CN101065146A - Method of preventive treatment of allergy by mucosal administration of an allergy vaccine - Google Patents
Method of preventive treatment of allergy by mucosal administration of an allergy vaccine Download PDFInfo
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- CN101065146A CN101065146A CNA2005800408274A CN200580040827A CN101065146A CN 101065146 A CN101065146 A CN 101065146A CN A2005800408274 A CNA2005800408274 A CN A2005800408274A CN 200580040827 A CN200580040827 A CN 200580040827A CN 101065146 A CN101065146 A CN 101065146A
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Abstract
The present invention relates to a method of preventive treatment of allergy to an allergen in a subject comprising administering an allergy vaccine containing the allergen as active substance to a mucosal surface of the subject, a) wherein the subject to be treated is sensitised so as to exhibit an IgE response specific to the allergen, b) wherein the subject to be treated is free of clinical symptoms of the allergy associated with the allergen, and c) wherein the preventive treatment is aimed at preventing or reducing subsequent clinical symptoms of the allergy associated with the allergen.
Description
Invention field
The present invention relates to that prophylactic treatment is to the anaphylactoid method of anaphylactogen in subject, the mucomembranous surface that is included in object is used allergy vaccine.
Background of invention
Anaphylaxis is the main health problem that adopts Western lifestyle country.In addition, the popular of anaphylactic disease increases day by day in these countries.Although in general, anaphylaxis is not considered to the disease of dangerous life, and annual asthma can cause a large amount of death.In the teenager about 30% unusual popular, caused quality of life, the remarkable reduction of working day and money, and constituted the main type of health problem in the Western countries.
Anaphylaxis is complicated disease.Caused irritated incident by multiple factor, comprising the susceptibility of the individuality that is determined by influencing each other of fully understanding as yet between the some kinds of genes.Another key factor is the anaphylactogen that contact surpasses certain threshold value.It may be important that some environmental factorss are arranged in sensitization process, comprises pollution, childhood infection, parasitic infection, enteric microorganism etc.In case individual by sensitization, and set up allergic immune response, just the existence of minute amounts of allergen just can effectively change symptom into.
The natural process of anaphylactic disease is accompanied by increasing the weight of on two kinds of levels usually.At first be the development and the severity of disease of symptom, and advancing of disease, for example, be transformed into asthma from Hay Fever.Secondly, the propagation of the anaphylactogen of invasion is modal to be to cause the multiple reaction of anaphylaxis.Chronic inflammatory disease causes the overall weakening of mucosal defense mechanisms, has caused nonspecific stimulation, and finally destroys described mucosal tissue.Thereby may be main because food, i.e. milk product and allergy causes eczema or gastrointestinal disorder; But, modal is that they above-mentioned symptom spontaneously occurs.Described baby can suck anaphylactoid danger subsequently in their life.
Most important anaphylactogen source is the modal granule of specific size in our inhaled air.Described source obviously is general, and comprises grass pollen and house dust mite faecal particles, they caused altogether all anaphylactoid about 50%.What have global importance also comprises the animal soft flocks, i.e. cat and Pilus Canitis bits, and other pollen, as Folium Artemisiae Argyi pollen, and micro-fungus, as Alternaria.On region base, also have other pollen to play dominating role, as Northern Europe and Central European birch pollen, the artemisiifolia at eastern united states and middle part, and the Japanese cedar pollen of Japan.Insecticide, i.e. Apis and wasp venom, and food account for separately all anaphylactoid about 2%.
Anaphylaxis, i.e. I type allergy are to be caused by the unsuitable immunoreation to the non-morbid substance of external source.Anaphylactoid important clinical performance comprises asthma, Hay Fever, eczema, gastro intestinal disorders.Anaphylaxis takes place rapidly when the anaphylactogen of contact invasion, and peaks within 20 minutes.In addition, anaphylaxis is specific, and promptly specific individuality is to specific anaphylactogen sensitivity, and described individuality not necessarily produces anaphylaxis to notifying other materials that cause anaphylactic disease.The feature of allergic phenomena is the remarkable inflammation of the mucosa of Target organ, and the allergen specificity antibody of IgE type is in blood circulation and in mastocyte and the lip-deep existence of basophilic granulocyte.
Irritated attack is reacted by external source anaphylactogen and allergenic specific IgE antibody and causes, this moment, described antibody combined with mastocyte and the lip-deep IgE specific receptor of basophilic granulocyte with high affinity.Described mastocyte and basophilic granulocyte comprise preformed amboceptor, i.e. histamine, trypsinlike enzyme and other materials, and they are to discharge when the IgE of two or more receptors bind is antibody linked.IgE antibody is in conjunction with crosslinked by an allergen molecule time.Therefore, follow the principle that the allogenic material that has only an antibodies epi-position can not cause allergic reaction.Be combined in receptor crosslinked of the lip-deep IgE of mastocyte, also caused being responsible for the eosinophilic granulocyte, the cytotaxis of allergen specificity T-cell and other types is to the release of the signal transduction molecule of irritated reactive site.Described cell and anaphylactogen, IgE and effector lymphocyte interact, and cause after contact allergy is former occurring once more in 12-24 hour allergic symptom (late phase reaction).
Anaphylactic disease control comprises diagnosis and treatment, comprises prophylactic treatment.Anaphylactoid diagnosis relates to checking allergenic specific IgE and definite anaphylactogen source.Under many circumstances, conscientious anamnesis just is enough to diagnosis of allergy, and determines the anaphylactogen source material of invasion.But, modal is that diagnosis is by objective determination, supports as skin penetrating test, blood count or provocative test.
The treatment option is divided into three kinds of main types.First kind may be to avoid anaphylactogen or reduce contact.And avoid anaphylactogen is conspicuous, for example, is exactly like this for food allergen.But also may be difficulty or expensive, as for the house dust mite anaphylactogen, or perhaps it be infeasible, as for pollen allergens.Second kind and the most widely used Therapeutic Method are out the typical symptomatic treatment medicine in place, as anti--histamine and steroid.The symptomatic treatment medicine is safe and effective; But they can not change the natural cause of disease of diseases related, can not control disease propagate.The third therapeutic scheme is a specific allergy vaccination, under most of situation, does like this and can alleviate or alleviate the allergic symptom that is caused by relevant anaphylactogen.
Traditional specific allergy vaccination is the causal treatment of anaphylactic disease.It can disturb fundamental immunity mechanism, causes the persistency of patient's immune state to be improved.Therefore, the protective effect of specific allergy vaccination extended to above treatment time, and is opposite with the symptomatic drugs treatment.Some patient who receives treatment has been cured, in addition, most of patient experience disease severity and experience the alleviation of symptom, or suppressed advancing of disease at least.Therefore, specific allergy vaccination has preventive effect, can reduce the risk that hay fever develops into asthma, and has reduced and new anaphylactoid risk occurs.
