DCs observed in
sublingual mucosa, PAMPs can be presented and recognized by
PRRs more effectively (119). Studies confirm that mucosal DCs
interact with lipopeptide antigens more eagerly than
macrophages; thus, enabling an innovative noninvasive vaccine
option not requiring any additional adjuvants (120).
Furthermore, smaller doses of BLs are necessary when
administered sublingually, hence the absence of medicament’s
neutralization with gastric acidity (121). One encouraging benefit
is excellent compliance with sublingual bacterial lysate therapy in
all children, even the youngest (122).
CLINICAL EFFECTS OF BLS THERAPY
Numerous studies proved BLs’efficacy in treating not only
recurrent RTIs but also various allergic diseases (77).
As aforementioned, thanks to their ability to induce both
humoral and cellular immunity, bacterial preparations restore
the immune imbalance at the core of allergic pathogenesis (18).
Here we describe and analyze the impact of BLs on the
prevention and treatment of asthma, AR, and AD with
particular consideration of pediatric patients (Table 1).
Asthma
Razi and colleagues assessed the effect of PCBL in preventing
wheezing attacks induced by acute respiratory illnesses in 75
preschool children with recurrent wheezing. Patients were
treated for 3 consecutive months with OM-85 or a placebo
following the typical regimen. Then they were followed up for
9 months. It has been shown that OM-85 significantly reduced
the rate and duration of wheezing attacks. In addition, this study
also reported a reduction of RTIs, which was considered to be
most likely to explain the observed reduction in wheezing
attacks (48).
In 2015 Lu et al. presented the results of a study that they
conducted in order to assess the effect of OM-85 combined with
conventional treatment on the course of asthma in children.
Sixty patients were included in the study and divided into two
groups, one treated with PCBL in combination with inhaled
corticosteroid (ICS), the second only with ICS. In the PCBL-
treated group, there was a significant reduction of RTIs, the
frequency of asthma attacks, and antibiotic therapy (37).
Another study was conducted by Han et al., who focused on
the effects of BLs therapy on capillary bronchitis secondary
bronchial asthma. They enrolled 136 children who were
divided into two groups, the control one (n=62) treated with
ICS, aminophylline, and antibiotics, and the observation one
(n=74) additionally receiving OM-85 orally. The follow-up
period was set out for 12 months. The results in the PCBL
group presented a significant decline in the frequency and
duration of capillary bronchitis and asthma compared to the
control group (18).
A randomized, double-blind, placebo-controlled study
conducted by Emeryk et al. enrolled 152 children divided into
the placebo group and the observation group undergoing PMBL
therapy. The trial lasted 9 months, and its’results indicated a
significant reduction in the frequency and duration of asthma
exacerbations and in the use of reliever medications in the PMBL
group vs. placebo group. This intervention also prolonged the
time to the next exacerbation (46). Laboratory results from this
study were presented in 2021 by Bartkowiak-Emeryk et al.
(Table 1)(57).
Roßberg et al. conducted a randomized, placebo-controlled
study to evaluate the effect of oral BLs administered in infancy on
the risk of developing AD, AR, and asthma. The study enrolled
606 infants with a family history of allergic diseases, 402 of which
were followed until reaching the school age of 6-11 years. The
observation group was treated with orally applied BLs three
times daily from 5 weeks to 7 months of life, with the placebo
group adequately following the same regimen. BLs have not been
shown to reduce the risk of allergic diseases, for instance asthma
was diagnosed in 9% of patients in the observation group and in
6.6% of patients in the placebo group (59).
Kaczynska et al. Immunomodulatory Effects of Bacterial Lysates
Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 9071498
In 2021 Nieto et al. presented the results of a randomized,
double-blind, placebo-controlled study in which they assessed
the efficacy and safety of MV130 in preventing wheezing attacks
in children. However, it should be mentioned that patients with
allergies were excluded from this trial. The whole study lasted 12
months, with 6 months of treatment plus 6 additional months of
follow-up. There was a significant reduction in the number of
wheezing attacks in the observation group, and a reduction in
symptoms and medication scores compared to the placebo
group. Moreover, a high safety profile of this therapy has been
demonstrated (60).
Finally, the ORBEX study, a large, multicenter, randomized,
double-blind, placebo-controlled study, iscurrently ongoing in the
USA. The study enrolls children aged 6-18 months presenting a
high risk of asthma development (diagnosed with AD and/or with
a family history of asthma). The main objective of this study is to
assess whether OM-85 given for 10 days per month for two
consecutive years can extend the time to the first episode of
wheezing or lower respiratory tract illness during a three-year
observation period without therapy. According to data available
on clinicaltrials.gov, the study is expected to end in 2025 (123).
Literature data indicate that therapy with BLs does not have a
preventive effect on the occurrence of asthma, but it reduces the
frequency of exacerbations in patients already diagnosed with asthma.
Allergic Rhinitis
In 2007 Banche et al. conducted a trial to assess the PMBLs’
influence on the clinical manifestations of AR. 41 patients with
SAR and PAR were enrolled and randomly assigned to the
observation group (n=26) and the placebo group (n=15). The
participants were administered either placebo or PMBL for 10
days each month for 3 consecutive months, with no other
antiallergic drugs. Eventually, the results showed significant
alleviation of symptoms in the observation group with the
decrease of nasal congestion, rhinorrhea, and ocular symptoms (50).
To further expand the research, Meng et al. evaluated the
clinical effects of OM-85 in 60 patients with PAR. The
participants were randomly assigned to the PCBL group
(n=30) and the placebo group (n=30), with an average age of
33 and 29 years, respectively. Both groups followed the regimen
of oral administration in 3 cycles consisting of consecutive 10
days of intake followed by a 20-days break. Clinical symptoms
were measured at baseline, immediately after the third cycle of
PCBL, and 4 and 8 weeks after the end of treatment. In the end,
the PCBL group presented a significant decrease in medication
score, a drop in the total nasal symptom scores, itching score,
nasal rhinorrhoea score, and sneezing score (11).
