Allergic diseases are diseases characterized by an abnormal immune response to frequently encountered environmental antigens (allergens). The most important role in the immunopathogenesis (formation mechanisms) of these diseases is assumed by the helper T (Th) cells that develop specifically for allergens. The mentioned Th cells are effective in processes that result in chronic inflammation from the acute (early) phase of allergy, which occurs with the activation of many inflammatory cells and the secretion of mediators. Current treatment approaches are treatments aimed at suppressing inflammation and controlling symptoms (signs) with drugs. Although this treatment is known to be beneficial, unfortunately, it is not curative unless it suppresses immune pathological processes. Therefore, today, more effective treatment approaches that change the immune mechanisms of allergic inflammatory processes are emphasized. Allergen-specific immunotherapy (vaccine therapy) is the most used immune modulation treatment today. Recently, anti-IgE therapy that blocks IgE, which is the antibodies that play a role in allergy, has been used in patients with allergic asthma. Apart from these, the use of microbial agents that suppress Th2-type immunological events, the use of molecules that suppress allergic cytokines, chemokines or other Th2-derived mediators are the immunomodulatory treatment methods under investigation.
Allergic diseases affect approximately 20% of the population in industrialized countries. It causes a wide spectrum of diseases including severe respiratory disorders and life-threatening anaphylactic shock. The incidence of allergic diseases has increased in the past 40 years. In particular, the average disability and mortality outcomes of asthma have doubled over the past decade. Currently, anti-allergic drugs developed are unfortunately not effective in providing a permanent cure of the disease. Current drug regimens such as antihistamines, leukotriene antagonists, and corticosteroids primarily target symptom control and/or suppression of inflammation without significantly affecting allergic pathogenesis. These treatment regimens cannot be used for long periods of time and their effects last as long as the patient takes the drug. Current academic and industrial research is aimed at changing the immune mechanism abnormalities that lead to the development of acute allergic reaction and chronic inflammation. In order to better define these targets, it is necessary to better understand the immunopathogenesis of allergic diseases.
ALLERGY: ABNORMAL IMMUNE RESPONSE TO NON-HARMFUL ENVIRONMENTAL PROTEINS
Allergic diseases abnormal immune response to generally harmless environmental proteins (allergens) such as pollen, house dust mites, mold fungus spores, animal allergens, food, insect venoms characterized by a response. We are all exposed to these allergens. However, immune tolerance is shown to such allergens in healthy individuals and an effective response is not established. However, allergic individuals develop an active immune response against the allergen and tolerance cannot develop. The conductor in the pathogenesis of allergen immune response in allergic diseases is allergen-specific CD4+ T cells. These cells are necessary not only for allergen sensitization, but also for the emergence of all inflammatory processes of allergic diseases. Activated specific T cells are very high in the blood circulating in the veins of allergic patients. However, they are mainly found in target organs such as the nose, lungs, skin and intestines (1-3). In animal models of allergic sensitization, inactivation or removal of these T cells with blocking antibodies suppressed the development of the disease (4,5). Allergen-specific CD4+ T cells regulate allergic inflammation with Th2-type cytokine profile such as IL-4, IL-5, IL-9 and IL-13 (1-7). The presence of such Th2-type cytokines at high levels in the immune environment causes the pathogenesis to shift towards allergic disease (1,2,8). For example; IL-4 and IL-13 provide IgE type antibody production from B cells, which is the antibody responsible in allergy. IL-5 is responsible for eosinophil proliferation and maturation, which is one of the most important cells in allergic inflammation, and recruitment of eosinophils to the inflammation site; IL-9, on the other hand, triggers the activation of mast cells and basophils, which are the source of many mediators such as histamine, which are responsible for allergies (8,9). In addition to all these, some Th2-type cytokines can directly cause disease-specific findings such as airway hyperresponsiveness and mucus hypersecretion (3,10).
The transformation of Th cells originating from the bone marrow into a Th2 type cell and the secretion of Th2 cytokines are regulated by a complex network of intracellular signaling molecules. For the initiation of Th2-type cytokine production, the presence of IL-4 locally in allergic rhinitis (hay fever), for example in the nose, is absolutely necessary (11). With the stimulation of the IL-4 receptor, some intracellular molecules are activated, so that the genes required for Th2 cytokine production occur in the nucleus of the Th cell (11,12). Activation of STAT6, one of these molecules, is very important for effective IL-4 formation and Th2 conversion (12,13). Th2 cell development is insufficient in mice with the STAT6 gene deleted, therefore there is also a deficiency in IL-4 production (13). After STAT6 activation, factors such as GATA-3 are increased in Th2 cells. Th2-type development is achieved with GATA-3 in Th cells (14).