Still do not understand the details of the amynologic mechanism of supporting successful allergy vaccination.Known, specific immune response is the adaptive immunity reaction as the production of antibodies of anti-special pathogen.This reaction is different from the innate immunity reaction, and the innate immunity reaction is the nonspecific reaction at pathogen.Allergy vaccine is devoted to solve the problem of adaptive immunity reaction, and it comprises cell and the molecule with antigenic specificity, as the B-cell of T-cell and generation antibody.If do not have the help of corresponding specific T-cell, the B-cell can not be ripe for producing the cell of antibody.The T-cell that participates in the allergic immune response attack mainly is the Th2 type.Having proposed equilibrated foundation new between Th1 and the Th2 cell already is favourable with important for the amynologic mechanism of specific allergy vaccination.Whether this is to reduce by the Th2 cell, the skew from Th2 to the Th1 cell, or the rise of Th1 cell caused be suspicious.Recently, having proposed regulatory T-cells already is important to the mechanism of allergy vaccination.According to this model regulatory T-cells, i.e. Th3 or Tr1 cell have been reduced and have been had specific Th1 of corresponding antigen and Th2 cell.Although there are these uncertainties, it is generally acknowledged that active vaccine must possess the allergen specificity of stimulation T-cell, the ability of preferred TH1 cell.
Although possess advantage, special allergy vaccination is not extensive use of, and this mainly is owing to two reasons.A reason is, the inconvenience relevant with the traditional vaccine vaccination regimen, and this scheme comprises multiple vaccination, promptly injects in the time at some months.Another prior reason is the danger of allergic side reactions to occur.At the common vaccination of infectious agent by once or heavy dose of several times immunity inoculation effectively carry out.But, this method can not be used for allergy vaccination, because the pathologic immunoreation had taken place already.
Therefore, conventional specific allergy vaccination is undertaken by repeatedly subcutaneous immunity inoculation in a long time.This process can be divided into two stages, escalated dose stage and maintenance stage.In the escalated dose stage, from little dosage, increase dosage of inoculation, continue 16 time-of-weeks usually.When reaching the maintenance dose of recommendation, adopt this dosage in the maintenance stage.Usually per six weeks injection once.After per injection, the patient must accept 30 minutes medical treatment nurse, because there is the danger of anaphylaxis side reaction, although very rare, this in principle side reaction may life-threatening.In addition, the equipment of clinic should be supported emergency treatment.There is no doubt that, can eliminate or reduce having now based on the vaccine of different administration approach, and help using widely, even can carry out self-vaccination at home based on the inherent anaphylaxis side reaction of subcutaneous injection vaccine.
Improve the trial of specific allergy vaccination and carried out more than 30 years already, and comprise various methods.Existing some kinds of methods concentrate on anaphylactogen itself by changing the IgE reactivity.
(Int.Arch.Allergy Immunol such as Fanta, 1999,120:218-224) relate to the research that in grass pollen allergic patients group, changes by the inductive immunology of SLIT, described patient is according to following Standard Selection: have clinical symptoms (rhinitis and/or seasonal bronchial asthma) season in the grass pollen loose powder, the grass pollen extract is shown positive skin prick test, with the specific IgE to grass pollen, this determines by RAST-CAP.SLIT is undertaken by the drop that sublingual administration is used the anaphylactogen extract.
Holt etc. (" Suppression of IgE responses following inhalationof antigen ", Immunology Today, vol.8, No.1,1987) mentioned the following fact, as to contact reaction that suck or the anaphylactogen that mouth and nose splash into, induced corresponding to the toleration that passes through the inductive reaction of dietary antigens at gastrointestinal tract at upper respiratory tract.
Holt etc. (" Sublingual allergen administration.I.Selectivesuppression of IgE production in rats by high allergen doses ", Clinical Allergy, 1988, Volume 18, pages 229-234) relates to the continuous sublingual administration that the rat that is used to first test was carried out in seven days anaphylactogen (ovalbumin), the last time after the sublingual administration 5 days, carry out parenteral with ovalbumin and attack, the result shows the selective inhibitory that IgE is special to ovalbumin.By inference, described treatment mechanism relates to the attack that anaphylactogen-specificity suppresses cell.The document has also disclosed the treatment that is proposed, and to be used to the animal of testing first relevant, and should be different from the Sublingual desensitization method.
WO 95/17208 has disclosed the method for Polyglucan disease, comprise the anaphylactogen of using doses to former unsensitized object, this dosage effectively induced hypersensitivity former-foundation of the stable colony of specificity T-auxiliary-1-sample memory lymphocyte, described cell can suppress anaphylactogen-specificity T-auxiliary-lymphocytic activity of 2-sample.Preferred 3 months to 7 years old of the described object that will treat is big.For example, can be dermatophagoides pteronyssinus as anaphylactogen, grass pollen and trees pollen.The administration of described anaphylactogen can be passed through the oral cavity, intranasal, and mouth and nose, rectum, intradermal, intramuscular or subcutaneous route are carried out.
For example, homepage www.immunetolerance.org has disclosed not the preventative-therapeutic planned clinical research to the child of inhalant sensitization on (on October 11st, 2004), wherein, use the Sublingual drop that contains any allergen (dermatophagoides pteronyssinus, timothy grass and cat) for described child, and wherein, anaphylaxis appearred in described child at 3 years subsequently.The described child that this research is recruited has atopic dermatitis or food anaphylaxis reaction medical history, and they biology mother or father or a compatriot have the specific reaction history of venereal disease.
The purpose of this invention is to provide improving one's methods of prophylactic treatment individuality, particularly child.
Summary of the invention
Realized this purpose by the present invention, the present invention relates in subject prophylactic treatment to the anaphylactoid method of anaphylactogen, the mucomembranous surface that is included in object is used and is comprised the allergy vaccine of described anaphylactogen as active substance,
A) wherein, the described object that will treat is reacted the special IgE of described anaphylactogen so that show by sensitization,
B) wherein, the described object that will treat do not have the relevant anaphylactoid clinical symptoms of described anaphylactogen and
C) wherein, described preventative-therapeutic purpose is prevention or alleviates the relevant anaphylactoid clinical symptoms subsequently of described anaphylactogen.
