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Stem Cells offers the best and the most advanced treatment and  health with  of A1 Embryonic stem cells. Stem Cells offer the selection of Autologous Embryonic cells and standard embryonic stem cells. Stem cell has the capability to offer the Autologous embryonic stem cells using the advanced cloning techniques. After the harvesting of the cells, the talented technicians remove the DNA of those cells and replace with your DNA. Autilogpus stem cells can be understood as the best product in the market in the process of healing and rejuvenation.
The Embryonic cells, which are used by the Stem Cells, are being manufactured under a rigorous protocol in order to maintain the perfect condition of the product. Our patient coordinator is there to help you to select the most suitable option for your treatment. After the completion of all the necessary tests, one of our experienced doctors will decide the amount of the embryonic stem cells for your requirement. The patients must have given with 1-12 injections and the amounts of the cells in each injection, vary between 5-20 millions of Embryonic stem cells. Embryonic Stem cells can be used to address various types of diseases such as immune response diseases, nerve damages or disorders and aging.
The genetic defects cannot be treated by Embryonic Stem Cells, but it can be used to minimize the effects and also to repair the damages to a certain extent.
The dedicated research team of Stem cells is doing continuous researches and evaluations in order to enhance the success of the protocol, and also to invent and develop new applications of Embryonic Stem cells.
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From Molecular Cloning to Vaccine Development for Allergic DiseasesJose Cantillo1 and Leonardo Puerta1[1] Institute for Immunological Research, University of Cartagena, Colombia1. Basal Cell Carcinoma (BCC) is the most common type of skin cancer and accounts for approximately 80% of skin cancers in the United States. Patients who develop any suspicious lesions that are changing, growing, bleeding or not healing, should consult a dermatologist for evaluation. Contact our office today at 817-427-3376 to learn more about Basal Cell Carcinoma or to make an appointment with Dr. Any electronic communication taking place through our website or email contains no encryption protection and therefore may not be secure. You agree that you will hold harmless Northstar Dermatology, its doctors, employees and affiliates from any form of unauthorized use of your personal information by outside parties. In majority of the individuals, the diagnosis of urinary bladder cancer is made at an early stage, thus making the chances of treating the cancer high. Treatment for urinary bladder cancer depends on the stage of the cancer and patient's general health and it includes: Surgery, radiation therapy, chemotherapy and immunotherapy. The type of the urinary bladder cancer depends on the bladder cell type where the cancer has originated. Squamous Cell Carcinoma: In this type, the cells of the bladder, due to recurrent irritation and infection turn cancerous.
Transitional Cell Carcinoma: This type develops in the cells which are lining the internal side of the bladder.
Adenocarcinoma: This type of urinary bladder cancer develops in the cells of the glands which secrete mucus in the bladder.
White individuals are at a higher risk for developing bladder cancer when compared to other races.
Certain chemical exposure, such as to arsenic, and other chemicals which are used in manufacturing of rubber, dyes, textiles, paint products and leather increases the risk of having bladder cancer. Taking certain medications for diabetes, such as pioglitazone (Actos), for long duration increases the risk of bladder cancer. Treatment for previous cancer, such as with cyclophosphamide (Cytoxan), which is an anti-cancer drug; or radiation therapy to the pelvis for treatment of other cancers, increases the risk of having bladder cancer. Recurrent or chronic urinary infections or cystitis increases the risk of developing squamous cell bladder cancer.
A certain parasitic infection (schistosomiasis) increases the risk of bladder cancer in certain parts of the world. Having a family history of Lynch syndrome, which is also known as hereditary nonpolyposis colorectal cancer (HNPCC), increases the risk of bladder cancer along with the cancer of colon, ovaries and uterus. Having a family history or a previous history of urinary bladder cancer increases the chances of you having one.
Hematuria, which is blood in urine, makes the urine appear bright red, dark yellow or cola colored. Cystoscopy helps in viewing the inside of the bladder and urethra by inserting a cystoscope which is a narrow tube through the urethra. Biopsy can be taken during cystoscopy and the collected tissue sample is sent for testing for cancer cells.
Urine cytology where a urine sample is taken and microscopically analyzed for the presence of cancer cells.
Intravenous pyelogram uses dye for highlighting the urinary system (ureters, bladder, and kidneys).
CT (Computerized Tomography) scan helps in better assessment of the urinary system and its adjacent tissues.
Stage I: In this stage, the cancer is confined to the inner lining of the bladder and has not spread to the wall of the bladder. Stage II: In this stage, the cancer is still restricted to the bladder, but has infiltrated the bladder wall.
Stage III: In this stage, the cancer has metastasized through the wall to the adjacent tissues. Stage IV: In this stage, the cancer has metastasized to the lymph nodes and organs like liver, lungs or bones. Treatment for urinary bladder cancer depends on the stage and the type of the cancer, patient's general health and patient's treatment choices.