In 2021 Janeczek et al. presented the results of a double-blind,
placebo-controlled study investigating the impact of PMBL on
children with grass pollen-induced AR. The study included 70
patients aged 5-17 years who were randomly assigned to the
observation and placebo groups. The numerous measured
parameters included the total nasal symptom score, total
ocular symptom score, visual analogue scale, and peak nasal
inspiratory flow. The observation group received a PMBL tablet
sublingually once per day in the fasting state on the first 10 days
of each month for 3 months. Consistently, the placebo group
followed the same regimen. Finally, the PMBL group showed a
significant decrease in total nasal symptom score, visual analogue
scale for nasal symptoms, as well as a significant increase in peak
nasal inspiratory flow compared with the placebo group (41).
What is more, Koatz et al. presented an open-label, sequential
study concerning the implications of OM-85 on RTIs in patients
with AR, asthma, or chronic obstructive pulmonary disease. The
included 84 patients were between the ages of 16-65 years and
were administered OM-85 orally for 10 days per month, for 3
months, with a 6-month follow-up. Before the study, patients
received only standardized optimized care for one year. In the
end, the observation group showed a decrease in the frequency of
RTIs and primary disease exacerbation rates (61).
Based on the above-mentioned studies, BLs appear to be a
promising therapeutic option for AR patients, including those
with SAR and PAR.
Atopic Dermatitis
As mentioned before, the use of oral BLs in early infancy over 6
months does not affect the development of AD at school age (59).
In 2017 Bodemer et al. presented the results of the study
concerning the clinical efficacy of OM-85 in the treatment of
children with AD. One hundred seventy patients were enrolled
in the study. Apart from conventional therapy with emollients
and topical corticosteroids, the participants took one capsule of
OM-85 or a placebo daily for 9 months. The results confirmed
BLs efficacy, as patients in the observation group had
significantly fewer and delayed new flares (62).
We have to conclude that there is an urgent need for high-
quality and large sample size studies on the clinical efficacy of
BLs with different bacterial antigen compositions, methods of
preparation, and routes of administration.
CONCLUSIONS
As common as allergic disorders are, there is yet to know about their
exact pathogenesis and indications. With an escalating prevalence, it
is crucial to thoroughly clarify the individual predispositions
and risk factors for atopic diseases development. Although various
burdensome clinical manifestations characterize the heterogeneous
group of allergies, the search for an effective, inclusive, and
noninvasive treatment continues to last.
BLs promise new therapeutic possibilities in AD, AR, and
asthma; however, their exact effects are not fully elucidated.
Various clinical effects are observed with the main differences
in PCBLs and PMBLs’obtainment. As stated before, PCBLs
present reduced immunogenicity due to protein denaturation.
PMBLs, on the other hand, are known to induce a better immune
response. Further differences among preparations are caused by
the diversity of bacteria species used to obtain the mixture. Little
is currently known about the exact impact of specific antigens on
the immune response; thus, further research is still needed.
Our paper shows a significant indissolubility between innate
and adaptive responses. BLs act as immunomodulators and
promote DCs’activation and maturation via TLR 2/6 and TLR
Kaczynska et al. Immunomodulatory Effects of Bacterial Lysates
Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 9071499
9. Stimulated DCs produce multiple cytokines that affect innate
and adaptive responses; thus, they appear to be a bridge between
them. Indeed, the enhanced innate immune response plays a vital
role as the first-line defense against pathogenic agents, which
allows the host to tackle atopic reactions and maintain
homeostasis. IFN-gand IL-12 deserve special attention, as they
promote macrophage and NK cell development along with Th1
and Treg lymphocytes differentiation. Furthermore, B cells
activation and IgA and IgG1 secretion provoked by IL-6 and
IL-10 lead to allergy symptoms reduction. Finally, Th2
lymphocyte diminution is a significant sign of allergy restriction.
On the other hand, the mentioned immunological outcomes may
vary according to the way of BLs administration. That being said, the
sublingual route of administration, in particular the preparations
obtained by the mechanical lysis, seems to be the most effective;
however, this hypothesis is not entirely proven. Furthermore, the
other medications’influence on BLs action is still under research, as
the examined interactions regard mostly antiallergic
preparations. The results of the studies indicate a beneficial effect of
BLstherapyontheclinicalcourseofallergicdiseases.Furthermore,it
is extremely important to identify those patients who may
significantly benefit from this therapy. Notwithstanding, the exact
number of high-quality RCTs remains insufficient. Furthermore,
they vary in study design and patients’clinical picture; thus,
comparing their findings is troublesome.
To sum up, BLs are promising immunomodulators that may
change therapeutic approaches to allergic diseases. Nevertheless,
more rigorous and detailed trials are demanded to draw definitive
conclusions about the efficacy of BLs in terms of atopic diseases’
prevention and treatment.
AUTHOR CONTRIBUTIONS
AK contributed to the conception and design of the work,
acquired, and analyzed of references for the work, wrote the
first draft the manuscript; MK contributed to the conception
and design of the work, acquired, and analyzed of references for
the work; wrote the first draft the manuscript; KJ contributed to
the conception and design of the work;, acquired, and analyzed
of references for the work, drafting the work or revising it
critically for important intellectual content; MZ contributed to
the conception and design of the work;, acquired, and analyzed
of references for the work, drafting the work or revising it
critically for important intellectual content; AE contributed to
the conception and design of the work;, acquired, and analyzed
of references for the work, drafting the work or revising it
critically for important intellectual content. All authors
contributed to the article and approved the submitted version.
FUNDING
The authors declare that this study received funding from Celon
Pharma. The funder was not involved in the study design,
collection, analysis, interpretation of data, the writing of this
article or the decision to submit it for publication.
