WO2001030383A2 - Arzneimittel für die toleranzinduktion - Google Patents
Arzneimittel für die toleranzinduktion Download PDFInfo
- Publication number
- WO2001030383A2 WO2001030383A2 PCT/EP2000/010594 EP0010594W WO0130383A2 WO 2001030383 A2 WO2001030383 A2 WO 2001030383A2 EP 0010594 W EP0010594 W EP 0010594W WO 0130383 A2 WO0130383 A2 WO 0130383A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- antigen
- inhibitor
- medicament according
- medicament
- hydroxysteroid dehydrogenase
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/35—Allergens
- A61K39/36—Allergens from pollen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/44—Oxidoreductases (1)
- A61K38/443—Oxidoreductases (1) acting on CH-OH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/001—Preparations to induce tolerance to non-self, e.g. prior to transplantation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/53—DNA (RNA) vaccination
Definitions
- the invention relates to a medicament for inducing tolerance, for immunomodulation and / or for anti-inflammation, comprising inhibitors of 1 1 - /? - hydroxysteroid dehydrogenase (1 1 /, - HSD), optionally in combination with an antigen.
- the immune system is characterized by the ability to distinguish between dangerous, disease-promoting endogenous and / or foreign and harmless antigens.
- Tolerance is the state that is characterized by systemic "passivity” or “ignorance” of the immune system towards a specific antigen. It does not matter whether this antigen is intrinsic to the body (self-antigens) or foreign to the body. A breakdown in tolerance leads to autoimmune diseases if the body's antigens continuously maintain an immune system. Overreactions against environmental antigens that do not promote disease per se are summarized under the term allergies. In the field of transplantation medicine, unwanted immune reactions are referred to as a rejection reaction against the graft or, in the case of a defense reaction of the transplanted material against the recipient, of "graft versus host disease” (GVHD).
- GVHD graft versus host disease
- the term tolerance includes, in particular, desensitization, so that exogenous substances are tolerated, and mechanisms that lead to a reduction in immune reactions to the body's own substances.
- the quality of the immunological tolerance depends on the type of antigen, as well as on the form and dose with which it is presented to the immune system.
- tolerance can be based on at least three different mechanisms.
- dangerous, potentially autoreactive T cells that react in the thymus with antigens present there are negatively selected, i.e. they are killed (deletion).
- Another mechanism is clonal anergy. T cells that recognize an antigen on an antigen-presenting cell are deactivated, but not if there are costimulatory signals present at the same time, and can no longer later produce an immune reaction against this antigen.
- the third component of tolerance is assumed to be regulatory T cells, so-called suppressor T cells, which can have an immunomodulatory effect on immunological processes that have already been triggered.
- regulatory T cells help to restore an immunological balance and to terminate the immune reaction.
- a lack of self-regulation from an unexplained cause or the hindrance thereof e.g. medication can lead to a pathological condition, such as autoimmunity and allergies, or to an undesirable immune response in the field of transplant medicine.
- Oral tolerance is based on the fact that orally ingested antigens generally do not cause immune reactions and also prevent the same antigen from causing an immune response if it later enters the organism via a route that normally produces immune responses. This led to intensive attempts to modify or restore by the presentation (in particular by mucosal administration) of a suitable specific antigen or another antigen which brings about an immune response similar to the disease-relevant antigen (Liblau, Tisch et al. 1 997; Weiner 1 997; Bonnin and Albani 1 998; Strobel and Mowat 1 998).
- Cytokine patterns in turn suggest different T helper cell populations. A distinction is made between Th 1, Th2 and recently also Th3 cells.
- Another theory postulates a "bystander suppression" regulation as a possible mechanism which is dependent on direct contact between individual T cells and has not yet been characterized in more detail (Tsitoura, DeKruyff et al. 1 999). Still other hypotheses postulate different influences of different cytokines or mechanisms of tolerance induction independent of cytokines (Segal and Shevach 1 998; Lundin, Karlsson et al. 1 999; Rizzo, Morawetz et al. 1 999; Seddon and Mason 1 999).
- the cytokine environment in which the immune reactions take place seems to be of crucial importance in the induction of active bystander suppression; ie the predominant proliferation of presumably protective Th2 / 3 T cells can only take place in a suitable environment (Liblau, Tisch et al. 1 997; Weiner 1 997; Strobel and Mowat 1 998).
- milieu in immunology means the composition of various purely immunological factors that determine the direction of an antigen-induced immune response. Hormones and other factors that influence the immune system are not included in this classic immunological approach.
- the goal in the development of novel substances and methods is to optimize this environment. Firstly, the desired immune response should be safe and targeted and secondly, the necessary amount of antigen should be minimized.
- WO98 / 21 951 Discloses general methods for oral tolerance induction using an antigen with a derivatized amino acid as an adjuvant.