The present invention is based on following new discovery, can prevent in individuality to occur symptoms of allergic to described anaphylactogen, the immune system of described individuality had contacted anaphylactogen already, but wherein, described immunoreation does not also develop into and clinical symptoms, as rhinitis, conjunctivitis, rhinorrhea, nasal obstruction, sinusitis, sneeze, atopic dermatitis, pruritus, shed tears, rhinorrhea, the state relevant of stridulating with skin irritation.Believe always that up to now the individuality that will treat should be by sensitization in order to obtain anaphylactoid effective prophylactic treatment.In addition, believe always that up to now the mechanism relevant with Polyglucan reaction is to induce and by dietary antigens inducing at gastrointestinal tract inductive reaction corresponding oral cavity toleration.But,, confirm surprisingly that by treating sensitization already, but the individuality that does not show any clinical symptoms as yet can obtain preventive effect according to the present invention.The preventive effect that it is believed that acquisition works by certain mechanism, and this mechanism is partially or completely similar to the mechanism of the desensitization that takes place in specific allergy vaccination (immunotherapy).
Believe that also it is the most effective beginning further to carry out prophylactic treatment as quickly as possible before anaphylaxis Th2 cell effect development at immune system response after sensitization.In other words, it generally is favourable treating when they are as far as possible little after child's contact allergy already is former.In addition, it is believed that because the effect of early prevention treatment, treatment can with littler dosage still less application times and/or shorter treatment time carry out, more than relatively be the adult's specific allergy vaccination that has occurred clinical symptoms relatively.Because the soft property of method of prophylactic treatment, it is applicable to the general method of vaccination of all children or large-scale particular child colony.
Other advantages of the inventive method are that sensitized individuals is that anaphylactoid individuality appears in most probable, so the individuality of sensitization has constituted and carries out preventative-therapeutic maximally related crowd.
The invention still further relates to anaphylactogen is used to produce and be used for the purposes of in the subject anaphylactoid mucosal vaccine of prophylactic treatment,
A) wherein, the described object that will treat is reacted the special IgE of described anaphylactogen so that show by sensitization,
B) wherein, the described object that will treat do not have the relevant anaphylactoid clinical symptoms of described anaphylactogen and
C) wherein, described preventative-therapeutic purpose is prevention or alleviates the relevant anaphylactoid clinical symptoms subsequently of described anaphylactogen.
Brief description of drawings
Figure 1A represents the sensitized mice clinical data (sneeze number of times) with 5000 SQ Phl p or the attack of buffer intranasal.
Serum IgE level in the sensitized mice body that Figure 1B represents to attack with 5000 SQ Phl p or buffer intranasal.
BALIgE level in the sensitized mice body that Fig. 1 C represents to attack with 5000 SQ Phl p or buffer intranasal.
NALIgE level in the sensitized mice body that Fig. 1 D represents to attack with 5000 SQ Phl p or buffer intranasal.
NAL eosinophil levels in the sensitized mice body that Fig. 1 E represents to attack with 5000 SQ Phl p or buffer intranasal.
Fig. 2 A represents to carry out SLIT or buffer and handles, and with Phl p carry out the intranasal attack the clinical data (sneeze number of times) of sensitized mice.
Fig. 2 B represents to carry out SLIT or buffer is handled, and carries out the respiratory tract anaphylaxis reaction of the sensitized mice of intranasal attack to the reaction (weighing by the Penh value) of methacholine chloride attack with Phl p.
Fig. 3 A represents to carry out SLIT or buffer is handled, and carries out the interior serum IgE level of sensitized mice body that intranasal is attacked with Phl p.
Fig. 3 B represents to carry out SLIT or buffer is handled, and carries out the interior serum IgG of sensitized mice body that intranasal is attacked with Phl p
1Level.
Fig. 4 A represents to carry out SLIT or buffer is handled, and carries out the interior BAL IgE level of sensitized mice body that intranasal is attacked with Phl p.
Fig. 4 B represents to carry out SLIT or buffer is handled, and carries out the interior NAL IgE level of sensitized mice body that intranasal is attacked with Phl p.
Fig. 4 C represents to carry out SLIT or buffer is handled, and carries out the interior BAL IgA level of sensitized mice body that intranasal is attacked with Phl p.
Fig. 4 D represents to carry out SLIT or buffer is handled, and carries out the interior NAL IgA level of sensitized mice body that intranasal is attacked with Phl p.
Fig. 5 A represents to carry out SLIT or buffer is handled, and carries out the BAL eosinophile peroxidase level of the sensitized mice of intranasal attack with Phl p.
Fig. 5 B represents to carry out SLIT or buffer is handled, and carries out the NAL eosinophile peroxidase level of the sensitized mice of intranasal attack with Phl p.
Fig. 6 A represents to carry out SLIT or buffer and handles, and carries out the T cell proliferation in the sensitized mice spleen of intranasal attack with Phl p.
Fig. 6 B represents to carry out SLIT or buffer is handled, and carries out the intracellular T cell proliferation of sensitized mice lymph node (LN) that intranasal is attacked with Phl p.
Detailed description of the invention
Anaphylactogen
The anaphylactogen of preparation of the present invention can be already to have reported when contact is individual repeatedly to lure Lead anaphylaxis, i.e. anaphylactoid any naturally occurring albumen of IgE mediation. Naturally occurring The example of anaphylactogen comprises pollen allergens (trees, medicinal herbs, weeds and grass pollen allergens), Insect allergy former (inhalant, saliva and venom allergens, for example, acarid anaphylactogen, cockroach With midge anaphylactogen, hymenopteran (hymenopthera) venom allergens), animal hair And dandruff allergens (for example, from dog, cat, horse, rat, mouse etc.), and food Anaphylactogen. Pollen allergens from trees, careless class and medicinal herbs is: below on the taxology The purpose plant: Fagales, olive order (Oleales), pinales and Platanaceae comprise Birch (Betula), alder (alder), hazelnut (Corylus), Carpinus (CarpInus) And olive (Olea), cdear (Cryptomeria and Chinese juniper belong to), plane tree (oriental plane tree), standing grain This order (Poales) comprises that Lolium, ladder forage spp, Poa L., bermuda grass belong to, cat Tail grass, Holcus, phalaris arundinacea, buckwheat and sorghum, chrysanthemum order and Urticales comprise Ambrosia, The medicinal herbs of artemisia and Parietaria. Other important inhalant allergens are from the family with the subordinate Front yard dirt mite: Dermatophagoides and Europe mite belong to, the storage mite belongs to, and for example, LepIdoglyphys eats sweet mite Belong to and Tyrophagus, from the anaphylactogen of cockroach, midge and flea, for example, Blatella, big Lian Genus, Chironomous and Ctenocepphalides, and from mammal, such as cat, dog and horse Anaphylactogen, venom allergens, comprise as stinging or biting insects from stinging, as from taxology On Hymenoptera, comprise honeybee (Superfamily Apidae), wasp (Superfamily wasp section) and ant The anaphylactogen of (Superfamily Formicidae). From the important suction anaphylactogen of fungi, as from side chain The anaphylactogen that spore belongs to and cladosporium belongs to.