REFERENCES
1. Wong GWK, Li J, Bao YX, Wang JY, Leung TF, Li LL, et al. Pediatric Allergy
and Immunology in China. Pediatr Allergy Immunol (2018) 29(2):127–32.
doi: 10.1111/pai.12819
2. Yang L, Fu J, Zhou Y. Research Progress in Atopic March. Front Immunol
(2020) 11:1907. doi: 10.3389/fimmu.2020.01907
3. Wong GW, Li ST, Hui DS, Fok TF, Zhong NS, Chen YZ, et al. Individual
Allergens as Risk Factors for Asthma and Bronchial Hyperresponsiveness in
Chinese Children. Eur Respir J (2002) 19(2):288–93. doi: 10.1183/
09031936.02.002319.02
4. Spergel JM. From Atopic Dermatitis to Asthma: The Atopic March. Ann Allergy
Asthma Immunol (2010) 105(2):99–106. doi: 10.1016/j.anai.2009.10.002
5. van der Hulst AE, Klip H, Brand PL. Risk of Developing Asthma in Young
Children With Atopic Eczema: A Systematic Review. J Allergy Clin Immunol
(2007) 120(3):565–9. doi: 10.1016/j.jaci.2007.05.042
6. Haapakoski R, Karisola P, Fyhrquist N, Savinko T, Lehtimäki S, Wolff H, et al.
Toll-Like Receptor Activation During Cutaneous Allergen Sensitization Blocks
Development of Asthma Through Ifn-Gamma-Dependent Mechanisms. JInvest
Dermatol (2013) 133(4):964–72. doi: 10.1038/jid.2012.356
7. Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, et al.
Randomized Trial of Peanut Consumption in Infants at Risk for Peanut
Allergy. N Engl J Med (2015) 372(9):803–13. doi: 10.1056/NEJMoa1414850
8. Katz Y, Rajuan N, Goldberg MR, Eisenberg E, Heyman E, Cohen A, et al.
Early Exposure to Cow’s Milk Protein Is Protective Against Ige-Mediated
Cow’s Milk Protein Allergy. J Allergy Clin Immunol (2010) 126(1):77–82.e1.
doi: 10.1016/j.jaci.2010.04.020
9. Lannero E, Wickman M, van Hage M, Bergstrom A, Pershagen G, Nordvall
L. Exposure to Environmental Tobacco Smoke and Sensitisation in
Children. Thorax (2008) 63(2):172–6. doi: 10.1136/thx.2007.079053
10. Esposito S, Soto-Martinez ME, Feleszko W, Jones MH, Shen KL, Schaad UB.
Nonspecific Immunomodulators for Recurrent Respiratory Tract Infections,
Wheezing and Asthma in Children: A Systematic Review of Mechanistic and
Clinical Evidence. Curr Opin Allergy Clin Immunol (2018) 18(3):198–209.
doi: 10.1097/ACI.0000000000000433
11. Meng Q, Li P, Li Y, Chen J, Wang L, He L, et al. Broncho-Vaxom Alleviates
Persistent Allergic Rhinitis in Patients by Improving Th1/Th2 Cytokine Balance
of Nasal Mucosa. Rhinology (2019) 57(6):451–9. doi: 10.4193/Rhin19.161
12. Di Cicco M, D’Elios S, Peroni DG, Comberiati P. The Role of Atopy in
Asthma Development and Persistence. Curr Opin Allergy Clin Immunol
(2020) 20(2):131–7. doi: 10.1097/ACI.0000000000000627
13. Stern J, Pier J, Litonjua AA. Asthma Epidemiology and Risk Factors. Semin
Immunopathol (2020) 42(1):5–15. doi: 10.1007/s00281-020-00785-1
14. Feldman AS, He Y, Moore ML, Hershenson MB, Hartert TV. Toward
Primary Prevention of Asthma. Reviewing the Evidence for Early-Life
Respiratory Viral Infections as Modifiable Risk Factors to Prevent
Childhood Asthma. Am J Respir Crit Care Med (2015) 191(1):34–44.
doi: 10.1164/rccm.201405-0901PP
15. Stein MM, Hrusch CL, Gozdz J, Igartua C, Pivniouk V, Murray SE, et al.
Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children.
N Engl J Med (2016) 375(5):411–21. doi: 10.1056/NEJMoa1508749
16. Frew JW. The Hygiene Hypothesis, Old Friends, and New Genes. Front
Immunol (2019) 10:388. doi: 10.3389/fimmu.2019.00388
17. Morandi B, Agazzi A, D’Agostino A, Antonini F, Costa G, Sabatini F, et al. A
Mixture of Bacterial Mechanical Lysates Is More Efficient Than Single Strain
Lysate and of Bacterial-Derived Soluble Products for the Induction of an
Activating Phenotype in Human Dendritic Cells. Immunol Lett (2011) 138
(1):86–91. doi: 10.1016/j.imlet.2011.03.006
18. Han RF, Li HY, Wang JW, Cong XJ. Study on Clinical Effect and
Immunologic Mechanism of Infants Capillary Bronchitis Secondary
Kaczynska et al. Immunomodulatory Effects of Bacterial Lysates
Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 90714910
Bronchial Asthma Treated With Bacterial Lysates Broncho-Vaxom. Eur Rev
Med Pharmacol Sci (2016) 20(10):2151–5.
19. Blumenthal MN. Genetic, Epigenetic, and Environmental Factors in Asthma
and Allergy. Ann Allergy Asthma Immunol (2012) 108(2):69–73.
doi: 10.1016/j.anai.2011.12.003
20. Ruan Z, Shi Z, Zhang G, Kou J, Ding H. Asthma Susceptible Genes in
Children: A Meta-Analysis. Med (Baltimore) (2020) 99(45):e23051.
doi: 10.1097/MD.0000000000023051
21. Chen F, Lin Z, Chen R, Norback D, Liu C, Kan H, et al. The Effects of Pm2.5
on Asthmatic and Allergic Diseases or Symptoms in Preschool Children of
Six Chinese Cities, Based on China, Children, Homes and Health (Cchh)
Project. Environ pollut (2018) 232:329–37. doi: 10.1016/j.envpol.2017.08.072
22. Thurston GD, Balmes JR, Garcia E, Gilliland FD, Rice MB, Schikowski T,
et al. Outdoor Air Pollution and New-Onset Airway Disease. Off Am Thorac
Soc Workshop Rep Ann Am Thorac Soc (2020) 17(4):387–98. doi: 10.1513/
AnnalsATS.202001-046ST
23. Huff RD, Carlsten C, Hirota JA. An Update on Immunologic Mechanisms in
the Respiratory Mucosa in Response to Air Pollutants. J Allergy Clin
Immunol (2019) 143(6):1989–2001. doi: 10.1016/j.jaci.2019.04.012
24. Edwards MR, Walton RP, Jackson DJ, Feleszko W, Skevaki C, Jartti T, et al.
The Potential of Anti-Infectives and Immunomodulators as Therapies for
Asthma and Asthma Exacerbations. Allergy (2018) 73(1):50–63.