- U.S. Patent No. 5,935,577 to Weiner et al. an attempt was made to improve tolerance induction by administering a bystander antigen in combination with methotrexate.
- One goal was to reduce the amount of methotrexate that had severe side effects due to its toxicity. From today's perspective, however, it is desirable to be able to do without substances such as methotrexate, since methotrexate has a cumulative toxicity, ie liver damage occurs from a certain amount.
- WO95 / 27500 discloses a method for oral tolerance induction using a bystander antigen together with cytokines, especially II-4, which direct the immune system towards a response more dominated by type 2 helper cells (Th2).
- WO98 / 1 6248 uses inhibitors of IL-1 2 in oral tolerance induction.
- oral tolerance induction sometimes includes therapy cycles in which the antigen has to be taken daily for several weeks. It can currently be assumed that these cycles must be repeated several times, since the status of tolerance may require the continuous presence of the antigen, at least until complete healing has occurred. It is not possible to deduce from the previously published data whether a complete cure is possible.
- Glucocorticoids are known for their anti-inflammatory (anti-inflammatory) and immunosuppressive properties (Cupps and Fauci 1,982; Chrousos 1,995; Marx 1 995; Almawi, Beyhum et al. 1 996, Wilckens and Derijk, 1 997). They are therefore preferred for the treatment of inflammatory diseases and also for the treatment of autoimmune diseases.
- glucocorticoids are able to down-regulate the production of certain cytokines.
- IL-2 interleukin-2
- IFN ⁇ interferon- ⁇
- the GC concentrations in the tissues and in the plasma are in turn regulated by several mechanisms, namely by cytokines, GC receptor expression and by certain enzymes, e.g. the 1 1 - /? - hydroxysteroid dehydrogenase (1 1 -ß-HSD; Hult, Jornvall et al. 1 998; Krozowski 1 999; Stewart and Krozowski 1 999).
- the cytokine pattern may shift towards a Th2-like cytokine profile.
- Th2 cytokines are not sufficient as a therapy for an autoimmune process, even in the context of measures to induce tolerance.
- Both the application of Th2 cytokines and the transfer of Th2 cells cannot completely prevent an autoimmune reaction (Mason and Powrie 1 998; Segal and Shevach 1 998).
- a recent study has shown that inhibition of 1 1-J HSD as well as glucocorticoid injection leads to the destruction of immature T cells in the thymus (Gruber, Sgonc et al. 1 994; Horigome, Horigome et al.
- glucocorticoids have a similar effect on peripheral T cells and on undifferentiated, naive and immature T cells (Cupps and Fauci 1 982).
- the induction of tolerance propagates, among other things, the activation and proliferation of these immature T cells, while memory cells apparently cannot be tolerated (Chung, Chang et al. 1 999).
- glucocorticoids inhibit the antigen presentation (Piemonti, Monti et al. 1 999; Piemonti, Monti et al. 1 999), which additionally prevents tolerance induction from being supported.
- Immunological therapy methods are currently failing due to the poor ability to control the immune response and also because of the high amounts of protein, peptide antigen and DNA that have to be used to induce relevant clinical effects in humans. While considerable progress has been made in identifying possible antigens, there are currently no suitable methods available for use in humans that are suitable for long-term use. Immunological approaches currently appear to be less promising due to uncontrollable side effects.
- the object of the present invention was therefore to improve and / or optimize the tolerance induction by the administration of certain antigens in combination with a new adjuvant.
- a new medicament comprising, as active ingredient, inhibitors of 1 1 -? -Hydroxysteroid dehydrogenase in combination with one or more antigens and the use of the medicament for inducing tolerance.
- the 1 1 -? -Hydroxysteroid dehydrogenase (1 1 -? -HSD) is an enzyme which is responsible for the interconversion of biologically active forms of glucocorticoids in and out of their inactive forms.
- inhibitors of enzymes which regulate the cortisol metabolism in particular inhibitors of the 1 1-J-HSD in combination with an antigen, are able to induce tolerance.
- a particularly advantageous effect is achieved in combination with at least one antigen.
- 1 1 -? -HSD is a member of short chain dehydrogenases / reductases (SDR; short chain dehydrogenases / reductases).
- SDR short chain dehydrogenases / reductases
- Members of the SDR family typically comprise about 250 amino acids and have an N-terminal coenzyme binding pattern (typically GXXXGXG) and an active binding site with the sequence YXXXK.
- the SDR family is highly divergent with a typical identity match between 15% and 30% between the individual members.
- the SDR family of enzymes encompass a wide range of specific substrates, including steroids, alcohols and aromatic compounds (Jornvall et al., 1 999; Oppermann et al., 1 996).
- Hydroxy-steroid dehydrogenase is the key enzyme in the extra-hepatic conversion of 1 1 -.-Hydroxysteroids, such as cortisol and prenison, into their inactive metabolites.