In particular of the present invention, described anaphylactogen be Bet v 1, Aln g 1, Cor a 1 and Car b 1, Que a 1, Cry j 1, Cry j 2, Cup a 1, Cup s 1, Jun a 1, Jun a 2, jun a 3, Ole e 1, Lig v 1, Pla l 1, Pla a 2, Amb a 1, Amb a 2, Amb t 5, Art v 1, Art v 2 Par j 1, Par j 2, Par j 3, Sal k 1, Ave e 1, Cyn d 1, Cyn d 7, Dac g 1, Fes p 1, Hol l 1, Lol p 1 and 5, Pha a 1, Pas n 1, Phl p 1, Phl p 5, Phl p 6, Poa p 1, Poa p 5, Sec c 1, Sec c 5, Sor h 1, Der f 1, Der f 2, Der p 1, Der p 2, Der p 7, Der m 1, Eur m 2, Gly d 1, Lep d 2, Blo t 1, Tyr p 2, Bla g 1, Bla g 2, Per a 1, Fel d 1, Can f 1, Can f 2, Bos d 2, Equ c 1, Equ c 2, Equ c 3, Mus m 1, Rat n 1, ApIs m 1, ApI m 2, Ves v 1, Ves v 2, Ves v 5, Dol m 1, Dil m 2, Dol m 5, Pol a 1, Pol a 2, Pol a 5, Sol i 1, Sol I 2, Sol i 3 and Sol i 4, Alt a 1, CIa h 1, Asp f 1, Bos d 4, Mal d 1, Gly m 1, Gly m 2, Gly m 3, Ara h 1, Ara h 2, Ara h 3, Ara h 4, Ara h 5 or from above-mentioned any one reorganization (shufflant) of molecule breeding Heterozygote.
In a preferred embodiment of the invention, described anaphylactogen is selected from following one group: trees Pollen allergens, grass pollen allergens, medicinal herbs anaphylactogen and zoo-anaphylactogen, preferably described Anaphylactogen be selected from grass pollen allergens, dust mite allergen, Ambrosia anaphylactogen, cdear pollen, Cat anaphylactogen and birch anaphylactogen.
In another embodiment of the invention, described preparation comprise at least two kinds dissimilar Anaphylactogen, described anaphylactogen is from identical anaphylactogen source or from different irritated original The source, for example, 1 type and 5 types grass class anaphylactogen, or 1 type and 2 type acarid anaphylactogens, respectively from Different acarids and careless class, weeds antigen, such as short and small and huge Ambrosia anaphylactogen, different Studies On Fungus Allergy is former, as alternaria and cladosporium genus, trees anaphylactogen, as birch, hazelnut, Carpinus turczaninowii, Oak Tree and alder anaphylactogen, food allergen is such as peanut, soybean and milk allergy Former.
The anaphylactogen that mixes in the described preparation can be form of extract, the anaphylactogen of purifying, The anaphylactogen of modification, the mutant of recombinant allergens or recombinant allergens. The anaphylactogen extract can Natural one or more heterogeneous that contain identical anaphylactogen, and usually only representative of recombinant allergens A kind of heterogeneous of anaphylactogen. In preferred embodiments, described anaphylactogen is form of extract . In another kind of preferred embodiment, described anaphylactogen is recombinant allergens. At another kind In the preferred embodiment, described anaphylactogen is that naturally occurring low IgE-is in conjunction with variant or recombinate low IgE-is in conjunction with variant.
Anaphylactogen can exist with identical molal quantity or the ratio of existing anaphylactogen passable Preferably fluctuate by 1: 20.
In another embodiment of the invention, described low IgE is such as WO in conjunction with anaphylactogen 99/47680, WO 02/40676 or the described anaphylactogen of WO 03/096869 A2.
Prophylactic treatment
Since this century already with specific allergy vaccination (SAV), be referred to as in the past Be specific active immunotherapy or desensitization, be used for the treatment of the anaphylactia of 1 type IgE mediation.
The general advantage that obtains by SAV comprises: a) alleviate allergic conditions and Medical Consumption, B) at eyes, improve tolerance and c to described anaphylactogen in nose and the lung) to alleviate skin anti-Answering property (early stage and late phase response).
The basic mechanism of the improvement that obtains by SAV is not still understood, but, can extract multinomial common trait from the multinomial SAV research of in the past decade carrying out: 1) total IgE quantity does not change during treating, 2) during escalated dose, the quantity short time of allergenic specific IgE increases, fall back to initial (pretreatment) level then again, 3) epitope specificity of IgE and affinity remain unchanged, 4) allergen specificity IgG, IgG4 particularly, during SAV, raise 5 fast) started new Th0/1/Reg reaction and 6 on the surface) as if not change of Th2 reaction.There is not dependency by SAV between the outbreak of inductive effect and specific IgG.
SAV has induced new immunoreation, and it is ripe (raised Th0/1 T-cell, started allergen specificity IgX (X may be A1, A2, G1, G2, G3, G4, M or D)) during treating.Affinity (or quantity/affinity) as new antibody response, IgX was ripe already, IgX may with the described anaphylactogen of IgE effective competition, suppress the anaphylactic reaction of " normally " Th2 type, be feature with the crosslinked of IgE of mastocyte and the lip-deep receptors bind of basophilic granulocyte.Therefore, clinical symptoms can alleviate gradually.
It is believed that the prophylactic treatment that carries out among the present invention can work by the mechanism identical with SAV mentioned above at least to a certain extent.
The mucosa of using described allergy vaccine can be any suitable mucosa, and route of administration comprises in the oral cavity (by the digestive system mucosa), nasal cavity, vagina, Sublingual, eyes, rectum, urethra, mammary gland, lung, in ear (promptly passing through ear) and buccal administration, preferably buccal or sublingual administration (mouth mucosa drug administration).Described allergy vaccine can be preparation, vagina holder (vagitories), suppository or pessulum (uteritories) form in spray, aerosol, mixture, suspension, dispersion liquid, emulsion, gel, paste, syrup, emulsifiable paste, ointment, implant (ear, eyes, skin, nose, rectum and vagina), the breast.
By inference, preferably carry out the mucosa delivery of vaccine by mucosa, described mucosa contacts antigen preparation naturally.Therefore, for the anaphylaxis that gas carries the mucosa antigen preparation, preferably pass through the respiratory system administration, preferred mouth mucosa drug administration.Correspondingly, for the anaphylaxis of mucosa antigen preparation, it will contact with the mucosa of digestive system, preferably adopts oral administration.