The development of a Th2 type response causes allergic symptoms to occur as a result of increased allergen-specific IgE production. Presence of high level of IgE is necessary for both acute allergic reaction and chronic inflammation (15). Allergen-specific IgE mainly binds to the IgE receptor (FcεRI) on mast cells and circulating basophils in tissues. As a result of cross-linking of IgEs on the cell surface with specific allergens, inflammatory mediators such as histamine, leukotriene, prostaglandin and PAF are released from the granules of these cells. Then, within minutes, some cytokines are released. As a result of these, acute allergic reaction responses such as smooth muscle contraction, mucus production and extravasation of fluid occur (15). Subsequently, a prolonged allergic inflammatory state is triggered by the recruitment of cells such as Th2 cells, eosinophils, basophils and monocyte cells to the allergen exposure area via these allergic mediators (15). The exaggerated symptoms of the early phase reaction and damage to the local tissue occur with the new mediators released from the cells collected in this region. If the allergen exposure is persistent, the inflammatory changes pass into the severe and irreversible phase. In this case, very serious tissue damage and target organ abnormalities occur. The roles of allergens in chronic allergic inflammation are well defined. However, non-allergic stimuli also have a role in this phenomenon (16). For example, infections cause not only a temporary exacerbation of allergic symptoms, but also increased inflammation, which leads to disease progression and increased tissue damage (16). Non-specific irritants, intrinsic proteins that cross-react with allergens, self-stimulation of inflammatory cells, and damage to epithelial cells also cause the continuity of inflammation (16,17). The chronic form of allergic inflammation is caused by an extremely complex immune mechanism. Here, it is known that besides Th2 cells, cytokines of Th1 type cells can be detected and even found in CD8+ T lymphocytes (17,18).
The recruitment of cells to this region after allergen exposure is controlled by a number of chemokines and adhesion molecules in the regional immune environment. A number of chemokines (such as eotaxin, RANTES, MCP-3, MCP-5, and MDC) are rapidly released into the environment after allergen exposure in susceptible individuals, and they act to attract allergic cells to this area (9,19). These secreted chemokines increase the emergence of some cell adhesion molecules in blood vessels, after which white blood cells (leukocytes) pass into the tissues (20). These molecules, which we call chemokines, are effective only for cells that carry their own special receptors. In this way, chemokines determine which type of inflammation will occur (19-21). Th1 and Th2 cells carry chemokine receptors separately. Therefore, they are localized to separate regions of the inflammation area (22,23). CCR3, CCR4, CCR8 receptors that selectively bind to CCL11, CCL22, CCL17 chemokines released in the area of allergic inflammation are expressed in Th2 cells; therefore, Th2 cells are preferentially recruited to these regions (23). Among these chemokine-chemokine receptor systems, which play a role in allergic inflammation, the eotaxin system is the most well-known (24). In animal models with eotaxin receptor deficiency such as CCR2 and CCR3, despite allergen stimulation, eosinophilic infiltration was not observed in the lungs or skin, and airway hyperresponsiveness could not be achieved clinically (24).
Unlike allergic people, healthy people do not develop a systemic or local reaction due to tolerance to the allergen. In studies conducted in animals, it has been observed that some immune tolerance mechanisms such as T cell destruction, T cell unresponsiveness and T cell suppression are rapidly activated as a result of respiratory or gastrointestinal allergen stimulation (25,26). As a result of these mechanisms, the development of allergic inflammation is protected. In healthy individuals, small amounts of allergen-specific Th1 cells are found in the peripheral blood after allergen exposure; however, the main cell is the allergen-specific regulatory T (Treg) cell (27). Allergen-specific Treg cells produce a very high amount of IL-10, and this cytokine is a cytokine with immunosuppressive power (28). It has been observed that allergy can be overcome as a result of increasing the number and functions of such cells in people with allergies (29). When allergic individuals were investigated, it was observed that there were very few allergen-specific Treg cells in their blood taken from their veins (29). It has been observed that allergen-specific Th2 cell development or immunosuppressive Treg development is achieved after exposure to allergens at different doses, and allergic inflammation or healthy state develops. Naturally inducible Treg cells appear to be very important in the development of tolerance to allergens and the prevention of allergic diseases (29). On the basis of tolerance stimulation, there are other local immune regulatory mechanisms other than peripheral T cells. For example, local epithelium, organ-specific cells (such as alveolar macrophages in the lungs), local immunosuppressive cytokines (such as TGF-beta) are helpful in maintaining immune regulation and balance (30).