- Hydroxy steroid dehydrogenase is a bidirectional enzyme which, depending on the environment or the isoform, has a reductase or / and a dehydrogenase activity.
- the reductase activity of 1 1 -? -Hydroxysteroid dehydrogenase converts a 1 1 -ketosteroid, for example the inactive cortisone, into a 1 1 -?
- 1 1 -? -HSD type 1 is a bidirectional enzyme that mainly acts as a reductase in vivo.
- 1 1 -? -HSD type 2 is a unidirectional enzyme in vivo and acts exclusively as a NAD-dependent dehydrogenase.
- the inhibitor of 1 1 - /? - hydroxysteroid dehydrogenase used here is preferably an inhibitor for the reductase activity and particularly preferably an inhibitor of 1 1 - /? - HSD-1.
- the medicament according to the invention contains, as an active ingredient, a combination of two or more substances, both as a mixture or formulation, and separately, for. B. may be present as a kit.
- the drug contains one or more antigens, which are used to trigger a specific immunological tolerance reaction.
- Suitable antigens of this type are all substances which cause undesired immune reactions, such as, for example, those which are associated with autoimmune diseases, e.g. Rheumatoid arthritis including juvenile forms, lupus erythema dots, multiple sclerosis, uveitis, type I diabetes (autoimmune diabetes) and those associated with allergies and / or asthma.
- autoimmune diseases e.g. Rheumatoid arthritis including juvenile forms, lupus erythema dots, multiple sclerosis, uveitis, type I diabetes (autoimmune diabetes) and those associated with allergies and / or asthma.
- substances which cause an infection can also be used as antigens, it being possible for the medicament according to the invention to induce a tolerance which can reduce or eliminate disadvantageous or pathological reactions to the infectious pathogen.
- Bacteria, viruses or other microorganisms are examples of infectious pathogens.
- the medicament according to the invention can comprise specific epitopes or antigens of such infectious pathogens, but it is also possible to use all or part of the microorganism.
- a pathogen is administered to the patient intravenously, which causes protective immunity.
- vaccination protection can be achieved not only in a conventional manner, but also by induction of tolerance through mucosal administration of antigens (McSorley, 1 999).
- Such an effect is further enhanced by the pharmaceutical combination according to the invention, so that a combination of 1 1 -? -HSD inhibitor and antigen can advantageously be used as a tolerogenic oral vaccine.
- a tolerance for example by mucosal administration of the antigen and simultaneous administration of a 1 1 - /? - HSD inhibitor, the adverse effect of the antigens causing an overreaction can be eliminated, so that the rest of the immune system can perform its protective function.
- tolerance induction for protection against or for curing infectious diseases, it is usually preferred to promote a Th 1 -like reaction and to switch off a Th2-like reaction. Accordingly advantageously creates a tolerance to antigens that elicit a Th2-like response.
- An antigen is preferably selected which is associated with a bacterial or viral infection, for example flu, Leishmania, fungal infections, cytomegaly, pneumonia, streptococci B, chlamydia, helicobacter, hepatitis C, herpes, human papilloma virus, mycobacteria tuberculosis and others.
- the antigen used according to the invention can preferably be a natural or synthetic protein, protein component or peptide, in particular also a so-called altered peptide ligand (APL), but carbohydrates including polysaccharides and lipopolysaccharides are also suitable, and antigens from biological resources.
- APL altered peptide ligand
- the latter include antigens which play a role in the development and / or healing of autoimmune diseases, allergies, or the desired and undesirable immune reaction in the context of transplantation medicine.
- the tolerance induction which is brought about according to the invention can thus also be advantageous in the case of transplantations.
- the antigen can be one against which an immune response is generated directly. However, it can also be a so-called bystander antigen, which elicits an (auto) immune reaction against epitopes that are adjacent or related to a protein.
- Altered peptide ligands are peptides that essentially correspond to an antigen against which an immune response is triggered.
- APLs have been replaced with individual amino acids.
- antigens which are suitable according to the invention.
- Benzylpenicilloyl, insulin, ovalbumin, lactalbumin are preferred, but also various pollen, food antigen, dust mites and their constituents, their excrement and the like.
- Suitable antigens include the body's own and other heat shock proteins (Prakken et al. (1 997); Prakken et al. (1 998)), thyroglobulin, cell components of the uvea, the skin, various epithelia, the thyroid gland, the basement membrane, and the muscles , myelin sheaths, nerve cells, thymus, red blood cells, other blood components and cells, proteolipid, myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), or other components of normal or diseased body tissue.
- Prakken et al. (1 997); Prakken et al. (1 998) thyroglobulin
- cell components of the uvea the skin, various epithelia, the thyroid gland, the basement membrane, and the muscles , myelin sheaths, nerve cells, thymus, red blood cells, other blood components and cells, proteolipid, myelin basic protein (MBP), mye
- a combination is furthermore preferred which contains a vaccine according to Rock et al. (2000), in particular a bacterial vaccine.
