动物实验,过敏原免疫疗法 z-bo 2020-08-25 676

　　When and why were aluminum adjuvants introduced into medicine?

　　Glenny et al. reported for the first time that aluminum, in the form of a potassium salt, could be used in vaccine formulations in 1926. Because it can induce and enhance the immunogenicity of toxoid preparations. Later, some studies compared different aluminum compounds, especially aluminum hydroxide and aluminum phosphate adjuvants. Since then, the most important vaccines are formulated and tested using aluminum hydroxide, such as diphtheria toxin, diphtheria and tetanus toxoid. The most important vaccine approved by the US Food and Drug Administration today is formulated with sodium hydroxide. At least in the primary immune aluminum preparation has superiority, although the booster immune effect is small. Aluminum hydroxide is also widely used in the veterinary field. The last one is not the least important, aluminum hydroxide is introduced to heal and prevent gastric ulcers and intestinal fistulas. Compared with other compounds, its superior proton buffering capacity has been confirmed in dog model experiments.

　　Review: Mechanism of Action of Aluminum Adjuvant in Systemic Allergen Immunotherapy

　　"Type I allergy is characterized by specific IgE, typically IL-4 and IL-13 related to Th2 response, sometimes accompanied by eosinophilic inflammation. It is understood that systemic allergen immunotherapy (SIT) enhances Th2-type immunity and leads to a balance of Th1-type and Th2-type immune responses. Or induce immune tolerance of T cells and B cells, accompanied by the production of IL-10, IFN-γ and TGFβ. Systemic allergen immunotherapy (SIT) is the only etiological therapy, which is a long-term treatment and problem-solving method for many years through subcutaneous (SCIT) or sublingual administration (SLIT). It is well known that when aluminum adjuvants are used, IgE levels generally increase at the beginning of SIT. Long-term immunity results in "modified Th2 immunity" with protective properties. Although there is still no consensus on the down-regulation of specific IgE, it has been accepted for a long time that the induction of IgG antibodies, especially non-inflammatory IgG4, is a sign of allergen immunotherapy. There is no convincing data to show that any changes in antibody subclasses, cytokines or factors are related to clinical outcomes and can be regarded as a biomarker. In fact, when Noon and Freeman used allergen extracts as a preventive vaccine in 1911, they did not use aluminum compounds. In 1937, aluminum was introduced for the first time in allergen vaccines. Some authors have studied different aluminum forms, such as aluminum hydroxide (Al(OH)3), aluminum phosphate (AlPO4), or aluminum stearate, focusing on the precipitation and storage effects of adjuvants. Today, aluminum compounds are used as adjuvants for allergy vaccines in Europe, while adjuvants for allergy vaccines in the United States are free and soluble. Aluminum compound adjuvants promote immunization against allergies, and its popularity even predates the discovery time of IgE immunoglobulins and has been studied in human and animal models. It is recognized that an independent antigen and vaccination aluminum can be predetermined as the type of antigen continuous immunity. For example, rats immunized with pertussis toxin and Al(OH)3 showed increased IgE to the allergen ovalbumin. This "non-specific enhancement of allergic reactions" was confirmed after the rats were injected with the vaccine, but the authors showed that the effect was caused by the use of aluminum adjuvants only.

　　In 1972, young healthy people were immunized against ryegrass pollen allergens and aluminum compounds. They developed type I skin hypersensitivity, specific histamine release capacity, and passive transfer of IgE antibodies. However, the study subjects have no clinical symptoms, which may be due to the fact that agglutinating antibodies (IgG) are formed. According to the current point of view, it can be used as a blocking antibody. This human model was also shown on a canine model that the sensitized 2,4-dinitrobenzene combined with ovalbumin resulted in the formation of IgE. When IgE levels are high enough, bronchoconstriction can cope with the challenge of allergens. It was reported in the same year that the immune response in other mammals may be different: when the foot-and-mouth disease virus of dairy cows is treated with Al(OH)3 adjuvant vaccine, reactin and agglutinating antibodies are produced. But there are no parameters related to the size of the intradermal test.