There are many surgical procedures available and the choice of the procedure depends on the cancer stage, patient's general health and treatment preferences. Transurethral Resection (TUR) is a surgical procedure which is commonly done to remove cancer which is restricted to the inner layers of the urinary bladder. Segmental Cystectomy Or Partial Cystectomy comprises of removing the tumor along with a small part of the bladder containing cancerous cells. Radical cystectomy is where the entire urinary bladder along with the surrounding lymph nodes is removed. Immunotherapy, also known as Biological Therapy, is a treatment where the body's immune system is enhanced or used to fight against cancer cells.
Radiation therapy involves the use of high-energy beams, such as x-rays, which are directed at the area of the body where the cancer is present, to kill cancer cells. They differ from the Adult stem cells, as they have the ability to differentiate into 221 cell types in the body. The embryonic stem cells are mostly found in the 5 days old blastocyst, which is the basic step of the embryonic formation.
Standard lines of Embryonic cells are the ones, which are harvested at the cell 150 stage of the egg.
Animal feeder layers are not used in the process of growth so there is not any risk of contamination.
We can make an estimate of your required amount, with our 4 years experience in ESC treatments. The Parkinson patients playing the musical instruments and the depressed patients are moving into the real life without any medications. The successful action of the therapy has been very carefully and comprehensively checked and proved by our experienced medical partners and the biochemists for the following diseases.
Our company has invested in a clinical trial to offer successful treatments for Glaucoma and muscular Degeneration. Introduction Allergic diseases are manifested in susceptible individual by exposure to proteins named allergens that induce an immune response mediated by IgE antibody. It commonly presents as a slow growing pink pearly growth, sometimes with crusting or bleeding. Patients with a history of sun damage, precancerous lesions, or skin cancers may need routine skin examinations.
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To enhance your browsing experience, please upgrade to a more current browser such as Firefox, Safari or update to Internet Explorer 9. This type of urinary bladder cancer is more common in those parts of the world where schistosomiasis, which is a parasitic infection, is widespread. Transitional cell carcinoma is one of the frequently occurring types of urinary bladder cancer in America. Experts believe that DNA mutations in the cells cause uncontrollable and rapid dividing of the cells leading to build up of abnormal cells which result in cancer or tumor.
Passing a special instrument via the cystoscope into the bladder to collect tissue sample or biopsy is known as transurethral resection (TUR).
In this procedure, the surgeon passes a small sized wire via the cystoscope into the bladder.
Segmental cystectomy is done when the cancer is confined to a part of the urinary bladder and can be easily removed without damaging the bladder function.
This also includes removing the seminal vesicles and prostate in men; and ovaries, uterus and a portion of the vagina in females. Drugs used in chemotherapy for treating urinary bladder cancer may be two or more drugs used in combination.
Like chemotherapy, radiation therapy can also be done after the surgery to destroy or kill any remaining cancer cells. They are called as “pluripotent” They are consisted with special information, which can be exchanged with the adjoining cells.
Each batch of cells is manufactured just before the injection and they are injected into the body, while it is alive. As any other types of treatments the degree of the result may vary from patients to patient. After vaccination, allergen is taken up by antigen presenting cells leading to the differentiation of naive T cells to inducible T regulatory cells.
Numerous allergens from different sources such as plants, insects, mites and mammals have been obtained as recombinant molecules by molecular cloning. This type of cancer rarely spreads to other body parts and tends to grow locally in the same area. The most common treatment for basal cell carcinoma consists of surgical excision in which the tumor is surgically removed and stitched up. So, patient should do follow-up tests for many years after they are declared cancer free to catch any recurrence of urinary bladder cancer. This test can also be done for treating urinary bladder cancer and is commonly done using general anesthesia. Women will suffer from premature menopause and infertility due to removal of uterus and ovaries. Chemotherapy drugs can be administered intravenously or directly into the bladder, which is known as intravesical therapy. When it has about 150 cells in total, the cells are separated and cultured under precious laboratory conditions to create millions of embryonic stem cells in order to treat patients. There is a very small number of patients, who do not show any response to the embryonic stem cells. These cells with the thymus-derived FOXP3+CD4+CD25+ T regulatory cells, suppress allergic response by the following mechanisms.
These types of molecules have shown molecular, functional and immunological properties similar to the corresponding natural allergens and, therefore, could be used for in vitro and in vivo diagnosis test of allergy.


Common risk factors for basal cell carcinoma include fair skin color, sun exposure, increased age, and exposure to other forms of UV radiation such as tanning beds. Larger tumors or lesions on cosmetically sensitive areas may require Mohs Micrographic Surgery, a tissue-sparing procedure in which the tumor is excised in layers and mapped out. Chemotherapy is also done before surgery to shrink the tumor or after the surgery to kill any remaining cancer cells.