- the antigen can also be present as a nucleic acid or oligonucleotide in the medicament according to the invention.
- the nucleic acid or the oligonucleotide can itself represent the antigen.
- the nucleic acid can code for a specific peptide antigen. It can be given via various routes of administration, e.g. by injection, intravenously, intramuscularly, subcutaneously or with the help of the gene gun.
- the antigen presentation can preferably also be done by dendritic cells.
- Dendritic cells are the most important cells in the immune system for the presentation of the body's own and foreign antigens. They are therefore very potent stimulators of an immune response.
- dendritic cells can be grown from monocytes or bone marrow cells in a manner known in the art (D. Rea et al. (2000); E. Dejong et al. (1 999); M. Mathiszak et al. (2000)). Dendritic cells can be used for antigen-specific immunotherapy (Fairchild et al. (2000); Reid et al. (2000); Kapsenberg et al. (1 998)).
- Dendritic cells can also be stimulated by gene transfer to express the respective antigen, which means that they produce it themselves. It is also possible to stimulate cells already loaded with antigen to proliferate ex vivo and then reinject them into the body.
- the antigen presentation by means of dendritic cells is particularly preferably carried out according to the invention in that dendritic cells are ripened into the medium in vitro with the addition of glucocorticoids, for example cortisone, to a tolerance-inducing phenotype and then reinfused.
- glucocorticoids for example cortisone
- the tolerance can surprisingly be increased in addition to the increase which usually occurs in an antigen presentation by dendritic cells and the immune response.
- dendritic cells In addition to a genetic modification of dendritic cells to express desired antigens, it is also possible to isolate dendritic cells with the desired antigen from patients suffering from the corresponding disease. Artificial antigen-presenting cells and / or artificial dendritic cells are preferably used for antigen presentation (Faicioni et al. (1 999); Latouche et al. (2000); Wu et al. (2000)).
- the antigen is presented by T cells. Regulatory and / or antigen-specific T cells can be generated, for example, in vitro (Ramirez et al. (2000); Shevach (2000)).
- the antigen is presented by T cells and / or antigen-specific T cells can be influenced by regulatory T cells.
- inhibitors of 1 1 - /? - hydroxysteroid dehydrogenase are all inhibitors which have been known to date but which may not yet have been identified.
- the inhibitors preferably inhibit all isoforms of the 1 1 - /? - HSD, in particular, however, the 1 1 -? -HSD-1, further preferably also additional isoforms, and tissue-specific isoforms.
- a not yet clearly identified isoform, which is also preferably inhibited, is the 1 1-S-HSD-3.
- the inhibitors are preferably selected from endogenous and exogenous inhibitory substances.
- endogenous inhibitory substances are the following: Substrates for the 1 1 -? -HSD, such as 1 1 -OH-progesterone, 3-alpha, 5-beta-tetrahydro-progesterone, 3-alpha, 5-beta-tetrahydro-1 1 - deoxy-corticosterone, 1 1 -epicortisol, chenodeoxycholic acid, cholic acid.
- exogenous inhibitory substances are glycyrrhetic acid (3 /?
- glycyrrhizin glycyrrhizic acid and carbenoxolone
- Furosemide and derivatives thereof Flavonoids and derivatives thereof, such as naringenin
- Triterpinoids e.g. CHAPS
- ketoconazole Saiboku-To, Gossypol, Metyrapon, 1 1 - epiprednisolone
- Other suitable inhibitors are steroid-like, such as Dexamethasone, budesonide, deflazacort and stanozolol. Unidentified derivatives are suspected to be ACTH-dependent inhibitors.
- Glycyrrhetic acid and derivatives in particular glycyrrhizic acid, glycyrrhizin, glycyrrhitic acid and derivatives thereof, and in particular carbenoxolone, are particularly preferred.
- Glycyrrhetinic acid is an extract from licorice (Glycyrrhiza glabra) and inhibits the metabolism of endogenous glucocorticoids by blocking the enzyme 1 1 - /? - hydroxysteroid dehydrogenase.
- Carbenoxolone is a derivative of GA, which has a higher affinity for 1 1 -ß- HSD (Hult, Jornvall et al. 1 998).
- Carbenoxolone like GA, has been investigated in a large number of studies with regard to pharmacokinetics, toxicity and possible dosing regimens or application options in humans and has already been approved for use in humans; possible side effects are not to be expected or are harmless and reversible (Ulick, Wang et al. 1 993; Bernardi, D'lntino et al. 1 994; Krahenbuhl, Hasler et al. 1 994; Schambelan 1 994).
- Antibodies against 1 1 - /? - HSD or fragments thereof can also be used as inhibitors for 1 1 - /? - HSD.
- Such antibodies against 1 1 - / .- HSD can be e.g. be produced as monoclonal or polyclonal antibodies.