　　Itaya and colleagues confirmed in mice that aluminum compounds are good IgE-inducing adjuvants, while other adjuvants containing LPS cannot induce IgE. Interestingly, when adjuvants containing aluminum compounds are given before sensitization, they inhibit continuous allergic reactions.

　　In addition, it is reported that the intramuscular injection of aluminum hydroxide and aluminum phosphate in rabbits increases the level of aluminum in the blood for 1 hour. After 28 days, 3 times of Al(OH)3 remained absorbed in the body in the following tissues: kidney?>?spleen?>?liver?>?heart?>?lymph nodes?>?brain. At present, most subcutaneous allergen immunotherapy uses aluminum hydroxide as an adjuvant, rarely calcium phosphate. But the preparation of SLIT does not contain any adjuvants. Other preparations, such as prebiotics, mycobacteria (attenuated or ghost), virus particles, TLR ligands are still in the experimental stage.

　　The role and side effects of aluminum in allergic immunity: When using aluminum adjuvants and allergens to treat SIT, prolong the induction of allergen-specific IgG induced by immunity and ultimately dominate the IgE response. Long-term immunization is required because it is difficult to modify the established Th2 response, and it is easier to induce protective immunity through preventive vaccines. The induced IgG inhibits allergic reactions by inhibiting the interaction of IgE allergens and the presentation of related allergens. IgG and IgE compete by quantity rather than quality: the affinity of IgG to the important allergens Bet V 1 and Phl p 5 is significantly lower than that of IgE. Its main feature is due to the aluminum adjuvant: (1) The aluminum compound in the vaccine has a positive charge and can absorb negatively charged proteins. Through the electrostatic mechanism, the strength will depend on the affinity of the interaction. (2) Aluminum adjuvants are made into nanoparticles with allergens through adsorption and embedding methods. Phagocytes involve mast cells and macrophages through natural immunity and preferentially adopt endocytosis mechanisms, possibly involving inflammasomes. This will cause the inflammatory Th1 and Th2 cytokines to immediately release endogenous IL-18 to promote IL-4 production. The characteristics of immune regulation, including the branches of innate immunity and adaptive immune system, are described in great detail. (3) Aluminum adjuvant increases the phagocytosis of allergens by dendritic cells DCS, and interestingly, in the absence of DC activation, it leads to antigen presentation 6 hours later. (4) Aluminum adjuvants can precipitate allergens and form a warehouse from where the allergens are slowly released. The local deposition prevents the immediate release of allergens in allergic patients and reflects the safety of adjuvants. Surprisingly, the recent Al(OH)3 compared with the Th1 adjuvant Montanide, induces almost the same adenovirus-like related particle humoral immune response. In addition to Montanide into more obvious IgG2a and IgG2b. In early studies, the use of ragweed pollen or white pollen vaccine aluminum adjuvants showed excellent results in one-to-one comparison with other adjuvants. Considering the contradictory facts, the treatment of SIT aluminum adjuvants that can induce Th2 immune response is used to treat Th2 immune diseases. From an immunological point of view, it is surprising that these adjuvants can achieve high efficacy. However, the results of SIT can be improved by avoiding increased IgE and by adjusting the immune system more effectively, which can completely shorten its duration. Therefore, it is recommended to improve allergen immunotherapy by increasing immune-enhancing substances to induce Th1 immune response or through granular immune regulation, increasing the obvious TLR binding ability, or through its mucosal adhesion performance. It should be noted that the preventive model most commonly used in preclinical studies is different from the Th2 immune response associated with sensitized patients. Therefore, in order to prove the concept of research, the treatment model should be favored. In fact, based on the treatment of a mouse model, the grass pollen allergen microparticle oral vaccine can modify the established allergic reaction when the vaccine is targeted at mucosal M cells. This method uses aluminum adjuvant independently. Another adjuvant is also required and expected to induce cytotoxic T cell response and a higher degree of antigen presentation in addition to high levels of antibodies, such as cancer vaccines.

　　It has been reported so far that allergy vaccines using aluminum adjuvants have only mild side effects. For example, after 33-70% injection, acute and transient local pruritic nodules, sometimes particles, may appear. It is generally believed that local inflammation at the vaccine injection site is one of the important reasons for inducing an effective immune response. Recently, the induction of aluminum contact dermatitis after vaccination can be demonstrated in 5/78 children and 3/127 adults skin tests.

