1 History of immunotherapy
Allergen specific immunotherapy, or immunotherapy for short. It used to be called specific desensitization or specific hyposensitization, but as the understanding of its mechanism has improved, it is now called immunotherapy.
For nearly a century, allergen-specific immunotherapy has been widely used for allergic rhinitis/conjunctivitis, allergic asthma, and insect sting-induced allergic reactions. However, due to the differences in their allergen purity, potency, injection dose and duration of treatment. The efficacy varies greatly, and some patients have severe allergic reactions after allergen injection. Therefore, for many years, immunotherapy has been a mixed blessing. However, the efficacy and safety of immunotherapy have been further improved with the recent standardization of allergen extracts for clinical use and the standardization of injection doses and regimens. 1998 WHO guideline document Allergen immunotherapy: Therapeutic vaccines for allergic diseases [1] (Allergen immunotherapy: Therapeutic vaccines for allergic diseases) was published in 1998. The 2001 WHO expert report, Allergic Rhinitis and Its Impact on Asthma (ARIA), summarized a large number of previous studies and confirmed the importance of allergen immunotherapy for allergic diseases. The efficacy of immunotherapy in allergic rhinitis/conjunctivitis, allergic asthma and other allergic diseases has been well recognized by ARIA. The name “allergen extract” was changed to “allergen vaccine”, and the standardized allergen vaccine should be used in immunotherapy.
2 Mechanism of action
2.1 Antibody response in serum
Immunotherapy with inhaled allergens is always accompanied by an increase in serum levels of specific IgG1, IgG4 and IgA
levels are increased. IgG (mainly IgG4), as a blocking antibody, not only blocks allergen-induced IgE-dependent histamine release. It can also inhibit late allergen-specific T-cell responses by inhibiting the adhesion of allergen-IgE complexes to antigen-presenting cells. One of the important reasons why the “closed antibody” doctrine has fallen into disfavor in recent years is that changes in serum IgG concentrations do not seem to have a necessary correlation with the clinical response to therapy. For example, during rush immunotherapy (RI), the improvement in symptoms precedes the change in serum antibody synthesis. Recent studies have shed some new light on this phenomenon: it has been found in a murine model of immunotherapy that high concentrations of allergens alter the number of serum antibodies as well as the affinity and specificity of the antibodies. In addition, Pierson-Mullany et al. tried to use the concept of antibody binding capacity ([Ig]×KA) to represent the affinity and concentration of allergens with specific IgG or IgE [3]. Their results showed that the antibody-binding volume of IgG4 was 1.6 log units higher than that of the control group after immunotherapy, while the antibody-binding volume of IgE was 1.2 log units lower than that of the control group. Therefore, the role of closed antibodies in immunotherapy should not be measured only by their amount in the serum, but also by the activity of allergen-specific IgG complexes and their affinity for antigen-presenting cells.
2.2 Response of T lymphocytes
In the discussion of the mechanisms of immunotherapy, most people accept the idea that immunotherapy suppresses Th2-type responses and stimulates Th1-type responses. It is not very clear which came first.Oda et al [4] established T-cell lines before, after 3 months, and after 18 months of shock immunotherapy in patients with mite allergy. All mite specific T-cell lines showed a characteristic TH2 pattern before RI, manifested by the production of high levels of IL-4 and an undetectable small amount of IFN-. In contrast, the cytokine expression profile of the T cell lines after 18 months showed a clear shift towards TH0 or TH1 (marked IFN-
production was increased and IL-4 production was decreased). Interestingly, only few T-cell lines could be established after 3 months of receiving RI. and these T-cell lines did not show any predisposition. This suggests that suppression of TH2 responses occurs early in immunotherapy followed by a slow and selective activation of TH1 and
After 1998, a large number of studies on the effect of immunotherapy on cytokine production by peripheral blood T cells have been reported, however some results are contradictory [5, 6]. It is evident that not all studies reflect a shift from Th2 to Th1 responses. One possible explanation is that the suppression of peripheral T-cell proliferation and TH2-type responses is not an essential phenomenon in immunotherapy. In contrast, increased IL-10 production in peripheral blood T cells following immunotherapy is a frequent finding.