The majority of the patients will show major improvement in their health condition.  There should be adequate time for the body to get out of its ailments, so it is better to wait until 3 weeks for the total recovery.
An important step was done with the development of variants of allergens with reduced allergenicity and preserved immunogenicity, which paved the way toward its rational use in allergen specific immunotherapy to treat allergies. There are also rare genetic conditions which increase the risk of developing basal cell carcinomas at an earlier age.
Other options include curettage and electrodesiccation in which the lesion is shaved, scraped and burned with an electrical needle. Older adults are commonly affected by this disease; however, bladder cancer can occur in individuals from any age group. Few of the allergens cloned have been developed to a stage at which they are suitable for use in clinical studies. Topical chemotherapy creams can also be used for superficial basal cell carcinomas in patients who are not surgical candidates. However, today the academic and scientific communities note a broad and important activity to offer in the near future preparations with enhanced clinical efficacy and safety.
Depending on your skin type, size and location of the lesion, a dermatologist can help determine which treatment option is best.
Induction of IgG4 antibodies production from B cells that block the binding of allergen with the IgE. In this work, basic aspects and experimental and clinical results of this process are presented. Progress in the molecular cloning and production of allergens The molecular cloning has provided a practical and efficient way to obtain highly purified molecules for different purposes; in the biomedical sciences this is evident by the increasing amount of biological products, obtained by recombinant DNA technology, which are commercially available for diagnosis and treatment of different diseases, as well as the wide variety of reagents for basic research. The era of molecular cloning of allergen molecules was initiated in 1988 with the report of a cDNA clone coding for the allergen Der p 1 isolated from a cDNA library of the house dust mite Dermatophagoides pteronyssinus, screened with rabbit anti -Der p 1 antiserum [1, 2]. This strategy was useful to explore the whole spectrum of IgE binding proteins in a natural source and to isolate positive clones to express the molecules [4, 5].
Often, the amount of insulin needed over the course of 24 hours varies depending on factors like exercise, activity level, and sleep. The development and optimization of technology based on the polymerase chain reaction (PCR), have given an important impulse to cloning and identification of new allergens. PCR can be applied to screen cDNA library and amplify specific clones, or to obtain by RT- PCR the nucleotide sequence coding for specific allergens and then cloning in an appropriate vector for expression [6-10]. The numerous nucleotide sequences of allergens reported in data bank have facilitated the isolation of new allergens from RNA material using PCR technology, avoiding the construction of cDNA library and the use of sera from allergic subjects for screening, which is time consuming [11-14]. An expressed sequence tagging (EST) approach was applied to obtaining a large sampling and overview of expressed genomes of several mite species [15], the EST approach involved the partial sequencing of random clones selected from cDNA libraries, allowing the identification of allergens with homology to genes from more distantly related species or even across taxonomic kingdoms. It comes with a transfer guard (blue piece at the top that is removed before inserting the reservoir into the pump) that assists with pulling the insulin from a vial into the reservoir. Infusion Set An infusion set includes a thin tube that goes from the reservoir to the infusion site on your body. However, by genetic engineering modified strains of this bacteria and novel expression vectors have been obtained, which allow expression of heterologous protein in soluble form with functional properties and high yield; Origami, Rosetta or BL21(DE3)-CodonPlus-pRIL and Rosetta-gami are strains commercially available for obtain recombinants with some pos-translational modifications [20].
The GST tag used in the expression of the first recombinant allergens have been replace for His x6 tag, which is shorter, the recombinant can be analyzed without removing the tag due to the negligible effect on the properties of the molecule, and several efficient purification systems are commercially available.The eukaryotic expression system have the capacity of performing many of the post-translational modifications including signal sequences, disulfide bond formation, and addition of lipid and carbohydrates. A variety of eukaryotic expression systems like yeast, insect cells, mammalian cells and plants are available.
Several recombinant allergens have been obtained by expression in this yeast and their biologic properties demonstrated by different methods, this system have resulted especially practical when post-translational modifications or biochemical activity exist [26-29]. The human cells have been used to obtain the Phleum pretense allergen, Phl p 5, as a secreted or membrane-anchored protein and showed to be biologically active, with capacity to bind human IgE, to induce mediator release from basophiles and to stimulate T cell proliferation [30].
A large percentage of allergens are from plants, thus the plant-based expression systems are ideal for the production of certain recombinant allergens, which could have problems such as incorrect processing, incorrect folding and insolubility when expressed in bacteria or other non-plant systems.