　　Aluminum exposure, dosage and side effects: Aluminum is a rich compound, and we live in an aluminum environment. Many new materials, such as textiles or toothpaste, have nano-aluminum that can promote the comfort of their use. However, the physical and chemical forms of aluminum determine its bioavailability and toxicity. Insoluble aluminum compounds may form particles, which can cause inflammation through ingestion or breathing.

　　Aluminum intake in drinking water varies greatly, but in some places it may exceed 15 times the weekly tolerable aluminum intake (TWI) recommended by the World Health Organization. Its solubility depends on the pH value and acidic conditions, and even reaches 90 mg/L, and the concentration in the air may be 0.0005 μg (at the level of the Arctic) 1 μg in industrial areas. Food and feed intake and additives contribute to aluminum consumption. In short, the European Food Safety Authority has determined that the TWI of all sources of aluminum is 1mg/kg. Breast milk contains 0.04mg/L aluminum. Therefore, breastfed infants up to the age of 6 months can completely consume 7 mg of aluminum, and formula milk can consume 38 mg of aluminum and soybean-fed can consume 112 mg of aluminum because soybeans are plants that accumulate aluminum.

　　A hot topic in the current debate is that aluminum is introduced into the human body through a vaccine. In the United States, 0.85 mg of aluminum is recommended, and under the record, the highest aluminum injection dose per single vaccine is 1.25 mg. Up to 1.25mg in Europe. For example, the information platform for vaccinated patients classified the 4.4 mg of aluminum from vaccines as infant vaccines.

　　At the time of injection, all possible forms of aluminum in the tissue, including ions, soluble aluminum, particulate form, alone or bound to antigens or tissue compounds, can be found. The biological activity of aluminum adjuvant after injection comes from Al3+ and aluminum (Al(OH)4?) ions, which can react with water and ultimately lead to the production of aluminum oxide. However, most of the injected aluminum will be swallowed to activate immune cells to recruit more inflammatory cells. Due to its high affinity with iron, aluminum can deplete mitochondrial iron and lead in cells to generate reactive oxygen species (ROS). Aluminum can induce nucleic acid damage through reactive oxygen species and has the effect of inducing cell apoptosis. This has been demonstrated through peripheral blood lymphocytes, especially in the G0/G1 phase of the cell cycle. However, the amount of soluble aluminum injected locally may not be sufficient to induce cell death. It may be considered that children are exposed to vaccines containing aluminum, and immune function and brain development may be affected.

　　The cytokines and factors of the two-way communication between the brain and the immune system have been confirmed. There are also reports that aluminum particles can be swallowed from muscles and transported to the brain. Therefore, it is not surprising that aluminum intake has been discussed for a long time in neurological diseases, especially Alzheimer's. In mammals, ferritin is the main storage site of iron. Recently, it has been recognized that aluminum may replace iron in ferritin. Through mass spectrometry, it was found that ferritin in Alzheimer's patients has a higher aluminum content, and its content depends on the stage of the disease. In some areas, increased intake of aluminum through drinking water is also associated with the development of Alzheimer's disease. However, bringing together the available data does not seem to be fully convincing, and part of the reason may be due to methodological limitations. A specific aluminum staining method is lacking so far, and it is only recently that fluorescent molecular probes have been developed to monitor aluminum and gallium. People should remember that oral antacids or sucralfate contain large amounts of aluminum compounds. We can show that oral intake of these aluminum compounds in a mouse model of food allergy supports the sensitization of Th2 cells with protein in food.

　　Recently, the so-called macrophage fasciitis has been attributed to the persistent presence of aluminum salts at the intramuscular injection site. Chronic fatigue syndrome and autoimmune diseases are also related to aluminum intake. The so-called autoimmune inflammatory syndrome ASIA is induced by adjuvants.

　　At present, it is recommended to refine the comprehensive review of the TWI aluminum dosage to reduce the aluminum in the infant parenteral nutrition solution (leading to bone mineralization). Coordinate the use of doses and reconsider its application in vaccines.