- the term inhibitor of 1 1 - /? - HSD, as used herein, also includes substances that regulate the transcription of 1 1 - / J-HSD.
- the amount of 1 1 - / .- HSD available in the body can be controlled.
- Suitable transcription regulators for 1 1 - / .- HSD are described, for example, by Williams et al. (2000) and particularly include members of the C / EBP family. It is further preferred to select the antigen and / or the 1 1 - /? - HSD modulator, in particular inhibitor, from low molecular weight substances which preferably have a molecular weight of ⁇ 500 Da, more preferably of ⁇ 250 Da.
- the inhibitors of 1 1 - / .- HSD mentioned, in particular glycyrrhetic acid and its derivatives, are non-toxic even in higher doses and have no serious side effects.
- the therapeutic use of GA or similar inhibitory substances of the 1 1 - / J-HSD is possible ad hoc.
- the combination of an inhibitory substance / method for inhibiting 1 1-J-HSD with an antigen thus represents a new therapeutic approach to the healing of various immunological diseases.
- Possible dosages of the inhibitors, in particular of GA and derivatives, are up to 1 g per dose unit in humans.
- the inhibitors are preferably used in an amount of at least 0.01, preferably at least 0.1, and particularly preferably at least 1 mg / kg body weight and day and up to 100, preferably up to 50, particularly preferably up to 10 mg / kg per day administered.
- a inhibitor of the 1 1 - /? - HSD is considered to be a compound which increases the in vivo 1 1 - /? - HSD activity by at least 10%, preferably at least 30%, more preferably at least 50%, particularly preferably at least 70% and most preferably inhibited at least 80%.
- the inhibitors preferably have IC 50 values, as determined in placental microsomes or MCF-7 cells, of ⁇ 100 ⁇ M, preferably ⁇ 30 ⁇ M, particularly preferably ⁇ 1 ⁇ M. Particularly potent inhibitors have IC 50 values of ⁇ 100 nM, preferably ⁇ 10 nM and particularly preferably ⁇ 1 nM.
- the K r values of the inhibitors used according to the invention are preferably ⁇ 1200 ⁇ M, more preferably ⁇ 100 ⁇ M and particularly preferably ⁇ 1 ⁇ M. Possible dosages of the inhibitors, in particular of GA and derivatives, are up to 1 g per dose unit in humans.
- an antisense nucleic acid which hybridizes with sequences which code for 11 -? - HSD as inhibitor. This can be particularly advantageous if an 11 -? - HSD is to be specifically inhibited in a certain tissue.
- the weight ratio of the constituents inhibitor and antigen is preferably 0.1 to 99.9 to 99.9 to 0.1, particularly preferably 90 to 10 to 10 to 90.
- the medicament of the invention can be present as a mixture or formulation of the two components antigen (s) and inhibitor.
- the two components are preferably not administered as one formulation, but rather separately.
- the medicament or the two active ingredient components can contain pharmaceutically acceptable auxiliaries and / or additives (e.g. suitable solvents or diluents) and / or adjuvants. These can easily be determined by a person skilled in the art.
- Another object of the present invention is therefore the use of an 11 - /? - hydroxysteroid dehydrogenase for the production of a medicament for the induction of tolerance, anti-inflammation or / and immune modulation.
- 11 - /? - HSD as a representative of the SDR family, immune diseases and in particular Autoimmune diseases can be positively influenced.
- allergies, graft rejection and GVHD can be treated therapeutically and / or prophylactically using 1 1 - / .- HSD.
- modulators such as inhibitors or promoters of 1 1 - /? - HSD can be used as the immunomodulatory substance in order to induce tolerance, inhibit inflammation and / or immunomodulation, in particular to combat autoimmune diseases, allergies, transplant rejection and / or GVHD.
- Known inhibitors of 1 1 - /? - HSD or substances which interact with 1 1 - /? - HSD and are found, for example, by screening or computer-aided methods, such as force field calculations, can be used as suitable immunomodulatory substances.
- substances known as inhibitors from other members of the SDR family and to test these substances for their interaction with 1 1 - /? - HSD by simple experiments.
- Another object of the present invention is the use of an inhibitor of 1 1 - /? - hydroxysteroid dehydrogenase for the manufacture of a medicament for the induction of tolerance, anti-inflammation and / or immune modulation.
- an inhibitor of 1 1 - /? - HSD can not achieve an immunosuppressive effect but rather a tolerance induction, immunomodulation or / and anti-inflammatory effect.
- An inhibitor of 1 1 - /? - HSD can generally be used to inhibit inflammation in acute and / or chronic inflammatory processes, including septic shock and sepsis. Beneficial effects have been observed in both infectious and non-infectious inflammation.
- Areas of application are in the field of autoimmune diseases, e.g. rheumatoid arthritis, including juvenile forms, lupus erythema dotes, multiple sclerosis, uveitis, type I diabetes, as well as in al le rgien and the tra ns pl antatio n sme d izi n, in particular graft rejection and GVHD.