doi: 10.1111/all.13257
25. Yin J, Xu B, Zeng X, Shen K. Broncho-Vaxom in Pediatric Recurrent
Respiratory Tract Infections: A Systematic Review and Meta-Analysis. Int
Immunopharmacol (2018) 54:198–209. doi: 10.1016/j.intimp.2017.10.032
26. Bessler WG, Vor dem Esche U, Masihi N. The Bacterial Extract Om-85 Bv
Protects Mice Against Influenza and Salmonella Infection. Int
Immunopharmacol (2010) 10(9):1086–90. doi: 10.1016/j.intimp.2010.06.009
27. Suarez N, Ferrara F, Rial A, Dee V, Chabalgoity JA. Bacterial Lysates as
Immunotherapies for Respiratory Infections: Methods of Preparation. Front
Bioeng Biotechnol (2020) 8:545. doi: 10.3389/fbioe.2020.00545
28. Jurkiewicz D, Zielnik-Jurkiewicz B. Bacterial Lysates in the Prevention of
Respiratory Tract Infections. Otolaryngol Pol (2018) 72(5):1–8. doi: 10.5604/
01.3001.0012.7216
29. Cazzola M, Anapurapu S, Page CP. Polyvalent Mechanical Bacterial Lysate
for the Prevention of Recurrent Respiratory Infections: A Meta-Analysis.
Pulm Pharmacol Ther (2012) 25(1):62–8. doi: 10.1016/j.pupt.2011.11.002
30. Ferrara F, Rial A, Suarez N, Chabalgoity JA. Polyvalent Bacterial Lysate
Protects Against Pneumonia Independently of Neutrophils, Il-17a or
Caspase-1 Activation. Front Immunol (2021) 12:562244. doi: 10.3389/
fimmu.2021.562244
31. Parola C, Salogni L, Vaira X, Scutera S, Somma P, Salvi V, et al. Selective
Activation of Human Dendritic Cells by Om-85 Through a Nf-Kb and Mapk
Dependent Pathway. PLos One (2013) 8(12):e82867. doi: 10.1371/
journal.pone.0082867
32. Luan H, Zhang Q, Wang L, Wang C, Zhang M, Xu X, et al. Om85-Bv
Induced the Productions of Il-1beta, Il-6, and Tnf-Alpha Via Tlr4- and Tlr2-
Mediated Erk1/2/Nf-Kappab Pathway in Raw264.7 Cells. JInterferon
Cytokine Res (2014) 34(7):526–36. doi: 10.1089/jir.2013.0077
33. Evans SE, Scott BL, Clement CG, Larson DT, Kontoyiannis D, Lewis RE,
et al. Stimulated Innate Resistance of Lung Epithelium Protects Mice
Broadly Against Bacteria and Fungi. Am J Respir Cell Mol Biol (2010) 42
(1):40–50. doi: 10.1165/rcmb.2008-0260OC
34. Kearney SC, Dziekiewicz M, Feleszko W. Immunoregulatory and
Immunostimulatory Responses of Bacterial Lysates in Respiratory
Infections and Asthma. Ann Allergy Asthma Immunol (2015) 114(5):364–
9. doi: 10.1016/j.anai.2015.02.008
35. Le Souef P. Viral Infections in Wheezing Disorders. Eur Respir Rev (2018) 27
(147). doi: 10.1183/16000617.0133-2017
36. de Boer GM, Zolkiewicz J, Strzelec KP, Ruszczynski M, Hendriks RW,
Braunstahl GJ, et al. Bacterial Lysate Therapy for the Prevention of
Wheezing Episodes and Asthma Exacerbations: A Systematic Review and
Meta-Analysis. Eur Respir Rev (2020) 29(158). doi: 10.1183/16000617.0175-
2019
37. Lu Y, Li Y, Xu L, Xia M, Cao L. Bacterial Lysate Increases the Percentage of
Natural Killer T Cells in Peripheral Blood and Alleviates Asthma in
Children. Pharmacology (2015) 95(3-4):139–44. doi: 10.1159/000377683
38. Roth M, Block LH. Distinct Effects of Broncho-Vaxom (Om-85 Bv) on
Gp130 Binding Cytokines. Thorax (2000) 55(8):678–84. doi: 10.1136/
thorax.55.8.678
39. Bowman LM, Holt PG. Selective Enhancement of Systemic Th1 Immunity in
Immunologically Immature Rats With an Orally Administered Bacterial
Extract. Infect Immun (2001) 69(6):3719–27. doi: 10.1128/IAI.69.6.3719-
3727.2001
40. Dang AT, Pasquali C, Ludigs K, Guarda G. Om-85 Is an Immunomodulator
of Interferon-bProduction and Inflammasome Activity. Sci Rep (2017)
7:43844. doi: 10.1038/srep43844
41. Janeczek K, Emeryk A, Rachel M, Duma D, Zimmer L, Poleszak E.
Polyvalent Mechanical Bacterial Lysate Administration Improves the
Clinical Course of Grass Pollen-Induced Allergic Rhinitis in Children: A
Randomized Controlled Trial. J Allergy Clin Immunol Pract (2021) 9
(1):453–62. doi: 10.1016/j.jaip.2020.08.025
42. Huber M, Mossmann H, Bessler WG. Th1-Orientated Immunological
Properties of the Bacterial Extract Om-85-Bv. Eur J Med Res (2005) 10
(5):209–17.