2.3 IL-10
The production of IL-10 in peripheral blood after immunotherapy with insect venom was first reported by Bellinghausen et al. It has a role in suppressing T-cell proliferative responses and T-cell production of cytokines in response to in vitro allergen stimulation. IL-10 is now thought to have a wide range of anti-metabolic activities, including: down-regulation of expression of the high-affinity receptor for IgE on the mast cell surface, Fc RI, and inhibition of IgE-dependent mast cell activation; inhibition of eosinophil survival and activity; modulation of IL-4-induced B-cell activity to produce a shift from IgE to IgG4 secretion; inhibition of TH2-type cytokine production such as IL-5; inducing hypersensitivity (hyporesponsiveness) or unresponsiveness (anergy) to allergen specificity. Thus, IL-10 production by T cells can be seen as an important component of successful immunotherapy, or at least a marker of successful downregulation of allergen-specific T cell responses after immunotherapy. Cells that produce IL-10 can be termed regulatory T cells (regulatory T cells) and are predominantly localized to CD4+CD25+ T cells [7].
2.4 The apoptosis theory of T cells
Guerra et al. introduced a new idea that immunotherapy can predispose IL-4-producing TH2 cells exposed to allergens to apoptosis [8]. They performed in vitro culture of peripheral blood lymphocytes from patients with grass pollen allergy and assayed cytokine expression after allergen stimulation. It was found that in the non-immunotherapy group, (71 ± 12) % of the cells expressed IL-4 and only (7 ± 3) % of the cells expressed IFN- . They then examined the apoptosis rate of the cultured cells by DNA end-labeling and found that a significant proportion (39 ± 14)%) of the lymphocytes in the immune-treated group were in an apoptotic state after allergen stimulation and that apoptosis occurred mainly in IL-4-expressing TH2 lymphocytes. It is concluded that the shift from TH2 to TH1 responses in allergic patients caused by immunotherapy is at least partly due to the induction of apoptosis of activated allergen-specific TH2 cells.
2.5 Activation of lymphocytes
Laksonen [9] studied the signaling lymphocytic activation molecule (SLAM) during immunotherapy.
SLAM) changes. SLAM mRNA is quite low in PBMCs of patients with allergic rhinitis compared to normal subjects. After 1 year of immunotherapy, SLAM mRNA expression was significantly higher and consistent with IFN-mRNA expression. SLAM is often increased in TH1-mediated autoimmune diseases, so this finding has been cited as an indirect evidence that immunotherapy promotes TH1 response.
2.6 B cells
Although the vast majority of studies have focused on T cells, Håkannson et al. enumerated changes in B cell surface antigen markers before and after pollen immunotherapy by means of flow cytometry. The untreated group during pollen season exhibited increased expression of the B-cell surface antigens CD23, CD40, and
HLA-DR expression increased along with an increase in IgE antibodies. In contrast, no such increase occurred in the immunotherapy group. The authors hypothesized that the predominance of TH1 T cells may be related to the deactivation of B cells under allergen exposure [10].
3 Efficacy
3.1 Dose of allergen vaccine
The dose of immunotherapy is related to efficacy and safety. Low doses of immunotherapy are ineffective, while too high doses may cause unacceptable and severe systemic reactions. Therefore, the ideal dose is defined as the allergen vaccine dose that induces a clinical effect in most patients without causing unacceptable side effects. For most allergen vaccines that have been standardized, the optimal dose for the major allergens among them is 5 to 20 μg.
3.2 Types of allergens suitable for immunotherapy
The ARIA article summarizes a large number of previous double-blind, placebo-controlled studies concluding that subcutaneous immunotherapy is effective in allergic rhinitis (and also conjunctivitis) induced by allergens. birch and birch family pollens, river grass pollen, ragweed pollen, wallflower genus pollen, a few other species of
house dust mites, cat allergens, Streptomyces spp. fungi, of which there are no studies on the effectiveness of immunotherapy with Mycosphaerella spp. in rhinitis. Specific immunotherapy with house dust, Candida albicans, bacterial vaccines, or other undefined allergens is not effective and is not recommended. In 43 placebo-controlled, double-blind studies, subcutaneous immunotherapy reduced symptoms by an average of 45% compared to placebo treatment. This was even better than the results of most drug treatments. Also, Abramson M has confirmed that immunotherapy is equally effective in asthma by summarizing the previous literature. However, it should also be noted that patients with multiple allergen sensitization may not benefit from specific immunotherapy as much as patients with single allergen sensitization [11].