Thaumatin or thaumatin-like proteins, only when expressed in Nicotiana benthamiana result in fully IgE-reactive proteins [31]. Interesting, expression in plants offers the opportunity for oral delivery of recombinant allergens of non- plant origin as a therapeutic approach for mucosal immunization for treating allergic diseases. Oral treatment of mice with squash extracts containing virus-expressed Der p 5 allergen caused inhibition of both allergen-specific IgE synthesis and airway inflammation [32], this plant-based edible vaccines is very promising.3.
Current vaccines for allergic diseasesAllergies are inflammatory diseases characterized by a Th2 biased response induced in atopic individuals for exposure to allergens.
The Th2 response is also induced by helminthes, which occur in an environment characterized by the presence of IL-4, IL-5 and IL-13. Nuocytes [33, 34], basophiles [35] and type 2 multi-potent progenitor cells [36] seem to be an important source of this cytokines and necessary for the development of allergic response. Allergen-specific IgE antibodies produced by B cells bind to Fc epsilon receptor 1 (Fc?RI) on basophiles or mast cells, sensitizing them. After consecutive exposure, allergen binds to IgE on these cells leading to the release of inflammatory mediators of immediate-type symptoms of allergic diseases and paves the way for late-phase inflammatory responses caused by basophiles, eosinophils and T cells. Allergen specific Th1, Th9, Th17 and Treg cells are also produced in this process [37, 38].
Allergen-specific immunotherapy (SIT) is the only curative and specific approach for treatment of allergies [39, 40]. The current SIT consists of gradual administration of increasing amounts of allergenic extract with the aim to avoid allergic symptoms associated to the exposition. The induction of allergen tolerance is the essential immunological mechanisms of SIT, and involve allergen-specific memory T and B-cell that lead to immune tolerance characterized by a specific noninflammatory reactivity to a given allergen and prevention of new sensitizations and progression of allergic disease. During the immunotherapy, different regulatory and effectors components of the immune system are involved (Figure 1). Allergen tolerance is characterized by the generation of two subgroups of Treg cells: FOXP3+ CD4+ CD25+ Treg cells and inducible Treg cells [41]. T-regulatory type 1 (Tr1) cells have shown to play a major role in allergen tolerance induced by SIT [42, 43].
The immunosuppressor mechanism of Treg cells is mediated by the production of high level of anti-inflammatory cytokines IL-10 and TGF-?, although IFN-? could also be produced [44-46]. The expression of different subtypes of antibodies during SIT is mediated by the activity of regulatory cytokines secreted by Treg cells; IL-10 is a potent suppressor of allergen-specific IgE and simultaneously increases IgG4 production [42].
The IgG4 seems to act as a blocking antibody that interacts with the allergen, avoiding interaction of allergen with the IgE [48].
Suppression of effector T cells.Vaccines composed of whole allergenic extract are complex mixtures of known and unknown material, prepared directly from the allergen source, thus containing allergenic and non-allergenic material and being difficult to standardize [49-51]. Some non-allergenic components have been shown to prime a Th2 response [52], which offset the efficacy of this type of vaccines. SIT with allergenic extract induce a variety of side effects ranging from local to systemic which in some case may be life-threatening [53]. Moreover, in some preparations the important allergens are not well represented or they exhibit poor immunogenicity [51]. Administration of whole allergenic extracts can induce new IgE specificities against allergens present which were not recognized by the patient before treatment [54].
Recombinant allergens for diagnosis and allergen-specific immunotherapyRecombinant allergens may be obtained with the same structural and immunological properties of its natural equivalent, therefore, the usefulness for diagnosis or immunotherapy is guarantee. Diagnosis of allergy A more appropriate diagnostic of allergic diseases would be obtained by identification of the particular molecules involved in allergic response, which could be done using purified wild type or recombinant allergens in order to define the sensitization profile of each allergic subject, the concept “Component-resolved diagnosis” was applied to this kind of diagnosis [56], that would allow a “component-resolved immunotherapy”, in which only the allergens involved in the sensitization are applied to an allergic subject, avoiding new sensitizations.
In allergies with a high compromise of cross-reactivity such as the pollen-related food allergy the power of in vitro testing using allergenic extracts is very low [60]. Component resolved diagnosis with recombinant allergens result in excellent sensitivity, when applied to allergy to hazelnut that shows cross-reactivity with pollen allergy. Vespid allergy is characterized by cross-reactivity between hymenoptera species, and it has been established that the true source of sensitization must be defined to ensure the efficacy of venom immunotherapy [61].
A combination of these four allergens is enough to differentiate the real causative venom in at least 69% of the population. In allergy with a wide spectrum of sensitization profile as the induced by Phleum pretense pollens, the use of recombinants is useful to establish a tailor made immunotherapy approach [63].
A hybrid molecule composed of several segments of a grass pollen allergen showed in skin tests on 32 allergic individuals that with only this molecule all the allergic patients can be identified [64].