43. Karaca NE, Gulez N, Aksu G, Azarsiz E, Kutukculer N. Does Om-85 Bv
Prophylaxis Trigger Autoimmunity in Iga Deficient Children? Int
Immunopharmacol (2011) 11(11):1747–51. doi: 10.1016/
j.intimp.2011.06.009
44. Esposito S, Marchisio P, Prada E, Daleno C, Porretti L, Carsetti R, et al.
Impact of a Mixed Bacterial Lysate (Om-85 Bv) on the Immunogenicity,
Safety and Tolerability of Inactivated Influenza Vaccine in Children With
Recurrent Respiratory Tract Infection. Vaccine (2014) 32(22):2546–52.
doi: 10.1016/j.vaccine.2014.03.055
45. Gutierrez-Tarango MD, Berber A. Safety and Efficacy of Two Courses of
Om-85 Bv in the Prevention of Respiratory Tract Infections in Children
During 12 Months. Chest (2001) 119(6):1742–8. doi: 10.1378/
chest.119.6.1742
46. Emeryk A, Bartkowiak-Emeryk M, Raus Z, Braido F, Ferlazzo G, Melioli G.
Mechanical Bacterial Lysate Administration Prevents Exacerbation in
Allergic Asthmatic Children-The Eolia Study. Pediatr Allergy Immunol
(2018) 29(4):394–401. doi: 10.1111/pai.12894
47. Sly PD, Galbraith S, Islam Z, Holt B, Troy N, Holt PG. Primary Prevention of
Severe Lower Respiratory Illnesses in at-Risk Infants Using the
Immunomodulator Om-85. J Allergy Clin Immunol (2019) 144(3):870–
2.e11. doi: 10.1016/j.jaci.2019.05.032
48. Razi CH, Harmanci K, Abaci A, Ozdemir O, Hizli S, Renda R, et al. The
Immunostimulant Om-85 Bv Prevents Wheezing Attacks in Preschool
Children. J Allergy Clin Immunol (2010) 126(4):763–9. doi: 10.1016/
j.jaci.2010.07.038
49. Janeczek KP, Emeryk A, Rapiejko P. Effect of Polyvalent Bacterial Lysate on
the Clinical Course of Pollen Allergic Rhinitis in Children. Postepy Dermatol
Alergol (2019) 36(4):504–5. doi: 10.5114/ada.2019.87457
50. Banche G, Allizond V, Mandras N, Garzaro M, Cavallo GP, Baldi C, et al.
Improvement of Clinical Response in Allergic Rhinitis Patients Treated
With an Oral Immunostimulating Bacterial Lysate: In Vivo Immunological
Effects. Int J Immunopathol Pharmacol (2007) 20(1):129–38. doi: 10.1177/
039463200702000115
51. Lau S. Oral Application of Bacterial Lysate in Infancy Diminishes the
Prevalence of Atopic Dermatitis in Children at Risk for Atopy. Benef
Microbes (2014) 5(2):147–9. doi: 10.3920/bm2013.0007
52. Cazzola M, Capuano A, Rogliani P, Matera MG. Bacterial Lysates as a
Potentially Effective Approach in Preventing Acute Exacerbation of Copd.
Curr Opin Pharmacol (2012) 12(3):300–8. doi: 10.1016/j.coph.2012.01.019
53. De Benedetto F, Sevieri G. Prevention of Respiratory Tract Infections With
Bacterial Lysate Om-85 Bronchomunal in Children and Adults: A State of
the Art. Multidiscip Respir Med (2013) 8(1):33. doi: 10.1186/2049-6958-8-33
54. OM-PHARMA. Summary of Product Characteristics (2016). Available at: https://
myhealthbox.eu/nl/view/1717481/1229962e24dc324b4c23f24db468f6ec/leaflet.
55. Cirauqui C, Benito-Villalvilla C, Sanchez-Ramon S, Sirvent S, Diez-Rivero
CM, Conejero L, et al. Human Dendritic Cells Activated With Mv130 Induce
Th1, Th17 and Il-10 Responses Via Ripk2 and Myd88 Signalling Pathways.
Eur J Immunol (2018) 48(1):180–93. doi: 10.1002/eji.201747024
56. Pivniouk V, Gimenes-Junior JA, Ezeh P, Michael A, Pivniouk O, Hahn S,
et al. Airway Administration of Om-85, A Bacterial Lysate, Blocks
Kaczynska et al. Immunomodulatory Effects of Bacterial Lysates
Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 90714911
Experimental Asthma by Targeting Dendritic Cells and the Epithelium/Il-
33/Ilc2 Axis. J Allergy Clin Immunol (2022) 149(3):943–56. doi: 10.1016/
j.jaci.2021.09.013
57. Bartkowiak-Emeryk M, Emeryk A, Rolinski J, Wawryk-Gawda E, Markut-
Miotla E. Impact of Polyvalent Mechanical Bacterial Lysate on Lymphocyte
Number and Activity in Asthmatic Children: A Randomized Controlled
Trial. Allergy Asthma Clin Immunol (2021) 17(1):10. doi: 10.1186/s13223-
020-00503-4
58. Braido F, Melioli G, Cazzola M, Fabbri L, Blasi F, Moretta L, et al. Sub-
Lingual Administration of a Polyvalent Mechanical Bacterial Lysate (Pmbl)
in Patients With Moderate, Severe, or Very Severe Chronic Obstructive
Pulmonary Disease (Copd) According to the Gold Spirometric
Classification: A Multicentre, Double-Blind, Randomised, Controlled,
Phase Iv Study (Aiace Study: Advanced Immunological Approach in Copd
Exacerbation). Pulm Pharmacol Ther (2015) 33:75–80. doi: 10.1016/
j.pupt.2015.03.006
59. Roßberg S, Keller T, Icke K, Siedmann V, Lau I, Keil T, et al. Orally Applied
Bacterial Lysate in Infants at Risk for Atopy Does Not Prevent Atopic
Dermatitis, Allergic Rhinitis, Asthma or Allergic Sensitization at School Age:
Follow-Up of a Randomized Trial. Allergy (2020) 75(8):2020–5.