In one embodiment of the present invention, described object has been accepted the vaccination scheme, comprises using described vaccine every day.In another embodiment of the invention, described vaccination scheme comprises per two days, per three days, or used one time vaccine in per four days.For example, described vaccination scheme comprises that using described vaccine surpassed for 4 weeks, preferably surpasses for 8 weeks, more preferably surpasses for 12 weeks, more preferably surpasses for 16 weeks, more preferably surpasses for 20 weeks, more preferably surpasses for 24 weeks, more preferably surpasses for 30 weeks, most preferably surpasses for 36 weeks.
Administration time can be continuous time.Perhaps, administration time is the discontinuous time of being interrupted by one or more not administration phases.Preferably, (always) time of (always) time ratio administration of not administration is short.
In another embodiment of the invention, used vaccine one time to trying individuality every day.Perhaps, use vaccine twice for every day the described individuality that tried.Described vaccine can be the vaccine of single dose.
Mouth mucosa drug administration
Mouth mucosa drug administration can comprise solution with any existing mouth mucosa drug administration preparation, suspension, and the fast-dispersing type, drop and lozenge carry out.
In a preferred embodiment of the invention, adopted Sublingual immunotherapy (SLIT), in this case, fast-dispersing type, drop and lozenge are preferred preparations.
The example of fast-dispersing type can be referring to US-A-5,648,093, WO 00/51568, WO 02/13858, WO99/21579, WO 00/44351, US-A-4,371,516 and EP-278877, and DK PA 2,003 00279 to be examined and DK PA 2,003 00318, all be with the name application of assignee ALK-Abell ó A/S.Preferred fast-dispersing type is produced by lyophilization.The preferred substrate of producing preparation is isinglass and modified starch.
Typical increment dosage hyposensitization can be used for the present invention, wherein, is increased to the dosage of the anaphylactogen of fast dispersing solid dosage form to greatest extent a certain.The preferred effectiveness of the unit dose of described dosage form is the 150-1000000SQ-u/ dosage form, preferred effectiveness is the 500-500000SQ-u/ dosage form, preferred effectiveness is the 1000-250000SQ-u/ dosage form, more preferably 1500-125000SQ-u/ dosage form, most preferably 1500-75000SQ-u/ dosage form.
In another embodiment of the invention, described dosage form is multiple single dose, preferably in 1500-75000SQ-u/ dosage form scope.
Sensitization
The object for the treatment of is by sensitization, so that show the IgE reaction special to using anaphylactogen.In the present invention, phrase " shows the reaction to the special IgE of described anaphylactogen " being illustrated in can detected anaphylactogen-specific IgE antibody level at least a immunoassay.The detection of described anaphylactogen-specific IgE antibody can be carried out with any routine immunization assay method, for example, and referring to WO 94/11734 and WO 99/67642.
In specific embodiments of the present invention, further described object is carried out sensitization, so that show the Th2 cell effect special to described anaphylactogen.
In specific embodiments of the present invention, further described object is carried out sensitization, so that in skin prick test (SPT), show positive anaphylactogen-specific reaction.
In other specific embodiments of the present invention, the age of described object preferably less than 30 years old, was more preferably less than 20 years old less than 40 years old, most preferably was 2-10 year.
Clinical symptoms
The object for the treatment of does not have the relevant anaphylactoid clinical symptoms of described anaphylactogen.
The anaphylactoid clinical symptoms that described anaphylactogen is relevant can be any common sympton, comprises rhinitis, conjunctivitis, rhinorrhea, nasal obstruction, sinusitis, sneeze, atopic dermatitis, pruritus, sheds tears, rhinorrhea, stridulates and skin irritation.
It is that anaphylactoid index takes place that multiple factor is arranged, and shows clinical symptoms subsequently in life.Show one or more these the indication factor following object be known as high-risk object.The indication factor of high-risk object is and the relevant anaphylactoid clinical symptoms of one or more anaphylactogens except the anaphylactogen of vaccine.Other indication factors of high-risk object are in one of father and mother or grand parents or both or one or more anaphylaxiss of existence in one or more Sibling.Prophylactic treatment of the present invention is specially adapted to high-risk object.But, the object that treat can also be the object that does not show the indication factor of high-risk object, for example, does not have the anaphylactoid clinical symptoms to other anaphylactogens.
The preparation of allergy vaccine
The allergy vaccine that is used for the inventive method can be to be fit to any dosage form that mucomembranous surface is used, and comprises spray, aerosol, mixture, tablet (enteric and non-enteric coated tablet), capsule (hard and soft, enteric and non-enteric), suspension, dispersion liquid, granule, powder, solution, emulsion, chewable tablet, drop, gel, paste, syrup, emulsifiable paste, lozenge (powder, granule, tablet), quick dispersible tablet, instillation liquid, gas, steam, ointment, bar, implant (ear, eyes, skin, nose, rectum and vagina), preparation in the breast, the vagina holder, suppository, or pessulum.
Should be understood that preparation of the present invention also comprises other adjuvants and other excipient that are fit to described preparation type.Described other adjuvants and excipient are conventionally known to one of skill in the art, and comprise, for example, and solvent, emulsifying agent, wetting agent, plasticizer, coloring material, filler, antiseptic, viscosity-controlling agent, buffer agent and mucosa emplastic etc.The example of compound method is well known to those skilled in the art.
Adjuvant
Described mucous membrane irritability reaction vaccine can comprise adjuvant, it can be any conventional adjuvant, comprise oxygen metal salt, thermal instability enterotoxin (LT), cholera toxin (CT), b subunit of cholera toxin (CTB), the polymerization liposome, the saltant toxin, for example, LTK63 and LTR72, microcapsule, interleukin (for example, IL-1 β, IL-2, IL-7, IL-12, INF γ), GM-CSF, the MDF derivant, the CpG oligonucleotide, LPS, MPL, phosphophazenes, Adju-Phos , glucosan, antigen preparation, liposome, DDE, DHEA, DMPC, DMPG, DOC/ Alumen complex, incomplete Freund, ISCOMs , LT Oral adjuvant, muramyldipeptide, monophosphoryl lipid A, muramyl-tripeptide, and PHOSPHATIDYL ETHANOLAMINE.