The technology of microarrays can be applied to target protein interactions and the serological immune response to antigens [65]. Microarrays are highly useful for detecting all antibodies isotypes and are a powerful tool for component-resolved diagnosis. The primary advantage of microarrays is that specific IgE to thousands allergens can be assayed in parallel with small amounts of serum, at the same time, much less amount of allergen is required.
The advantages of protein microarrays to detect specific-antibodies against multiple targets have been taken to develop component-based diagnosis tools. One of its potentials lies in the recognition of individual patterns of IgE reactivity to protein families with homologues across plant or animal species [66, 67]. When microarray test for diagnosis of birch and timothy allergy were compared with other in vitro tests (Phadia CAP-FEIA and in-house ELISA), a correlation greater than 0.9, with high sensitivity and specificity was obtained [68].
Latex allergy diagnosis is well known to be confounded by a high rate of false positive results when using conventional testing, and positive specific IgE results does not always mirror the clinical situation. A combination of recombinant latex allergens (Hev b 1, Hev b 3, Hev b 5 and Hev b 6.02) on a microarray, was enough to detect individuals allergic to latex with a sensitivity of 80%, and allows discrimination between genuine allergy and sensitization [69]. Recently, a library of 419 overlapping peptides corresponding to the aminoacid sequence of peanut allergens Ara h 1, Ara h 2 and Ara h 3, printed onto glass slides to asses IgE reactivity, was evaluated as a diagnostic tool that could replace the traditional used double-blind, placebo controlled food challenge, that is time consuming, expensive, stressful for the patient and have the risk for potentially life-threatening anaphylactic reaction [70, 71]. Based on the number or peptides that bind IgE and the intensity of the reaction, was possible to distinguish peanut allergic and peanut tolerant individuals with approximately 90% sensitivity and 95% specificity [71]. To evaluate the clinical significance and allergenicity of several recombinant allergens from B. No adverse reactions were observed in the allergic or control subjects who were skin tested.
Allergen-specific immunotherapy Allergen SIT with recombinant allergens was proposed when it was demonstrated that these molecules have similar or the same biological properties of their natural counterparts [73, 74], and the necessity of highly purified and well standardized allergens were required for overcome the problems related to difficult standardization and management of the doses observed with the whole allergenic extracts. A study with the recombinant pollen allergen Bet v 1 (rBet v 1) demonstrated that immunotherapy with a single allergen is effective for the specific treatment of allergy [75]. In a multicenter, double-blind, placebo-controlled clinical trial, patients with history of birch pollen–related rhinoconjunctivitis were divided in four groups and treated for two years with rBet v 1, natural birch pollen extract, natural Bet v 1 (nBet v 1) or placebo, to compare the efficacy of each preparation for allergen-specific immunotherapy. Treatment with rBet v 1 reduced symptoms of rhinoconjunctivitis and skin reactivity induced by birch pollen, and showed to be safety without serious adverse events. The immunotherapy showed a 36.5% lower median average symptom score for active treatment compared with placebo and reduction in the need for medication.
By the first and second pollen season, improvement in quality of life scores was present in the patients receiving active treatment.
Active treatment induced IgG1 concentrations approximately 60-fold, peaking during the rusty 12 months of the study and IgG4 levels showed a 4000 fold increase by the end of treatment. In contrast, after immunotherapy IgE levels in the active treated group were significantly lower than placebo group. This was the first clinical study of immunotherapy with a cocktail of 5 recombinant grass pollen allergens that showed its clinical efficacy, good tolerance and strong induction of allergen specific IgG antibody response.5. Approaches for an immunotherapy of allergy based on modified recombinant allergensSeveral in vitro and in vivo assays indicate that allergy vaccines based on recombinant allergens might have provide a safe and efficacious immunotherapy. However, recombinants with the same amino acid sequence and similar allergenic activity as the natural allergens can elicit IgE-mediated side effects, which are a major risk during allergen-speci?c immunotherapy. To overcome this problem different approach have been designed to obtain molecules without or reduced IgE reactivity [76]. Recombinant DNA technology has allowed the rational design and production of well-defined modified allergens for this purpose. Hypo-allergens are molecules derived from wild type allergen which exhibits reduced capacity to react with IgE antibodies and low ability to induce IgE-mediated mast cells or basophile degranulation.


They are designed to reduce the risk of anaphylaxis during the course of immunotherapy, are molecules with conserved T-cell epitopes that could be recognized by specific T lymphocytes to induce a protective response against wild-type allergen. Some allergens are present in the nature as a mix of several isoforms with high structural homology but different IgE reactivity.