3.3 Long-term efficacy of immunotherapy
In the last 5 years, the most important article on the issue of long-term efficacy of immunotherapy for clinicians came from Durham et al [12]. After 3 years of immunotherapy, 16 patients with hay fever continued to receive maintenance dose injections for 3 years (monthly injections of aluminum-absorbed pollen extract containing 20 μg of the major sensitizing protein), 16 patients received placebo treatment, and 15 new patients were followed up and bit given any treatment. After another 3 years, patients in both the maintenance dose and placebo groups showed similar symptom relief. The new patients exhibited more severe symptoms. Both the maintenance dose and placebo groups continued to show inhibition of late-phase skin responses. No rebound of CD3+ or IL-4+ cells was found in skin biopsies from the placebo group. This study demonstrates that immunotherapy can provide a long-term symptomatic improvement in patients with respiratory allergy. In another retrospective study of children with mite allergy, immunotherapy for more than 3 years had longer-term symptom relief than patients who received immunotherapy for shorter than 3 years.
4 Clinical risk factors
Immunotherapy has been shown to be effective in reducing the symptoms of allergic rhinitis and asthma. Nonetheless, concomitant desensitization subcutaneous injections have been associated with the development of fatal allergic reactions. Take North America as an example: in 1987, Lockey et al. first investigated the rate of fatal adverse reactions among patients receiving immunotherapy and allergen skin testing in North America between 1958 and 1984. The results showed that there were 24 deaths from immunodesensitization injections and 6 deaths from skin tests. It was concluded that dosing errors, concomitant use of beta-blockers during injections, previous systemic adverse reactions to immunotherapy, and peak seasonal allergen exposure were the main causes of fatal adverse reactions [; 6 years later Reid et al. (1993) reported 15 deaths from immunotherapy and 2 deaths from skin testing between 1985 and 1989 and found that Most of the above deaths were accompanied by moderate to severe asthma, and therefore moderate to severe asthma was considered an independent risk factor in immunotherapy and skin testing. The probability of fatal adverse reactions in the above 2 groups of studies was 1/2800000 injections and 1/2000000 injections, respectively.
Bernstein concluded that there were 41 deaths from immunotherapy and skin testing in North America during the 12-year period from 1990 to 2001. The probability of fatal adverse reactions was 1/2540000 injections, which is similar to the results of the above 2 groups of studies. Dosing errors and misuse of beta-blockers have been extremely rare. This is attributed to improved clinical practice and the popularity of clinical guidelines. In contrast to previous studies in which lethal adverse reactions were mostly seen in the dose accrual phase, the vast majority of lethal adverse reactions in this data set occurred in the maintenance dose treatment phase. This may also be due to a decrease in adverse reactions during the dose accrual phase, as further standardization of clinical practice has reduced dosing errors. The majority of deaths in this group were in patients with asthma whose symptoms were not well controlled, suggesting that uncontrollable asthma remains the primary risk factor for immunotherapy. In addition, immunization at home and in informal medical settings where resuscitation is not available should be prohibited. Bernstein summarizes some of the characteristics of this group of deaths and provides some recommended measures (see Table 1)
Table 1: Bernstein’s summary of questionnaires on lethal adverse reactions to immunotherapy injections and skin tests in North America from 1990-2001
Study Findings
Recommended measures
1 fatal adverse reaction following skin prick testing with multiple food allergens
Avoid skin testing in patients with uncontrollable asthma
Minimize the number of skin testing allergens in patients with severe asthma
60% of patients with lethal adverse reactions had poorly controlled asthma symptoms during immunotherapy; 50% of asthma patients had FEV1 <70% prior to treatment
Careful consideration of risk/benefit ratio before starting immunotherapy
If asthma is not well controlled, immunotherapy should be denied and asthma and peak flow rate should be assessed prior to injection
Lethal adverse reactions at home or in unsupervised outpatient settings
Self-injectable epinephrine should be given to high-risk patients; patients at risk should be observed for more than 30 min after injection; immunotherapy should be administered by a professional in a well-equipped hospital, and immunotherapy at home is strictly prohibited
Inadequate epinephrine administration
Give 1:1000 epinephrine 0.3-0.5mg intramuscularly, repeat 2 times the dose if necessary; if there is no response to the intramuscular route of administration, give 1:10000 epinephrine intravenously
Difficulties in establishing a patent airway
The clinician must be ready to establish and maintain a patent and open airway if necessary.