Described oxygen metal salt can be any oxygen metal salt, as long as the effect that needs can be provided.In preferred embodiments, the metal cation of described oxygen metal salt is selected from following one group: Al, K, Ca, Mg, Zn, Ba, Na, Li, B, Be, Fe, Si, Co, Cu, Ni, Ag, Au and Cr.In preferred embodiments, the anionic metal of described oxygen metal salt is selected from following one group: sulfate, hydroxide, phosphate, nitrate, iodate, bromate, carbonate, hydrate, acetate, citrate, oxalates and tartrate, and their mixed form.Example has aluminium hydroxide, aluminum phosphate, aluminum sulfate, aluminum acetate, aluminium potassium sulfate, calcium phosphate, Maalox (mixture of aluminium hydroxide and magnesium hydroxide), beryllium hydroxide, zinc hydroxide, zinc carbonate, zinc chloride and barium sulfate.
Referring to WO 04/047794, the allergy vaccine of aqueous solution or quick dispersible tablet form is particularly suitable for buccal and sublingual administration.
Use the method for the effect of mucosa delivery assessment immune modulating treatment method
The invention still further relates to and assess the method for immune modulating treatment method to the anaphylactoid effect of anaphylactogen in the experimental animal body, this method may further comprise the steps
A) make described animal to described anaphylactogen sensitization,
B) by contact in nasal cavity or the trachea described animal is carried out the anaphylactogen attack first time,
C) use mouth mucosa drug administration that described animal is implemented described Therapeutic Method,
D) level of biomarker is measured and
E) use described measurement result to assess the effect of described Therapeutic Method.
Herz etc. (Methods 32 (2004) 271-280) are one piece of review articles, have disclosed several animal models.In a kind of such model,, make mouse sensitization by peritoneal injection rBet v 1 with the aerosol challenge of Bet v 1 extract referring to 3.1 parts.Then, obtain immunoregulation effect by injecting immune advantage peptide or by mucosal administration rBet v 1, this carried out before or after sensitization.Intranasal or oral administration rBet v 1 have caused the inhibitory action of the anaphylactogen-specific antibody level of all isotypes, reduced IL-4, IL-5 and IFN-γ, and suppressed the respiratory inflammation and the respiratory tract anaphylaxis reaction of experimental animal and sensitized animal first.Herz etc. have disclosed multiple other models, referring to table 2, comprise equally with anaphylactogen and carry out various types of parenterals, intranasal and oral cavity sensitization, for example, administration of antibodies, cytokine are attacked and treatment, tuerculoderma, histamine release, eosinophilic granulocyte, respiratory inflammation and T cell or the like.
The present invention just is being based on so any, can attempt mouth mucosa drug administration is used in assessment immune modulating treatment method appraisal procedure to the anaphylactoid effect of anaphylactogen in experimental animal.
The principle of animal model test method of the present invention is, make experimental animal to anaphylactogen sensitization, promptly handle, so that show allergic immune response, attack with described anaphylactogen then, so that the induced hypersensitivity reaction to described anaphylactogen, can measure and assess then, wherein, further described animal is implemented Therapeutic Method, can study of the influence of described method then anaphylactic reaction.
Described experimental animal can be any animal that is often used as experimental animal, comprises rodent, for example, and mice, rat, Cavia porcellus and rabbit, pig, Canis familiaris L., cat and monkey.
In specific embodiments of the present invention, described mouth mucosa drug administration is sublingual administration (Sublingual immunotherapy (SLIT)).The described anaphylactogen and the preparation that are used for described Therapeutic Method can be top in conjunction with anaphylactoid method of prophylactic treatment disclosed any anaphylactogen and preparation.
When carrying out mouth mucosa drug administration, should guarantee that described preparation can keep the scheduled time at the predetermined position in oral cavity.In specific embodiments of the present invention, can prevent that described experimental animal from swallowing.For example, preventing to swallow can be by realizing with the fixing described animal of hands.For example, for rodent, can be fixed on by scrimp between two fingers so that the skin around the fastening head prevents to swallow with skin of neck.In addition, can also prevent to swallow by using anesthetis, as sucking anesthetis, for example, ether, Hal and sevoflurane, or injecting narcotic, for example, the mixture of fentanyl, fluanisone and midazolam, fentanyl, fluanisone and stabile mixture, restrain his life and the mixture of medetomidine, restrain him and order and the mixture of xylazine atipamezole, urethane and tribromoethanol.
In another embodiment of the invention, described Therapeutic Method carries out before the anaphylactogen attack after sensitization and in the first time.Perhaps, described Therapeutic Method carried out after the anaphylactogen attack in the first time.In a kind of example in back, attack and after described Therapeutic Method, to carry out by the optional anaphylactogen second time that contact in nasal cavity or the trachea is carried out.
In another kind of preferred embodiment of the present invention, described biomarker is selected from following one group: anaphylactogen-specific antibody, clinical symptoms and effector lymphocyte.Described antibody can be any kind, and hypotype or their combination comprise IgA, IgA1, IgA2, IgD, IgE, IgG, IgG1, IgG2, IgG3, IgG4, IgM.The detection of the antibody specificity of described anaphylactogen is to use any routine immunization assay method to carry out, and preferred method of immunity can be referring to WO 94/11734 and WO 99/67642.Clinical symptoms can be any symptom that is usually used in animal model, comprises the sneeze number of times, wipes nose number of times etc.For example described effector lymphocyte is selected from following one group: the eosinophilic granulocyte, and mastocyte, basophilic granulocyte, the B cell, the T cell, antigen-presenting cell (APC ' s) and by above-mentioned cell-derived cell.In one embodiment of the present invention, effector lymphocyte's level is the level determination by the measuring effect cell marking.Described labelling is preferably selected from following one group: secretion molecule, molecule in surface molecular and the cell.Preferably, described secretion molecule is selected from following one group: amboceptor, cytokine, cytotoxic protein and soluble recepter.
The effect of described Therapeutic Method is assessed according to above-mentioned measurement result, and measurement result is to carry out according to the general scientific knowledge to the successfully performance of the immunoreactive biomarker of treatment.
Definition
In the present invention, used to give a definition:
Term " mouth mucosa drug administration " expression is placed on described dosage form below the tongue or the route of administration Anywhere in the oral cavity, makes active component contact with the mucosa of patient oral cavity or throat, acts on so that obtain the local or systemic of described active component.The example of mouth mucosa drug administration approach is a sublingual administration.
Term " sublingual administration " expression route of administration wherein, is placed on dosage form below the tongue, so that obtain the part or the systemic effect of active component.
Term " SQ-u " expression SQ-unit: SQ-unit measures according to ALK-Abell ó A/S ' s " SQ biopotency "-standardized method, and wherein 100,000SQ unit equals the subcutaneous maintenance dose of standard.Usually, the extract of 1mg contains 100,000-1, and 000,000SQ-unit, this depends on the source and the employed production method of anaphylactogen.Can determine definite allergen content by immunoassay, promptly total main allergen content and total allergen activity.