The production by molecular cloning of natural isoforms with low IgE reactivity has been used to propose anti-allergy vaccines. There are several examples of this approach that illustrate the potential use for the development of new vaccines. Mouse allergic individuals are sensitized mainly against the major allergen Mus m 1 a urinary protein belonging to the lipocalin superfamily which have typicall ?-barrel fold, that can be modified by mutation in the Tyr 120 residue, [80, 81]. The mutants showed low capacity to react with IgE from allergic individuals and induced lower basophil degranulation than those induced by Mus m 1.
In lymphoproliferation assays, using cells from mouse allergic individuals the mutants induced similar lymphoproliferation to that induced by Mus m 1.
Using a different approach; mutations in residues involved in IgE binding but maintaining the 3D structure of the natural allergen, Spangforth et al. However, if these proteins conserve the T cell epitopes, they could induce a protective response after allergen challenge. A single molecule composed by different allergen polypeptides might reduce the number of molecules to be included in the vaccine. Furthermore, hybrid molecules consisting of several copies of homologous allergens or immunologically unrelated allergens could be used for the allergy treatment in the patients who are sensitized to several allergens. King, who constructed a molecule composed by two allergens from insect and demonstrated in vitro and mice models studies its anti-allergenic properties [85], pioneered the design of hybrid proteins for allergen immunotherapy. The hybrid protein induced T cell proliferation similar to the equimolar mix of individual allergens, the lymphocytes secreted regulatory and Th1 cytokines, IL-10 and IFN-?, showing capacity to induce immune deviation to a protective profile. In an allergic mouse model, exposure to hybrid molecule induced the production of IgG that blocked mast degranulation.
However, this molecule was also capable to bind IgE from allergic individuals, and to induce basophile degranulation, and high percentage of individuals allergic to timothy grass were identified using this molecule, suggesting a potential as a diagnosis reagent. The utility of hybrid proteins for the immunotherapy of house dust mite allergy have been studied by Asturias, et al. The QM1 structure was composed of almost the whole sequence of both allergens; a Der p 2-fragment from residues 5 to 123 at the N-terminus, introducing point mutations on cysteine 8 and 119 to serine to avoid the formation of a disulphide bridge, and a Der p 1-fragment from residues 4 to 222 at the C-terminus were joined. The QM2 structure, was composed with the residues 1 to 73 and 74 to 129 of Der p 2, linked to residues 5 to 222 of Der p 1. Western-blot assays with a serum pool from house dust mite allergic patients showed decrease IgE reactivity of QM1, while QM2 showed no detectable IgE binding capacity. In vitro test with sample from allergic patients QM2 induced similar lymphoproliferation that the induced by natural Der p 1 and Der p 2, whereas, QM1 induced higher proliferation. It was demonstrated that antisera raised by immunization of mice with QM1 or QM2 lead to the production of specific antibodies capable of blocking the binding of IgE reactivity to natural allergens.Recently, a hybrid protein composed of three allergens of Chenopodium album pollen, in the order Che a 3-Che a 1-Che a 2, was constructed by using overlapping extension polymerase chain reaction, expressed in E. Sera from allergic patients showed lower IgE binding affinity to the hybrid molecule than the mixture of recombinant allergens and the C. Most of the allergic patients showed positive skin test to a mixture of the three allergens, however, when tested with the hybrid molecule allergic patients showed negative test or highly reduced weal area compared to the mixture or to the pollen extract [89].Mosaic proteinsMosaic proteins are constituted by different segments of the same allergen, in different order as they are present in the native molecule, such re-arrange generate new intra-molecular interactions that alter B cell epitopes. A mosaic protein called P1m constructed with four segments of the pollen allergen Phl p 1, showed lower IgE reactivity compared to the natural allergen and was unable to induce histamine release from basophiles of allergic individuals. Immunized rabbits expressed IgG antibodies that blocked the binding of Phl p 1 to the IgE and inhibit histamine release from basophiles obtained from allergic individuals [90].
Other mosaic protein constructed with segments derived from Phl p 2 reassembled in altered order and expressed as a trimer showed absence of IgE reactivity with sera from allergic patients. Basophile activation and skin prick tests, showed reduction of the allergenicity of this molecule compared to recombinant Phl p 2. Furthermore, IgG antibodies produced by immunized mice were able to inhibit the binding of recombinant Phl p 2 to the IgE from allergic subjects [91].
Mosaic proteins have been studied as a potential vaccine for immunotherapy of birch allergy [92] and house dust mite allergy [93]. A mosaic protein composed of reorganized segments of Bet v 1 preserved the specific T cell epitopes and showed approximately 100-fold reduced allergenic activity compared with recombinant Bet v 1 [94, 95] and induced specific IgG antibodies inhibitors of IgE reactivity to Bet v1 of sera from patients with pollen allergy [96].