5 Epinephrine administration
When anaphylactic reactions occur, health care providers are often not determined to apply epinephrine early and in a timely manner; Norman (1989) reported that epinephrine was not used throughout the resuscitation process in 40% of the 24 deaths that occurred during immunotherapy; Hurst found that epinephrine was used in only 30% of cases with systemic adverse reactions and strongly recommended that epinephrine be administered at the time of anaphylaxis. and strongly recommended the early use of epinephrine at the onset of allergic reactions [13]. One of the reasons why some physicians do not use epinephrine is the concern that overdose may cause tachycardia or arrhythmias. As a compromise, some authors recommend repeated subcutaneous injections of small doses (0.1 to 0.2 ml) of 1:1000 epinephrine, thinking that this would be safer. However, contrary to this is the fact that single doses of epinephrine injections close to 1 ml are still routinely used in adult cardiac resuscitation. In recent years, intramuscular epinephrine has been advocated for the treatment of anaphylaxis because of its more rapid action. The United Kingdom Resuscitation Council (the
United Kingdom Resuscitation
Council) recommends giving an initial dose of 0.5 ml of epinephrine intramuscularly to patients over 12 years of age with fatal anaphylaxis, with repeat injections if necessary. When intramuscular injections are ineffective, epinephrine should be given promptly by the intravenous route.
6 Duration of observation after immunization injection
It is worth noting that some fatal reactions occur 30 min after injection. Late onset non-fatal systemic reactions are of course common for immunotherapy, accounting for 38% of all systemic reactions. The latest clinical guidelines for immunotherapy recommend routine observation for 20 to 30 min after immunization, but recognize that some patients may experience delayed systemic reactions. This guideline recommends the administration of self-injectable epinephrine and extended post-injection observation beyond 30 min for patients who are at high risk or have had a recent episode of delayed systemic reaction [14].
7 Immunotherapy in special populations
7.1 About immunotherapy in children
Immunotherapy in children requires special caution because there are some special problems in this age group. For example, the diagnosis of allergic rhinitis/ocular conjunctivitis is more difficult in children under 5 years of age. For example, allergic rhinitis is sometimes difficult to distinguish from recurrent acute episodes of upper respiratory viral infections. Most scholars advocate immunotherapy after 5 years of age. Immunotherapy for children aged 3 to 4 years has been reported [15]. However, controlled studies are needed to compare the risk/benefit ratio. If it is indeed suitable for children, the physician must have the ability to manage the possible systemic reactions in children.
Advantages of immunotherapy in children: immunotherapy in children is generally considered to be more effective than in adults. If the child has only allergic rhinitis/conjunctivitis, immunotherapy may prevent the development of asthma. Several controlled studies have shown that the probability of developing asthma in children with allergic rhinitis treated with immunotherapy is significantly lower than in control children treated with medication alone. In addition, a prospective non-randomized study showed that 45% of children in 2 groups of mite allergic children who received immunotherapy developed new allergies within 3 years, while all of the control group developed new allergies. This study suggests that immunotherapy may also alter the natural course of allergic reaction development by preventing the development of new allergies.
Problems with immunotherapy in children: (i) More research is needed to clarify how immunotherapy alleviates allergic disease and prevents its progression to asthma. (ii) Children <5 years of age are more susceptible to systemic reactions with the application of rapid immunotherapy, especially when bronchial reactions occur, which are more difficult to control than in children older than 5 years of age. ③Children and their parents are not aware of the discomfort caused by multiple injections and are easily neglected in the event of an adverse reaction. ④The optimal maintenance dose required for pediatric patients is still unclear. ⑤ It is still unclear whether repeated applications of aluminum hydroxide containing preparations in children can cause adverse reactions.
7.2 Safety of immunotherapy in pregnant women
Much attention has been paid to the use of drugs in pregnant women because they are not only relevant to the pregnant woman herself but also directly to the health of the fetus. The safety of immunotherapy in pregnant women has been questioned because of the possibility of systemic reactions, abortion due to uterine smooth muscle contraction, and effects on fetal development.Metzger et al. (1978) conducted a retrospective investigation of this issue. They collected data from three groups of patients, group 1 being pregnant women with allergic asthma and/or rhinitis who received immunotherapy, group 2 being pregnant women with allergic asthma and/or rhinitis who did not receive immunotherapy, and group 3 being healthy pregnant women. Numerous controlled observations have shown that immunotherapy during pregnancy is safe in terms of miscarriage, death, incidence of immature children, neonatal mortality and incidence of congenital malformations. In addition, local reactions occurred in 55 cases and systemic reactions in 7 cases of treatment received, but did not result in miscarriage. However, to avoid any allergic accidents, dose increases during pregnancy are not recommended, nor is the initiation of immunotherapy for allergic rhinitis during pregnancy.