doi: 10.1111/all.14247
60. Nieto A, Mazon A, Nieto M, Calderon R, Calaforra S, Selva B, et al. Bacterial
Mucosal Immunotherapy With Mv130 Prevents Recurrent Wheezing in
Children: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Am
J Respir Crit Care Med (2021) 204(4):462–72. doi: 10.1164/rccm.202003-0520OC
61. Koatz AM, Coe NA, Ciceran A, Alter AJ. Clinical and Immunological
Benefits of Om-85 Bacterial Lysate in Patients With Allergic Rhinitis,
Asthma, and Copd and Recurrent Respiratory Infections. Lung (2016) 194
(4):687–97. doi: 10.1007/s00408-016-9880-5
62. Bodemer C, Guillet G, Cambazard F, Boralevi F, Ballarini S, Milliet C, et al.
Adjuvant Treatment With the Bacterial Lysate (Om-85) Improves
Management of Atopic Dermatitis: A Randomized Study. PLos One
(2017) 12(3):e0161555. doi: 10.1371/journal.pone.0161555
63. Kaur BP, Secord E. Innate Immunity. Pediatr Clin North Am (2019) 66
(5):905–11. doi: 10.1016/j.pcl.2019.06.011
64. Vidya MK, Kumar VG, Sejian V, Bagath M, Krishnan G, Bhatta R. Toll-Like
Receptors: Significance, Ligands, Signaling Pathways, and Functions in
Mammals. Int Rev Immunol (2018) 37(1):20–36. doi: 10.1080/
08830185.2017.1380200
65. Coviello S, Wimmenauer V, Polack FP, Irusta PM. Bacterial Lysates Improve
the Protective Antibody Response Against Respiratory Viruses Through
Toll-Like Receptor 4. Hum Vaccin Immunother (2014) 10(10):2896–902.
doi: 10.4161/hv.29784
66. Duggan JM, You D, Cleaver JO, Larson DT, Garza RJ, Guzman Pruneda FA,
et al. Synergistic Interactions of Tlr2/6 and Tlr9 Induce a High Level of
Resistance to Lung Infection in Mice. J Immunol (2011) 186(10):5916–26.
doi: 10.4049/jimmunol.1002122
67. Roy S, Rizvi ZA, Awasthi A. Metabolic Checkpoints in Differentiation of
Helper T Cells in Tissue Inflammation. Front Immunol (2018) 9:3036.
doi: 10.3389/fimmu.2018.03036
68. Gardner A, de Mingo Pulido A, Ruffell B. Dendritic Cells and Their Role in
Immunotherapy. Front Immunol (2020) 11:924. doi: 10.3389/fimmu.2020.00924
69. Balan S, Saxena M, Bhardwaj N. Dendritic Cell Subsets and Locations. Int
Rev Cell Mol Biol (2019) 348:1–68. doi: 10.1016/bs.ircmb.2019.07.004
70. Macri C, Fancke B, Radford KJ, O’Keeffe M. Monitoring Dendritic Cell
Activation and Maturation. Methods Mol Biol (2019) 1988:403–18.
doi: 10.1007/978-1-4939-9450-2_28
71. Zelle-Rieser C, Ramoner R, Bartsch G, Thurnher M. A Clinically Approved
Oral Vaccine Against Pneumotropic Bacteria Induces the Terminal
Maturation of Cd83+ Immunostimulatory Dendritic Cells. Immunol Lett
(2001) 76(1):63–7. doi: 10.1016/s0165-2478(00)00326-6
72. Pasquali C, Salami O, Taneja M, Gollwitzer ES, Trompette A, Pattaroni C,
et al. Enhanced Mucosal Antibody Production and Protection Against
Respiratory Infections Following an Orally Administered Bacterial Extract.
Front Med (Lausanne) (2014) 1:41. doi: 10.3389/fmed.2014.00041
73. Spisek R, Brazova J, Rozkova D, Zapletalova K, Sediva A, Bartunkova J.
Maturation of Dendritic Cells by Bacterial Immunomodulators. Vaccine
(2004) 22(21-22):2761–8. doi: 10.1016/j.vaccine.2004.01.006
74. Dang AT, Pasquali C, Ludigs K, Guarda G. Om-85 Is an Immunomodulator
of Interferon-Beta Production and Inflammasome Activity. Sci Rep (2017)
7:43844. doi: 10.1038/srep43844
75. Liu YW, Dong SH, Zhan GY, Tan HZ, Peng YQ, Wei F. Analysis of the Effect
of Bacterial Lysate and the Immunologic Mechanism in Treating Infant
Bronchiolitis. Eur Rev Med Pharmacol Sci (2017) 21(14):3332–6.
76. Roth M, Khameneh HJ, Fang L, Tamm M, Rossi GA. Distinct Antiviral
Properties of Two Different Bacterial Lysates. Can Respir J (2021)
2021:8826645. doi: 10.1155/2021/8826645
77. Li C, Zhou H, Zhang W, Che D. Bacterial Lysate Treatment in Allergic
Disease: A Systematic Review and Meta-Analysis. Pediatr Allergy Immunol
(2021) 32(8):1813–23. doi: 10.1111/pai.13572
78. Tao Y, Yuan T, Li X, Yang S, Zhang F, Shi L. Bacterial Extract Om-85 Bv
Protects Mice Against Experimental Chronic Rhinosinusitis. Int J Clin Exp
Pathol (2015) 8(6):6800–6. doi: 10.2174/1574362410666150601210919
79. Guo Y, Cao W, Zhu Y. Immunoregulatory Functions of the Il-12 Family of
Cytokines in Antiviral Systems. Viruses (2019) 11(9). doi: 10.3390/
v11090772
80. Byl B, Libin M, Gerard M, Clumeck N, Goldman M, Mascart-Lemone F.
Bacterial Extract Om85-Bv Induces Interleukin-12-Dependent Ifn-Gamma
Production by Human Cd4+ T Cells. J Interferon Cytokine Res (1998) 18
(10):817–21. doi: 10.1089/jir.1998.18.817
81. Lanzilli G, Falchetti R, Tricarico M, Ungheri D, Fuggetta MP. In Vitro Effects
of an Immunostimulating Bacterial Lysate on Human Lymphocyte
Function. Int J Immunopathol Pharmacol (2005) 18(2):245–54.
doi: 10.1177/039463200501800207
82. Prado-Montes de Oca E. Human Beta-Defensin 1: A Restless Warrior
Against Allergies, Infections and Cancer. Int J Biochem Cell Biol (2010) 42
(6):800–4. doi: 10.1016/j.biocel.2010.01.021
83. Liao JY, Zhang T. [Influence of Om-85 Bv on Hbd-1 and Immunoglobulin in
Children With Asthma and Recurrent Respiratory Tract Infection].