Furthermore, immunization with Bet v 1 derivatives induced IgG antibodies that recognized Bet v 1 and inhibited IgE binding to Bet v 1 [92].Fragments of allergens or modification of these, might be poorly immunogenic because they don?t have enough T cell epitopes capable to stimulate a protective immune response. An increase of immunogenicity can be obtained when proteins are made as oligomers which enhance the number of T cell epitopes in the molecule. It has been observed that immunogenicity of Bet v1 increase when obtained as oligomer [97, 98]. By dot-blot analysis and lymphoproliferative responses in PBMCs from birch pollen allergic patients, trimers of re-organized segments of Bet v1 had lower capacity to bind IgE and enhanced capacity to stimulate lymphoproliferation. Molecules to target specific compartments or receptorsTargeting allergens to endoplasmic reticulumIt has been suggested that administration of higher allergen doses enhances the efficacy of immunotherapy [100]. One approach to overcome this problem is to deliver high doses of allergen to B and T cells directly, thus providing higher effective doses to stimulate a protective response, and avoiding the interaction of allergen with IgE antibodies [101]. An allergen vaccine for cat allergy composed of the major cat allergen Fel d 1 fused to the HIV-derived translocation peptide TAT was designed to mediate cytoplasmic uptake of extracellular proteins [102, 103]. Un modified version of this approach, denominated Modular Antigen Translocation (MAT) technology have been developed [104, 105], which consists of allergen fused to a peptide, to direct them to the cytosol, and a truncated human invariant chain (Ii), to target the protein to MHC class II heterodimers assembled in the endoplasmic reticulum and thus circumventing phagosomal uptake and degradation. The allergens Asp f 1, Der p 1, Bet v 1, PLA2 and Fel d 1 fused to MAT, induced lymphoproliferation of PBMCs stimulated ex vivo with low allergen doses, induced the secretion of Th1 type cytokines and IL-10, and inhibit the production of Th2 cytokines [105].
The cat allergen Fel d 1 fused to MAT (MAT- Fel d 1) when administered directly to the inguinal lymph nodes of allergic mice, showed capacity to stimulate the production of high levels of IFN-? and reduced levels of IL-4, compared to unmodified Fel d 1.
Immunized mice expressed higher levels of IgG2a and showed protection against the challenge of high doses of allergenic extract. Furthermore, MAT-Fel d 1 produced 100-fold less degranulation and histamine release from basophiles compared to unmodified Fel d 1 [106].Targeting allergens to receptors on dendritic cellsDendritic cells (DCs) play an important role in the initiation and maintenance of T cell response to allergens. Its role in the type of T cell response generated can be influenced by the maturation state, while mature DCs induce effector T cell responses characterized by Th1 or Th2 response [107], immature or semi-mature DCs are tolerogenic and have the ability to induce Tregs [108]. When stimulated with allergen, DCs express Fc?RI, and activated a signal-transducing cascade involving immunoreceptor tyrosine-based activation motif (ITAM), which result in increased production of proinflammatory cytokines and chemokines, the induction of robust proliferation of allergen-specific T cells and the development of allergic symptoms [109].
DCs also express the receptor Fc?RIIb that contains immunoreceptor tyrosine-based inhibition motif (ITIM) which induces inhibitory signaling events.
This receptor can co-aggregate with Fc?RI that activating a signaling cascade that culminates in inhibition of Fc?RI signaling.
A scheme of immunotherapy with high doses of GFD resulted in the inhibition of allergic response against Fel d 1, pulmonary inflammation and skin reactivity in sensitized animals. When applied to mice sensitized to Fel d 1 in a scheme of rush immunotherapy, GFD blocked acute systemic allergic reaction, mast cell degranulation, bronquial hyper-reactivity and pulmonary inflammation [111]. Recently, a fusion protein composed of Fc? chain and the Dermatophagoides farinae allergen, Der f 2, was obtained and tested in a Der f 2 allergic murine model [112]. After treatment with the fusion molecule, the levels of specific IgE to Der f 2, histamine and pro-inflammatory cytokines were lowered in the Fc?-Der f 2 treated allergic mice, compared to saline-treated allergic mice.
Flow cytometry analysis showed that H22-Fel d 1 binds to CD64 and reacted with IgE and IgG with similar affinity compared to native allergen. In vitro assays demonstrated that the fusion molecule stimulates the proliferation of T lymphocytes derived from allergic individuals and the secretion of IL-5, IL-10 and IFN-? [114].
Although H22-Fel d 1 is responsible of a positive effect that could result in a protective response against allergen challenge, it also stimulated Th2 cytokines, in a mechanism in which the thymic stromal lymphopoietin (TSLP) cytokine seems to be involved. This cytokine was shown to maintain and polarize circulating Th2 central memory cells, including allergen-specific T cells [115]. Therefore, the usefulness of this kind of preparation for allergy immunotherapy deserves further evaluation. Insect sting allergyInsect sting allergy are frequently caused by insect stings of the Apidae family (honeybees and bumblebees), those from the Vespidae family (Vespula, Dolichovespula, Vespa and Polistes genera) and, in some regions, also of the Formicidae family (ants).