- Tolerance induction can also be used in immunization against infectious agents, as explained above.
- the drug can be administered in various ways. It is possible to administer the inhibitor (s) of the 1 1 - /? - HSD, preferably together with the antigen (s) and optionally additional adjuvants, it being possible for the components mentioned to be present as a formulation.
- the two active ingredient components and any additional adjuvants or adjuvants can also be given via different routes of administration. On the one hand, mucosal routes are possible, e.g. intranasally, orally, sublingually or by inhalation, but also others such as intravenously, subcutaneously, intramuscularly and intraperitoneally.
- the gene gun can also be used when administering nucleic acids.
- the following application options are particularly suitable for presenting the antigen: the so-called mucosal, ie oral or nasal tolerance induction and more recently by the addition of DNA (Ragno, Colston et al. 1 997; Lee, Corr et al. 1 998; Lobell, Weissert et al . 1 999; McCIuskie and Davis 1 999; McCIuskie, Millan et al. 1 999), which codes for the antigen in question and is injected into the organism to be treated, for example a human.
- the antigen presentation can also be carried out by means of dendritic cells or T cells, as described above.
- the agent according to the invention is preferably used for mucosal induction.
- Mucosal means absorption through the mucous membranes and includes the administration of an antigen by, among other things, oral ingestion or instillation into the nose, or inhalation and absorption via the lungs.
- administration can also be subcutaneous, intravenous and / or intramuscular.
- Inhibitor and antigen can be administered together or separately via different routes and also at different times.
- a particularly advantageous dosage form is a capsule that consists of a 1 1 - /? - HSD inhibitor, e.g. Glycyrrhizin Textre or Glycyrrhetinklare exists, which encloses an antigen inside.
- a 1 1 - /? - HSD inhibitor e.g. Glycyrrhizin Textre or Glycyrrhetinklare exists, which encloses an antigen inside.
- the inhibitor can be administered via all known routes and is brought into the appropriate form, e.g. dissolved in a suitable solvent for injection. It is also possible to first remove the inhibitor, e.g. by injection intravenously, intramuscularly or subcutaneously, and then administer the antigen (s) via mucosal routes. It may be advantageous to give the inhibitor in multiple doses.
- Figure 1 shows the course of an experimentally induced arthritis without
- GABA glycyrrhetinic acid
- CFA complete adjuvant
- FIG. 2 shows the reinforcing effect of a 1 1 - /? - HSD inhibitor on the nasal tolerance induction by means of a peptide antigen.
- the peptide 1 76 to 1 90 (Prakken et al. (1 997)) was administered intranasally on days - 1 5, -1 1, -7 and - 3 in 3% sodium bicarbonate solution before induction of the onset of the disease.
- GRA was administered intranasally at a dose of 0.5 mg in 25 ul per nostril, i.e. added in total in an amount of 1 mg.
- the red curve shows a control group.
- the blue curve shows the course of the disease under peptide treatment (antigen) without adding GRA.
- the yellow curve shows the combination according to the invention of peptide (antigen) and GRA, which were administered intranasally.
- This animal model in which an arthritis-like autoimmune disease can be induced, is known in the prior art (Leech, Metz et al. 1 998; Prakken, Wauben et al. 1 998; Vaneden, Vanderzee et al. 1 998): This involves rats a suspension of oil and Mycobacterium injected into the tail (1 50 ⁇ l of a 1 0mg / ml suspension with Mycobacterium tuberculosis). After approximately 1 0-1 3 days, the animals develop joint inflammation that reflects certain characteristics of human rheumatoid arthritis.
- the development or the course of the disease can be positively influenced or prevented.
- tolerance to certain antigens of the Mycobacterium is induced in the rats before induction of the experimental arthritis.
- the antigen e.g. hsp60 or a so-called altered peptide ligand either presented orally or nasally as a protein or peptides to the immune system (Prakken, Wauben et al. 1 998), or administered as DNA (Ragno, Colston et al. 1 997) before the sensitization by means of the oil / mycobacterium mixture takes place.
- Administration e.g. of the APL takes place on the day - 1 5, -1 0, -5, and on the day of sensitization (1 00 ⁇ g intranasally).
- glycyrrhetic acid (GA) and a water-soluble derivative thereof, namely carbenoxolone, were used as 1 1 - /? - HSD inhibitor.
- the inhibitor e.g. 1-8 mg intraperitoneally in oil or intranasally in saline
- the antigen e.g. 1-8 mg intraperitoneally in oil or intranasally in saline
- the antigen is used together with the antigen until the oil / peptide mixture is injected, i.e. administered before sensitization
- the latter is enhanced in its effect and the amount of antigen required to induce tolerance is reduced.
- the disease of the rats is prevented or their incidence and the severity of the course weakened.