Zhongguo Dang Dai Er Ke Za Zhi (2014) 16(5):508–12.
84. Roth M, Pasquali C, Stolz D, Tamm M. Broncho Vaxom (Om-85)
Modulates Rhinovirus Docking Proteins on Human Airway Epithelial
Cells Via Erk1/2 Mitogen Activated Protein Kinase and Camp. PLos One
(2017) 12(11):e0188010. doi: 10.1371/journal.pone.0188010
85. Lee YG, Jeong JJ, Nyenhuis S, Berdyshev E, Chung S, Ranjan R, et al.
Recruited Alveolar Macrophages, in Response to Airway Epithelial-Derived
Monocyte Chemoattractant Protein 1/Ccl2, Regulate Airway Inflammation
and Remodeling in Allergic Asthma. Am J Respir Cell Mol Biol (2015) 52
(6):772–84. doi: 10.1165/rcmb.2014-0255OC
86. Girodet PO, Nguyen D, Mancini JD, Hundal M, Zhou X, Israel E, et al.
Alternative Macrophage Activation Is Increased in Asthma. Am J Respir Cell
Mol Biol (2016) 55(4):467–75. doi: 10.1165/rcmb.2015-0295OC
87. Larosa DF, Orange JS. 1. Lymphocytes. J Allergy Clin Immunol (2008) 121(2
Suppl):S364–9. doi: 10.1016/j.jaci.2007.06.016
88. Deniz G, Akdis M. Nk Cell Subsets and Their Role in Allergy. Expert Opin
Biol Ther (2011) 11(7):833–41. doi: 10.1517/14712598.2011.572549
89. Bonilla FA, Oettgen HC. Adaptive Immunity. J Allergy Clin Immunol (2010)
125(2 Suppl 2):S33–40. doi: 10.1016/j.jaci.2009.09.017
90. Butcher MJ, Zhu J. Recent Advances in Understanding the Th1/Th2 Effector
Choice. Fac Rev (2021) 10:30. doi: 10.12703/r/10-30
91. Luckheeram RV, Zhou R, Verma AD, Xia B. Cd4(+)T Cells: Differentiation and
Functions. Clin Dev Immunol (2012) 2012:925135. doi: 10.1155/2012/925135
92. Corre B, Perrier J, El Khouri M, Cerboni S, Pellegrini S, Michel F. Type I
Interferon Potentiates T-Cell Receptor Mediated Induction of Il-10-
Producing Cd4(+) T Cells. Eur J Immunol (2013) 43(10):2730–40.
doi: 10.1002/eji.201242977
93. Voehringer D, Reese TA, Huang X, Shinkai K, Locksley RM. Type 2
Immunity Is Controlled by Il-4/Il-13 Expression in Hematopoietic Non-
Eosinophil Cells of the Innate Immune System. J Exp Med (2006) 203
(6):1435–46. doi: 10.1084/jem.20052448
94. Silverberg JI, Kantor R. The Role of Interleukins 4 and/or 13 in the
Pathophysiology and Treatment of Atopic Dermatitis. Dermatol Clin
(2017) 35(3):327–34. doi: 10.1016/j.det.2017.02.005
95. Han L, Zheng CP, Sun YQ, Xu G, Wen W, Fu QL. A Bacterial Extract of
Om-85 Broncho-Vaxom Prevents Allergic Rhinitis in Mice. Am J Rhinol
Allergy (2014) 28(2):110–6. doi: 10.2500/ajra.2013.27.4021
Kaczynska et al. Immunomodulatory Effects of Bacterial Lysates
Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 90714912
96. Rodrigues A, Gualdi LP, de Souza RG, Vargas MH, Nunez NK, da Cunha
AA, et al. Bacterial Extract (Om-85) With Human-Equivalent Doses Does
Not Inhibit the Development of Asthma in a Murine Model. Allergol
Immunopathol (Madr) (2016) 44(6):504–11. doi: 10.1016/j.aller.2016.04.010
97. Liu C, Huang R, Yao R, Yang A. The Immunotherapeutic Role of Bacterial
Lysates in a Mouse Model of Asthma. Lung (2017) 195(5):563–9.
doi: 10.1007/s00408-017-0003-8
98. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal
Developmental Pathways for the Generation of Pathogenic Effector Th17
and Regulatory T Cells. Nature (2006) 441(7090):235–8. doi: 10.1038/
nature04753
99. Navarro S, Cossalter G, Chiavaroli C, Kanda A, Fleury S, Lazzari A, et al. The
Oral Administration of Bacterial Extracts Prevents Asthma Via the
Recruitment of Regulatory T Cells to the Airways. Mucosal Immunol
(2011) 4(1):53–65. doi: 10.1038/mi.2010.51
100. Lambrecht BN, Hammad H, Fahy JV. The Cytokines of Asthma. Immunity
(2019) 50(4):975–91. doi: 10.1016/j.immuni.2019.03.018
101. Ahrens B, Quarcoo D, Buhner S, Matricardi PM, Hamelmann E. Oral
Administration of Bacterial Lysates Attenuates Experimental Food Allergy.
Int Arch Allergy Immunol (2011) 156(2):196–204. doi: 10.1159/000322352
102. Litzman J, Lokaj J, Gerylovova A. Orally Administered Bacterial Lysate
Broncho-Vaxom for the Treatment of Common Variable
Immunodeficiency. Allerg Immunol (Paris) (1996) 28(3):81–5.
103. Quezada A, Maggi L, Perez MA, Rodriguez J. Effect of Bacterial Antigen
Lysate on Igg and Iga Levels in Children With Recurrent Infections and
Hypogammaglobulinemia. J Investig Allergol Clin Immunol (1999) 9(3):178–
82.