IMMUNEMODULATORY TREATMENTS USED IN CLINICAL PRACTICE:
Allergen Immunotherapy
The goal of immunotherapy with allergens is to eliminate allergic symptoms and achieve clinical allergen non-responsiveness. Allergen unresponsiveness (sensitization) is achieved by the administration of extracts made from substances that are essentially allergens, in continuously increasing doses. Subcutaneous (subcutaneous) allergen immunotherapy (SCIT) has been used in clinical practice for nearly 100 years and is the only widely used treatment. This therapy is more effective in individuals with IgE-mediated allergies and sensitivities to a limited number of allergens (eg seasonal allergic rhinitis, asthma or venom hypersensitivity). SCIT affects the early and late phases of the allergic response, and its effectiveness continues years after treatment is stopped (31). There is scientific evidence showing that SCIT provides efficacy by changing the immune response to allergens (31,32). Successful SCIT treatment causes an increase in the allergen-specific blocking antibody IgG (especially in the IgG4 subtype) and a decrease in IgE-mediated immune activity (33). In this case, IgG antibodies compete with IgE for allergen binding on the surfaces of basophils and mast cells (33). In addition, SCIT suppresses the allergen-specific Th2 response and provides tolerant T cell formation (32,33). In addition, after traditional and rapid-initiation SCIT protocols, the number of IL-10-producing Treg cells in peripheral blood and local tissues increases (34). In addition, some researchers believe that SCIT shifts the allergen-mediated immune response towards Th1.
Despite its effectiveness, there are some problems with the treatment of SCIT. It is used in patients who are sensitive to certain allergens. Since it takes a long time, patients’ participation in treatment also creates a significant problem. In addition, sublingual and oral (oral) allergen immunotherapies are in clinical practice. According to the evaluation results, it can be said that sublingual immunotherapy is safer than SCIT and does not have as much effect as SCIT in the treatment of allergic rhinitis and asthma. Higher doses of allergen should be given to obtain beneficial results by the sublingual route (35). In order to reduce the allergenic effect of allergen extracts (IgE reactivity) and to create a beneficial effect, as well as to apply less doses, chemical and physical modifications were made to the extracts (eg, prolongation of absorption). Various results have been obtained by absorbing allergens into aluminum hydroxide, calcium phosphate, tyrosine, liposome or by chemical modification with polyethylene glycol (PEG) or polymerization with formaldehyde, glutaraldehyde, alginic salt (allergoid) (31,36). Another method is to create allergen derivatives that have low IgE binding capacity, low allergenicity, but can stimulate T cells well, with the recently discovered recombinant technology (37). Another advantage of recombinant allergens is that they do not form new IgE antibodies (37). Despite all this, the effectiveness of immunotherapy with recombinant allergens still requires research.
Anti IgE
Since IgE is the key antibody in the pathogenesis of allergy, it has been tried to develop a safe molecule that will block the activity of IgE for years. The human recombinant monoclonal antibody, omalizumab, has recently been found; It is effective against IgE and prevents IgE from binding to the FcεRI receptor (38). It was first tested in patients with allergic asthma. Studies show that omalizumab is well tolerated in moderate and severe asthma (38,39). It has been shown to reduce asthma symptoms and improve lung functions (39). The improvement seen after omalizumab treatment is a decrease in free IgE level and FCεRI expression, as well as a decrease in early and late allergic activity following exposure to aereoallergen (40). Another important issue; is the cost of treatment. There is also a need for studies on its use in other allergic diseases such as atopic eczema, allergic rhinitis, food allergy. Apart from all these, good results are obtained in the treatment of hives (urticaria) resistant to other treatments, in our own practices and in some other clinical studies.
Immune Modulatory Methods under Evaluation
Understanding the central role of Th cells in allergic physiopathology has brought the development of anti-T cell therapy strategies to the agenda. As a result of experimental studies, it has been reported that chimeric anti-CD4 monoclonal antibody inhibits the allergic Th cell response in patients with asthma (3). In experimental studies, there was a decrease in the amount of CD4+ cells, asthma symptoms, and an increase in peak flow; however, no change was found in FEV1 (41). Recently, studies targeting the Th2 response have been carried out in order to avoid the side effects of suppressing all T cells. In addition, there are studies to inhibit the stimulatory pathways that provide Th2 cell formation (42). It is known that the interaction of CD28 with CD86 on the surface of antigen-presenting cells triggers Th2 formation (43). In mouse experiments, it has been shown that administration of antibodies that block the binding of CD28 to CD80/CD86 reduces Th2 cytokine level, lung inflammation and airway hyperresponsiveness (44). ICOS is another costimulatory molecule that is effective in the Th2 response to respiratory allergens. In some publications, it is seen that preventing ICOS from binding to its ligand reduces the occurrence of experimental allergic reactions (42-45). Costimulatory agents such as OX40, CD30 4-1BB and negative costimulators such as CTLA-4 are other potential targets in the treatment of allergy (42).