- the amount of peptide required for induction of tolerance can be reduced.
- the induced autoimmune arthritis coincides with the onset of the inflammatory reaction 10 days after the injection of Freund's adjuvant Mycobacterium or hsp60 fulminant monophasic with a disease peak around the 27th day; symptoms are no longer detectable after 40 days.
- the course of the inflammatory reaction can be positively influenced with altered peptide ligands (APLs) even after the onset of symptoms if the treatment is carried out within 24-48 hours after the onset of the first symptoms and is continued daily.
- APLs altered peptide ligands
- the inhibitor carbenoxolone is injected into rats during the nasal application of the protein antigen (hsp60) or the APL or instilled via the nose (concentrations as in Example 1).
- FIG. 2 shows the reinforcing effect of a 1 1 - /? - HSD inhibitor on nasal tolerance induction by means of a peptide antigen.
- peptide 1 76-1 90 was administered intranasally to all test groups on days -1 5, -1 1, - 7 and -3 before induction of a flare-up of experimentally induced arthritis (caused by CFA, as described in Example 3) in 3% sodium bicarbonate solution.
- GRA in (intranasal) was added in a dose of 0.5 mg in 25 ⁇ l per nostril, ie a total dose of 1 mg.
- the red curve shows a control group with systemic administration of glycyrrhizic acid in drinking water.
- the blue curve shows the course of the disease under peptide treatment without addition of GRA and the yellow curve shows the combination according to the invention of peptide (antigen) and 1 1 -ß-HSD inhibitor (eg GRA), both of which were administered intranasally.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Transplantation (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Hospice & Palliative Care (AREA)
- Emergency Medicine (AREA)
- Communicable Diseases (AREA)
- Psychiatry (AREA)
- Ophthalmology & Optometry (AREA)
- Dermatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Surgery (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020027005465A KR20020057986A (ko) | 1999-10-28 | 2000-10-27 | 내성을 유도하기 위한 약물 |
EP00983094A EP1223974A2 (de) | 1999-10-28 | 2000-10-27 | Arzneimittel für die toleranzinduktion |
CA002388974A CA2388974A1 (en) | 1999-10-28 | 2000-10-27 | Medicament in order to induce tolerance |
AU19972/01A AU784245B2 (en) | 1999-10-28 | 2000-10-27 | Medicament in order to induce tolerance |
NZ518567A NZ518567A (en) | 1999-10-28 | 2000-10-27 | Medicament comprising an inhibitor of 11-beta-hydroxysteroid dehydrogenase in combination with an antigen to induce and/or optimise tolerance induction |
JP2001532800A JP2003512438A (ja) | 1999-10-28 | 2000-10-27 | 免疫寛容を誘導するための薬剤 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19951970.6 | 1999-10-28 | ||
DE19951970A DE19951970A1 (de) | 1999-10-28 | 1999-10-28 | Arzneimittel für die Toleranzinduktion |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2001030383A2 true WO2001030383A2 (de) | 2001-05-03 |
WO2001030383A3 WO2001030383A3 (de) | 2001-11-08 |
Family
ID=7927188
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2000/010594 WO2001030383A2 (de) | 1999-10-28 | 2000-10-27 | Arzneimittel für die toleranzinduktion |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP1223974A2 (de) |
JP (1) | JP2003512438A (de) |
KR (1) | KR20020057986A (de) |
CN (1) | CN1391479A (de) |
AU (1) | AU784245B2 (de) |
CA (1) | CA2388974A1 (de) |
DE (1) | DE19951970A1 (de) |
NZ (1) | NZ518567A (de) |
WO (1) | WO2001030383A2 (de) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003086472A1 (fr) * | 2002-04-15 | 2003-10-23 | Keio University | Medicaments prevus pour etre utilises en therapie genique pour les maladies genetiques transmises de maniere recessive |
JP2006519187A (ja) * | 2003-02-28 | 2006-08-24 | アルカベロ アクチェセルスカプ | 糖類マトリックスを有する剤形 |
US7759339B2 (en) | 2005-03-31 | 2010-07-20 | Takeda San Diego, Inc. | Hydroxysteroid dehydrogenase inhibitors |
US7816336B2 (en) | 2002-04-19 | 2010-10-19 | Isis Pharmaceuticals, Inc. | Antisense modulation of hydroxysteroid 11-beta dehydrogenase 1 expression |