Phrase " immune modulating treatment " expression can be regulated the immunoreactive treatment of the object of receiving treatment.
Specific embodiments
The effect of example 1:SLIT on the mouse model of rhinitis
Ultimate principle:
Set up the rhinitis model, so that check Sublingual immunotherapy (SLIT) is in the effect that has on the mouse model of clinical manifestation.
Method:
Animal
To 6-10 week big female BALB/c mouse carry out stable breeding, and can keep with the special diet of the composition of the antiserum cross reaction of timothy grass (Phl p) with not containing.Each experimental group comprises 8-10 animal.
Zoopery
The Phl p extract that is adsorbed on the Alumen by three intraperitoneal (i.p.) injection carries out sensitization to mice, carries out Sublingual treatment 6-9 time-of-week with Phl p-extract or buffer then.With Phl p-extract mice is carried out intranasal subsequently and attack two time-of-weeks, and analyze clinical symptoms by the following method.After slaughtering blood-letting, collect bronchovesicular liquid (BAL), nasopharynx liquid (NAL), spleen and lymphonodi cervicales are used for analyzing.
Clinical data
Sneeze and wiping nose: after intranasal administration Phl, observed mice, and add up the sneeze number of times and wipe the nose number of times with 10 minute time.
Respiratory tract allergy: adopt whole health plethysmogram (pletysmograph), block by the concentration induced draft that strengthens aerosolized methacholine chloride.Pulmonary air flow blocks by using after the methacholine chloride in 6 fens clock times enhanced pause (penh) to be measured.
IgA analyzes
The Estapore magnetic bead (Estapore IB-MR/0,86) that is combined on the goat anti-mouse IgA is cultivated with BAL or NAL.Wash then and cultivate with biotinylated anaphylactogen.Wash then and cultivate, and after washing, measure luminous with photometer (Magic Lite Analyser EQ) with the LITE preparation of streptavidin labelling.
IgE analyzes
Be combined in Estapore magnetic bead (Estapore IB-MR/0,86 on the goat anti-mouse IgE; A0201) cultivate with mice serum.Wash then and cultivate with biotinylated anaphylactogen.Wash then and cultivate, and after washing, measure luminous with photometer (Magic Lite Analyser EQ) with the LITE preparation of streptavidin labelling.
IgG, IgG1 and IgG2a analyze
Phl p (10 μ g/ml) extract is added in the hole of ELISA flat board, and under 4-8 ℃ described flat board left standstill next day.At room temperature on vibration table, sealed one hour then with the flat board of buffer washing, and with 2% casein buffer through coating.After removing the casein buffer, the blood serum sample that dilutes is added on the described flat board, and at room temperature on vibration table, cultivated 2 hours.Wash described flat board, and with the biotinylated rabbit with 0.5%BSA buffer dilution anti--mice IgG/IgG1/IgG2a adds in each hole, and at room temperature placed one hour on vibration table.After washing, the streptavidin-HRP that is diluted in the 0.5%BSA buffer is added in each hole, and at room temperature on vibration table, placed one hour.Developed described dull and stereotyped 20 minutes with TMP substrate (3,3 ', 5,5 '-tetramethyl benzidine), stop with 0.5M H2SO4 then.Resulting reactant mixture carries out spectrophotometer measurement under the terminal point of 450nm.
The T-cell proliferation test
Spleen chosen be broken into single-cell suspension liquid, and with culture medium washing three times.The statistics cell quantity, and adjust to 1.67 * 10
6Cell/mL.With 3 * 10
5Cell adds in each hole of the flat culture plate in 96 holes, and attacks described cell with 0,10 and 40 μ g/mL Phl p extracts.At 37 ℃ and 5%CO
2The middle cultivation the 6 day time of described cell added in each hole by the last 18 hours 3H-thymus pyrimidines with 0.5 μ Ci at cultivation stage, and the radioactive label of harvesting and statistics integration is measured propagation then.
The result
Inducing of rhinitis
From Figure 1A-E, as can be seen, after peritoneal injection sensitization, mice is carried out intranasal (IN) attack and show clear and definite rhinitis symptom two weeks with Phl p extract (5000SQ/ mice/sky).At first, the obvious mice many (Figure 1A) of the number of times of their sneeze than the sensitization of attacking with buffer.Secondly, at serum, has higher IgE level (Figure 1B-D) among BAL and the NAL.The 3rd, the granulocytic flux enhancement of the eosinophilic granulocyte of these mices in NAL (Fig. 1 E).
The effect of SLIT on the rhinitis mouse model
In order to assess the effect of SLIT on the muroid model of above-mentioned rhinitis, with 125.000SQ Phlp extract or buffer sensitized mice is carried out the Sublingual and handle 9 time-of-weeks, carry out intranasal with Phl p then and attack.In addition, one group of sensitized mice does not carry out the Sublingual to be handled, and with buffer they is carried out intranasal and attack, and therefore is used as negative control.
Referring to Fig. 2, the SLIT-treatment can alleviate clinical symptoms, because compare with the mice of buffer-processing, the sneeze number of times significantly reduces (Fig. 2 A).Similarly, methacholine chloride is attacked the air flue allergy (by the measurement of Penh value) react alleviate, particularly with the dosage of 5-15mg/mL when hour attacking (Fig. 2 B).
In addition, the antibody horizontal in the serum is subjected to the influence of SLIT-treatment.Referring to Fig. 3, compare with the mice that buffer is handled, in the mice body that SLIT-handles, the serum levels of Phl p specific IgE (Fig. 3 A) and IgG1 (Fig. 3 B) significantly reduces.
The specific IgE level reduces equally in the BAL of the mice that SLIT-handles and NAL liquid, and specificity IgA level reduces in BAL, but not obvious in NAL liquid (referring to Fig. 4 A-C).
In addition, above result shows, compares with the mice that buffer is handled, and in the mice that SLIT-handles, eosinophilic granulocyte's granulocyte level of BAL and NAL all significantly reduces (referring to Fig. 5 A-B).
At last, checked the stripped reactivity of spleen and lymphonodi cervicales (LN) cell (tongue drain) when attacking again with Phl p extract.Although in spleen, there is the trend of Phl p-specificity T-cell effect downward modulation,, this trend not obvious statistically (Fig. 6 A).In contrast, compare with the mice of buffer-processing, the T-cell effect (Fig. 6 B) to Phl p among the cervical region LNs in drain in the mice that SLIT-handles significantly weakens.
Conclusion
Above result shows that it is clinical that the SLIT treatment can palliate a disease, serology and cell characteristic on the muroid model of rhinitis.