104. Man WH, de Steenhuijsen Piters WA, Bogaert D. The Microbiota of the
Respiratory Tract: Gatekeeper to Respiratory Health. Nat Rev Microbiol
(2017) 15(5):259–70. doi: 10.1038/nrmicro.2017.14
105. Rossi GA, Pohunek P, Feleszko W, Ballarini S, Colin AA. Viral Infections
and Wheezing-Asthma Inception in Childhood: Is There a Role for
Immunomodulation by Oral Bacterial Lysates? Clin Transl Allergy (2020)
10:17. doi: 10.1186/s13601-020-00322-1
106. Rial A, Ferrara F, Suarez N, Scavone P, Marques JM, Chabalgoity JA.
Intranasal Administration of a Polyvalent Bacterial Lysate Induces Self-
Restricted Inflammation in the Lungs and a Th1/Th17 Memory Signature.
Microbes Infect (2016) 18(12):747–57. doi: 10.1016/j.micinf.2016.10.006
107. Macpherson AJ, Geuking MB, Slack E, Hapfelmeier S, McCoy KD. The
Habitat, Double Life, Citizenship, and Forgetfulness of Iga. Immunol Rev
(2012) 245(1):132–46. doi: 10.1111/j.1600-065X.2011.01072.x
108. Triantafillou V, Workman AD, Patel NN, Maina IW, Tong CCL, Kuan EC,
et al. Broncho-Vaxom®(Om-85 Bv) Soluble Components Stimulate
Sinonasal Innate Immunity. Int Forum Allergy Rhinol (2019) 9(4):370–7.
doi: 10.1002/alr.22276
109. Rozy A, Chorostowska-Wynimko J. Bacterial Immunostimulants–
Mechanism of Action and Clinical Application in Respiratory Diseases.
Pneumonol Alergol Pol (2008) 76(5):353–9.
110. Brandtzaeg P. Mucosal Immunity: Induction, Dissemination, and Effector
Functions. Scand J Immunol (2009) 70(6):505–15. doi: 10.1111/j.1365-
3083.2009.02319.x
111. Bals R. Epithelial Antimicrobial Peptides in Host Defense Against Infection.
Respir Res (2000) 1(3):141–50. doi: 10.1186/rr25
112. Guani-Guerra E, Negrete-Garcia MC, Montes-Vizuet R, Asbun-Bojalil J,
Teran LM. Human Beta-Defensin-2 Induction in Nasal Mucosa After
Administration of Bacterial Lysates. Arch Med Res (2011) 42(3):189–94.
doi: 10.1016/j.arcmed.2011.04.003
113. Paplinska-Goryca M, Misiukiewicz-Stepien P, Proboszcz M, Nejman-Gryz P,
Gorska K, Zajusz-Zubek E, et al. Interactions of Nasal Epithelium With
Macrophages and Dendritic Cells Variously Alter Urban Pm-Induced
Inflammation in Healthy, Asthma and Copd. Sci Rep (2021) 11(1):13259.
doi: 10.1038/s41598-021-92626-w
114. Oliveira ML, Areas AP, Ho PL. Intranasal Vaccines for Protection Against
Respiratory and Systemic Bacterial Infections. Expert Rev Vaccines (2007) 6
(3):419–29. doi: 10.1586/14760584.6.3.419
115. Rial A, Lens D, Betancor L, Benkiel H, Silva JS, Chabalgoity JA. Intranasal
Immunization With a Colloid-Formulated Bacterial Extract Induces an
Acute Inflammatory Response in the Lungs and Elicits Specific Immune
Responses. Infect Immun (2004) 72(5):2679–88. doi: 10.1128/IAI.72.5.2679-
2688.2004
116. La Mantia I NF, Maiolino L, Serra A. Immunoprophylaxis of Recurring
Bacterial Infections of Respiratory Tracts in Pediatric Age: Clinical
Experience Through a New Immunestimulating Vaccine. GIMMOC (2007)
9:1e8.Q2.
117. Alecsandru D, Valor L, Sanchez-Ramon S, Gil J, Carbone J, Navarro J, et al.
Sublingual Therapeutic Immunization With a Polyvalent Bacterial
Preparation in Patients With Recurrent Respiratory Infections:
Immunomodulatory Effect on Antigen-Specific Memory Cd4+ T Cells and
Impact on Clinical Outcome. Clin Exp Immunol (2011) 164(1):100–7.
doi: 10.1111/j.1365-2249.2011.04320.x
118. Negri DR, Riccomi A, Pinto D, Vendetti S, Rossi A, Cicconi R, et al.
Persistence of Mucosal and Systemic Immune Responses Following
Sublingual Immunization. Vaccine (2010) 28(25):4175–80. doi: 10.1016/
j.vaccine.2010.04.013
119. Song JH, Kim JI, Kwon HJ, Shim DH, Parajuli N, Cuburu N, et al. Ccr7-
Ccl19/Ccl21-Regulated Dendritic Cells Are Responsible for Effectiveness of
Sublingual Vaccination. J Immunol (2009) 182(11):6851–60. doi: 10.4049/
jimmunol.0803568
120. BenMohamed L, Belkaid Y, Loing E, Brahimi K, Gras-Masse H, Druilhe P.
Systemic Immune Responses Induced by Mucosal Administration of
Lipopeptides Without Adjuvant. Eur J Immunol (2002) 32(8):2274–81. doi:
10.1002/1521-4141(200208)32:8<2274::AID-IMMU2274>3.0.CO;2-C
121. Cuburu N, Kweon MN, Song JH, Hervouet C, Luci C, Sun JB, et al.
Sublingual Immunization Induces Broad-Based Systemic and Mucosal
Immune Responses in Mice. Vaccine (2007) 25(51):8598–610.
doi: 10.1016/j.vaccine.2007.09.073
122. Rosaschino F, Cattaneo L. Strategies for Optimizing Compliance of
Paediatric Patients for Seasonal Antibacterial Vaccination With
Sublingually Administered Polyvalent Mechanical Bacterial Lysates
(Pmbl). Acta BioMed (2004) 75(3):171–8.
123. FD. M. Oral Bacterial Extract for the Prevention of Wheezing Lower Respiratory
Tract Illness (Orbex). ClinicalTrials.gov. Identifier: NCT02148796.
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