Immune Diversion with Microbial Agents
Since it is known that Th1 cells inhibit the proliferation and functions of Th2 cells with their antagonistic effects, the idea that a protective effect can be achieved in allergic patients by stimulating the Th1 immune system is plausible. Therefore, many experimental models have been developed to turn the Th2 response towards Th1. Microbes are the most effective way to activate the Th1 type immune response. For this purpose, attenuated microbes have been used alone or in combination with allergen immunotherapy (46). In experimental studies, it has been shown that the use of heat-killed Listeria and attenuated mycobacteria (BCG vaccine or Mycobacterium vaccae) at the right time prevents allergic reactions in mice (47-49). However, clinical experience is needed to evaluate the place of these methods in allergy treatment and prevention. Thanks to 3-deacylated monophosphoryl lipid A (MPL), which is a lipopolysaccharide derivative and used in viral vaccines, a lot of information has been provided about the effect of microbial products on this issue (46). In the first studies conducted with the combination of MPL and grass pollen, a decrease was found in allergic rhinitis symptoms and drug scores (46). Th2-modifying microbial adjuvants increase the Th1 response by stimulating IL-12 and IFN synthesis. In addition, these agents activate Treg cells and trigger IL-10 and/or TGF-β secretion (32,46). A safe way to stimulate Th1/Treg cells is using immunostimulatory DNA sequences (50). These sequences carry repeating cytosine-guanine dinucleotide (CpG) motifs. These sequences are found in microbial DNA but not in mammalian DNA. CpG motifs are recognized by toll-like receptors, which are members of the innate immune system in all vertebrates, and create a protective immune response (50). The use of synthetic oligodeoxynucleotides (ISS-ODNs) containing unmethylated CpG in mouse models of asthma has been shown to prevent and reverse the allergen-induced Th2 type response (51,52). It has been shown that ISS-ODNs conjugated with allergens effectively suppress the allergen-specific Th2 response in both mice and humans (52). In addition, it has been reported that ragweed-ISS-ODNs conjugates are 100 times less allergenic than conventional ragweed immunotherapy (53). This success in early phase clinical trials has increased enthusiasm for the development of DNA vaccines for the prevention of allergy.
Suppression (Inhibition) of Cytokine Network Involved in Allergic Inflammation
Some cytokines are responsible for the allergic response of T and B cells and consequently the formation of allergic inflammation. Therefore, blocking of key cytokines such as IL-4, IL-13 and/or IL-5 may affect not only the phenotype of the allergen-specific immune response but also the course of the disease. To investigate this hypothesis, anti-cytokine antibodies, cytokine receptor antibodies and soluble cytokine receptors have been developed (11,54,55). In early studies, IL-4 activity was inhibited by human anti-IL-4 monoclonal antibody (pascolizimab) and recombinant soluble IL-4 receptor. Although the results were promising in terms of Th2 and IgE inhibition, they were not clinically beneficial (56). Mepolizumab is an anti-IL-5 monoclonal antibody, and studies with this antibody have yielded mixed results regarding the treatment of asthma (57). However, in eosinophil-induced diseases such as hypereosinophilic syndrome, anti-IL-5 therapy has produced excellent results (57). Agents that inhibit pathways triggered by IL-13, such as the IL-13Ra2- IgGFc fusion protein, are still under development (58). Good results can be obtained in allergic inflammation by suppressing STAT6 or GATA3 activity (59).
Suppression of Inflammatory Cell Migration
Another method of treating allergic inflammation is to prevent aberrant leukocyte accumulation in areas of allergen exposure. This is achieved by regulating Th2, eosinophil, basophil and mast cell traffic by interfering with chemokines and adhesion molecules. For example; By blocking LFA1 or its ligand ICAM-1, inflammation is reduced as well as allergic early and late phase responses in animals (60). In the first studies, the mentioned results were obtained with the use of anti-LFA-1/CD11 monoclonal antibody (efelizumab) (60).
CONCLUSION
Immunomodulatory strategies will provide an alternative to the routine treatment of allergic patients. However, there are many issues that need to be evaluated before these methods can be used in the clinic; for example, the effectiveness, safety, sustainability of the treatments, the method of administration and the time of initiation of the treatment for maximum benefit. It may be possible to change the pathogenesis of the disease with early treatment; furthermore, progression in the stage of the disease can also be prevented. May create forms of prophylactic immunotherapy for high-risk atopic children. In allergic cases, inhibiting the immune pathways involved in allergic inflammation by testing intense, multiple strategies may help us to obtain better responses.
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Sağlıklı günler dileğiyle,
Prof. Dr. Cengiz KIRMAZ