8 New routes of immunotherapy
Subcutaneous injections, the main method of immunotherapy, are inconvenient because of the need for multiple injections, local discomfort of the injections, and the possibility of adverse reactions. Since the early 20th century, some scholars began to explore the local route for immunotherapy. Such as oral, intranasal, bronchial, and sublingual routes, with the aim of obtaining the same effect while reducing adverse effects, time, and cost.
According to a retrospective study by Canonica and Passalacqua [16], the intranasal and bronchial routes have been largely abandoned due to local adverse effects, and the oral route has been limited by the high doses required, which often lead to gastrointestinal side effects. The sublingual route of immunotherapy (SLIT) is currently being used.
immunotherapy (SLIT) is currently being supported by many studies in Europe. A large number of facts demonstrate the clinical efficacy of SLIT in inducing rhinitis in numerous allergens, such as grasses, mites, birch, wallabies, etc. Its clinical effectiveness ranges from 20% to 50%, approaching the subcutaneous route of immunotherapy. The most common side effect is oral-sublingual tingling sensation, mostly described as mild and self-resolving. One author writes, “Notably, no serious systemic adverse reactions have been documented in the literature in the past 15 years.” The appropriate dose is not yet known, and in the cited literature, effective doses range from 3 to 5 times the dose of immunotherapy by the subcutaneous route to 375 times the dose.
Comparative studies on SLIT and subcutaneous immunotherapy are scarce. khinchi performed the only double-blind, double-dummy controlled study to date [17]. After 2 years of treatment, patients in both groups showed desirable symptom relief. Five subsystemic reactions occurred in the subcutaneous group, two of which were treated with epinephrine. none of the systemic reactions occurred in the SLIT group, but most presented with local tingling and mild oral and pharyngeal edema.
Whether SLIT induces the same immune changes as subcutaneous immunotherapy is not well understood. Elevated levels of specific IgG4 and decreased levels of IgE have been found from time to time during SLIT, although this is not regular, and Fanta found that after one year of SLIT, the proliferative response of lymphocytes stimulated by allergens was significantly reduced, but there was no change in cytokine production by allergen-specific T-cell clones [18].
Several commercial allergen vaccines for sublingual use are about to be ready for application in Europe. However, such vaccines are not yet approved in the United States. A large number of questions need to be answered urgently, such as dose, regimen, and immunological changes, among others.
9 Future strategies for immunotherapy
9.1 Anti-IgE and immunotherapy
The combination of anti-IgE antibodies (omalizumab) and allergen immunotherapy may offer an unprecedented therapeutic advantage. Immunotherapy can reduce serum IgE levels but to an extremely limited extent, and anti-IgE therapy can fill this gap. Further studies have shown that anti-IgE measures during immunotherapy are effective in reducing IgE-mediated allergic reactions. The use of omalizumab during the maintenance dose phase of immunotherapy reduced the symptom load by 50% compared to immunotherapy alone [31]. However, its high price limits its use.
9.2 Adjuvants
The application of new adjuvants to enhance the ability of allergenic vaccines to induce an immune shift from TH2 to TH1 is also a new hot topic.
One of the newly discovered adjuvants is 3-deacylated monophosphoryl lipid A (MPL), derived from lipopolysaccharide (LPS), which is a potent promoter of the TH1 response and may induce IL-12 expression through antigen-presenting cells. Some studies have shown that the addition of MPL to Grass pollen extracts for immunotherapy significantly reduced the symptoms of allergic patients, reduced drug dosage and increased antigen-specific IgG levels [19]. In addition synthetic oligodeoxynucleotides containing CpG units (CpG-ODN) can also be used as adjuvants coupled to allergens for immunotherapy.
9.3 Recombinant allergens
Recombinant allergens have great advantages for both diagnostic and therapeutic use in allergic diseases, as they maintain a high level of purity, whereas natural allergens, even when standardized, can contain multiple non-active components that can compromise diagnosis and efficacy. In addition, the use of genetic engineering technology allows for the reduction of IgE-binding antigenic epitopes of recombinant allergens, which are not recognized by IgE, while retaining the associated T-cell antigenic determinants, which still have the ability to stimulate T cells. This reduces the occurrence of adverse reactions without compromising efficacy.
9.4 DNA vaccines
It was found that plasmid DNA (pDNA) encoding a certain allergen injected into muscle or subcutaneously can be taken up by somatic cells, including APCs, and synthesize allergens. The inoculation of mice with ovalbumin pDNA followed by ovalbumin excitation was found to inhibit eosinophil infiltration and reduce IgE antibody titers [21]. Therefore, it also holds some promise for application.