Claims (17)
1. prophylactic treatment comprises using to the mucomembranous surface of object and contains the allergy vaccine of described anaphylactogen as active substance the anaphylactoid method of anaphylactogen in subject,
A) wherein, the described object that will treat is reacted the special IgE of described anaphylactogen so that show by sensitization,
B) wherein, the described object that will treat do not have the relevant anaphylactoid clinical symptoms of described anaphylactogen and
C) wherein, described preventative-therapeutic purpose is prevention or alleviates the relevant anaphylactoid clinical symptoms subsequently of described anaphylactogen.
2. method as claimed in claim 1, wherein, described object is by sensitization, so that show the Th2 cell effect special to described anaphylactogen.
3. as the method for claim 1 or 2, wherein, described object does not have rhinitis, conjunctivitis, rhinorrhea, nasal obstruction, sinusitis, sneeze, atopic dermatitis, pruritus, sheds tears, rhinorrhea, stridulate and skin irritant clinical symptoms.
4. as method any among the claim 1-3, wherein, the age of described object preferably less than 30 years old, was more preferably less than 20 years old less than 40 years old, more preferably 2-10 year.
5. as method any among the claim 1-4, wherein, described anaphylactogen is selected from following one group: suck anaphylactogen and venom allergens.
6. method as claimed in claim 5, wherein, described anaphylactogen is selected from following one group: trees pollen allergens, grass pollen allergens, dust mite allergen, medicinal herbs anaphylactogen and zoo-anaphylactogen.
7. as method any among the claim 1-6, wherein, described administration is in oral cavity (by the mucosa of digestive system), nasal cavity, vagina, Sublingual, eyes, rectum, urethra, the mammary gland, lung, in ear (promptly passing through ear) or buccal administration.
8. method as claimed in claim 7, wherein, described administration is buccal or sublingual administration (mouth mucosa drug administration).
9. any one method as in the above-mentioned claim, wherein, the described object that will treat has and the relevant anaphylactoid clinical symptoms of one or more anaphylactogens except the anaphylactogen of described vaccine.
10. anaphylactogen is used to produce and is used for the purposes of in the subject anaphylactoid mucosal vaccine of prophylactic treatment,
A) wherein, the described object that will treat is reacted the special IgE of described anaphylactogen so that show by sensitization,
B) wherein, the described object that will treat do not have the relevant anaphylactoid clinical symptoms of described anaphylactogen and
C) wherein, described preventative-therapeutic purpose is prevention or alleviates the relevant anaphylactoid clinical symptoms subsequently of described anaphylactogen.
11. assessment immune modulating treatment method is to the method for the anaphylactoid effect of anaphylactogen in the experimental animal body, this method may further comprise the steps
A) make described animal to described anaphylactogen sensitization,
B) allow the described animals received anaphylactogen first time attack by contact in intranasal or the trachea,
C) by mouth mucosa drug administration described animal is implemented described Therapeutic Method,
D) level of biomarker is measured and
E) utilize described measurement result to assess the effect of described Therapeutic Method.
12. as the method for claim 11, wherein, described mouth mucosa drug administration is sublingual administration (Sublingual immunotherapy (SLIT)).
13. as method any among the claim 11-12, wherein, described Therapeutic Method is after sensitization, carries out before the first time, anaphylactogen was attacked.
14. as method any among the claim 11-12, wherein, described Therapeutic Method carried out after the anaphylactogen attack in the first time.
15., wherein, after described Therapeutic Method, carry out by the anaphylactogen attack second time that contact in nasal cavity or the trachea is carried out as the method for claim 14.
16. as method any among the claim 11-15, wherein, described biomarker is selected from following one group: antibody, clinical symptoms and effector lymphocyte.
17. as the method for claim 16, wherein, described effector lymphocyte is selected from following one group: eosinophilic granulocyte, mastocyte, basophilic granulocyte, B cell, T cell, antigen-presenting cell (APC ' s) and after step c) by its deutero-cell.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62645404P | 2004-11-10 | 2004-11-10 | |
| DKPA200401730 | 2004-11-10 | ||
| DKPA200401730 | 2004-11-10 | ||
| US60/626,454 | 2004-11-10 | ||
| US68691405P | 2005-06-03 | 2005-06-03 | |
| US60/686,914 | 2005-06-03 | ||
| PCT/DK2005/000716 WO2006050729A2 (en) | 2004-11-10 | 2005-11-08 | Method of preventive treatment of allergy by mucosal administration of an allergy vaccine |
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| CN101065146A true CN101065146A (en) | 2007-10-31 |
| CN101065146B CN101065146B (en) | 2012-11-14 |
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| CN2005800408274A Expired - Fee Related CN101065146B (en) | 2004-11-10 | 2005-11-08 | Method of preventive treatment of allergy by mucosal administration of an allergy vaccine |
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| DK (1) | DK1812059T3 (en) |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102014954A (en) * | 2008-04-11 | 2011-04-13 | 阿尔克-阿贝洛有限公司 | Mucosomal allergen-specific immunotherapy with initial dosing after start of pollen season |
| CN107375950A (en) * | 2017-08-02 | 2017-11-24 | 深圳大学 | One kind restructuring allergy environment tolerance induction models of Gal 1 and method for building up |
| RU2775129C1 (en) * | 2021-04-20 | 2022-06-28 | Федеральное государственное бюджетное образовательное учреждение высшего образования Волгоградский государственный медицинский университет Министерства здравоохранения Российской Федерации | Method for preventing autoimmune thyroiditis in the course of allergen-specific therapy |
-
2005
- 2005-11-08 ES ES05800771T patent/ES2344915T3/en active Active
- 2005-11-08 PT PT05800771T patent/PT1812059E/en unknown
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102014954A (en) * | 2008-04-11 | 2011-04-13 | 阿尔克-阿贝洛有限公司 | Mucosomal allergen-specific immunotherapy with initial dosing after start of pollen season |
| CN107375950A (en) * | 2017-08-02 | 2017-11-24 | 深圳大学 | One kind restructuring allergy environment tolerance induction models of Gal 1 and method for building up |
| CN107375950B (en) * | 2017-08-02 | 2020-10-09 | 深圳大学 | Recombinant Gal-1 allergic environment immune tolerance induction model and establishment method |
| RU2775129C1 (en) * | 2021-04-20 | 2022-06-28 | Федеральное государственное бюджетное образовательное учреждение высшего образования Волгоградский государственный медицинский университет Министерства здравоохранения Российской Федерации | Method for preventing autoimmune thyroiditis in the course of allergen-specific therapy |
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| CN101065146B (en) | 2012-11-14 |
| ES2344915T3 (en) | 2010-09-09 |
| PT1812059E (en) | 2010-07-26 |
| DK1812059T3 (en) | 2010-09-13 |
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