The sting can induce local or systemic IgE-mediated hypersensitivity reactions that can be fatal [116]. Prevalence of systemic reactions caused by insect stings are reported from 0,3% to 7,5% in the United States and Europe [117, 118]. Up to one fifth of these subjects will eventually experience severe life-threatening reactions. Hymenoptera venoms contain protein allergens, as well as non-allergenic components, including toxins, vasoactive amines, acetylcholine, and kinins.
Among the multiple allergens in Hymenoptera venoms, two allergens are importan, the phospholipase A2 from of honey bee (Apis mellifera) (Api m 1), and of the vespid venoms antigen 5 from Vespula vulgaris (common wasp) denominated Ves v 5.Several studies have demonstrated that immunotherapy for vespid allergy with venom extracts is clinically effective and improve the quality of life and allergic symptoms. However, severe and life-threatening anaphylactic side effects may be induced after the administration of crude allergen extracts [120].
One of the first attempts to obtain safer methods for immunotherapy of insect allergies was made with allergen-derived peptides, containing T-cell epitopes. Peptides derived from the bee allergen Api m 1, were applied to allergic individuals in different immunotherapy schemes. In vitro and clinical phase trials showed that T cells from such patients showed marked responsiveness to Api m 1 after long term treatment, a shift in the pattern of cytokine secretion form a Th0 to a Th1 profile and increase in specific IgG4 levels [121-123].The use of recombinant venom allergens for allergen specific immunotherapy has been analyzed in animal models. Pretreatment with the whole venom was less effective and caused toxic side reactions, suggesting a favorable use of the recombinant protein [124].
Hybrid proteins composed by allergens from bee venom have shown anti-allergenic properties in in vitro and animal models [85]. By the other hand, basophil degranulation and skin tests showed that this fusion protein have hypo-allergenic properties.
For example, the sting of Polybia scutellaris, a South American wasp, does not cause allergic symptoms, however it has been proven that its venom contain Antigen 5 (Poly s 5), an analogue of the allergen Pol s 5 [126, 127]. In mice, Poly s 5 induced IgG antibodies that cross react with Pol a 5, but induced only minimal amounts of IgE and was poor inducer of basophil-mediator release. Moreover, Poly s 5-specific serum showed a specific protective activity and was able to inhibit Pol a 5-induced basophil degranulation [128]. Despite the promising results observed with recombinant and modified allergens in in vitro and in vivo studies, more clinical phase studies need to be performed to demonstrate their applicability for the allergen specific immunotherapy of insect allergy.7. Recombinant allergy vaccines in clinical phase trialsClinical trials with recombinant wild type allergens, and modified allergens have been performed (Table 2).
The first studies of allergen SIT with purified molecules were done with peptides containing T cell epitopes either from the cat allergen Fel d 1 or from bee-venom-derived phospholipase, administered without adjuvant [122, 123, 129-135]. However, they induced late phase systemic side effects in different grades depending in the dose and route of administration [129, 132, 134, 135].
These IgG antibodies blocked allergen-induced basophile degranulation and were associated with the ability of patients to tolerate higher allergen concentrations in nasal provocation tests [136]. Immunotherapy with wild-type recombinant Bet v 1 has also been examined for tablet-based sublingual immunotherapy in a phase II, multicenter, double-blind, placebo-controlled, however, this study is still on course and only have been reported good tolerability of the preparation with no serious adverse events and most side effects observed locally [137]. In a clinical trial, a group of patients with grass pollen allergy was treated with a combination of the major grass pollen allergens (Phl p 1, Phl p 2, Phl p 5a, Phl p 5b and Phl p 6) or with placebo for subcutaneous immunotherapy [43].
Patients treated with the recombinants improve their symptom medication score and had high IgG antibodies levels against natural grass pollen allergens. Several studies of immunotherapy with these mixed allergens have been performed and registered in the National Institutes of Health Clinical trial database (Table 2). In a randomized double blind trial, intralymphatic immunotherapy (ILIT) with MAT-Fel d 1 in alum was compared with placebo, consisting in 3 injections of each preparation for two months. MAT-Fel d 1 caused reduced skin reactions compared to equimolar concentration of nFel d 1 by intradermal injection, which proved practically painless and reduced drug-related adverse effects compared to placebo group. After treatment, PBMCs from allergic individuals secreted higher levels of IL-10 when challenged with rFel d 1.
Immunotherapy with MAT-Fel d 1 showed to be successful because patients increased their tolerance to nasal challenge, skin prick and dermal test, with cat dander extract.
Improvement of quality of life of patients treated with MAT-Fel d 1 was maintained 300 days after immunotherapy.



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