US8012505B2 (en) | 2003-02-28 | 2011-09-06 | Alk-Abello A/S | Dosage form having a saccharide matrix |
US8048918B2 (en) | 2000-08-17 | 2011-11-01 | Vampex Limited | Treatment of hyperproliferative diseases |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SI1663185T1 (sl) * | 2003-09-22 | 2009-04-30 | Onepharm Res & Dev Gmbh | Preprečevanje in zdravljenje z vnetjem inducirane in/ali imunsko posredovane izgube kosti |
WO2006059507A1 (ja) * | 2004-11-30 | 2006-06-08 | Sankyo Company, Limited | 11β-HSD1アンチセンス化合物 |
CA3182519A1 (en) * | 2011-04-29 | 2012-11-01 | Selecta Biosciences, Inc. | Tolerogenic synthetic nanocarriers for antigen-specific deletion of t effector cells |
AU2014262163A1 (en) | 2013-05-03 | 2015-11-19 | Selecta Biosciences, Inc. | Delivery of immunosuppressants having a specified pharmacodynamic effective-life and antigen for the inducation of immune tolerance |
CN107073091A (zh) | 2014-09-07 | 2017-08-18 | 西莱克塔生物科技公司 | 用于减弱外显子跳读抗病毒转移载体免疫应答的方法和组合物 |
CN110612122A (zh) | 2017-03-11 | 2019-12-24 | 西莱克塔生物科技公司 | 与用抗炎剂和包含免疫抑制剂之合成纳米载体进行的组合治疗相关的方法和组合物 |
JP2019182845A (ja) * | 2018-04-02 | 2019-10-24 | 学校法人藤田学園 | キヌレニンアミノトランスフェラーゼ2(kat2)阻害剤 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1083815A (en) * | 1963-10-01 | 1967-09-20 | Wellcome Found | Vaccine adjuvants |
WO1990004399A1 (en) * | 1988-10-24 | 1990-05-03 | The University Court Of The University Of Edinburgh | Administration of corticosteroids |
WO1991004030A1 (en) * | 1989-09-25 | 1991-04-04 | University Of Utah | Use of steroid hormones in compositions for inducing t cell lymphokine production |
US5527890A (en) * | 1993-04-16 | 1996-06-18 | Glycomed Incorporated | Derivatives of triterpenoid acids and uses thereof |
US5591771A (en) * | 1991-12-17 | 1997-01-07 | Michel Fockerman | Use of propolis components as an adjuvant |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH04243833A (ja) * | 1991-01-28 | 1992-08-31 | Tsumura & Co | 11β−ヒドロキシステロイドデヒドロゲナーゼ阻害剤 |
US5883240A (en) * | 1995-08-24 | 1999-03-16 | Baker Medical Research Institute | Genetic sequences encoding glucocorticoid dehydrogenases and uses therefor |
-
1999
- 1999-10-28 DE DE19951970A patent/DE19951970A1/de not_active Ceased
-
2000
- 2000-10-27 CA CA002388974A patent/CA2388974A1/en not_active Abandoned
- 2000-10-27 AU AU19972/01A patent/AU784245B2/en not_active Ceased
- 2000-10-27 CN CN00815992A patent/CN1391479A/zh active Pending
- 2000-10-27 JP JP2001532800A patent/JP2003512438A/ja not_active Withdrawn
- 2000-10-27 KR KR1020027005465A patent/KR20020057986A/ko not_active Application Discontinuation
- 2000-10-27 EP EP00983094A patent/EP1223974A2/de not_active Withdrawn
- 2000-10-27 WO PCT/EP2000/010594 patent/WO2001030383A2/de active IP Right Grant
- 2000-10-27 NZ NZ518567A patent/NZ518567A/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1083815A (en) * | 1963-10-01 | 1967-09-20 | Wellcome Found | Vaccine adjuvants |
WO1990004399A1 (en) * | 1988-10-24 | 1990-05-03 | The University Court Of The University Of Edinburgh | Administration of corticosteroids |
WO1991004030A1 (en) * | 1989-09-25 | 1991-04-04 | University Of Utah | Use of steroid hormones in compositions for inducing t cell lymphokine production |
US5591771A (en) * | 1991-12-17 | 1997-01-07 | Michel Fockerman | Use of propolis components as an adjuvant |
US5527890A (en) * | 1993-04-16 | 1996-06-18 | Glycomed Incorporated | Derivatives of triterpenoid acids and uses thereof |
Non-Patent Citations (6)
Title |
---|
AUTERI A ET AL: "Effect of a long-term treatment with two different corticosteroids on patients suffering from rheumatoid arthritis: Clinical and immunological study." INTERNATIONAL JOURNAL OF IMMUNOTHERAPY, Bd. 10, Nr. 2, 1994, Seiten 67-75, XP001002029 ISSN: 0255-9625 * |
DATABASE WPI Section Ch, Week 199241 Derwent Publications Ltd., London, GB; Class B04, AN 1992-337593 XP002167668 & JP 04 243833 A (TSUMURA & CO), 31. August 1992 (1992-08-31) * |
DI ZHANG YIN ET AL: "Inhibition of 11-beta-hydroxysteroid dehydrogenase obtained from guinea pig kidney by furosemide, naringenin and some other compounds." JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, Bd. 49, Nr. 1, 1994, Seiten 81-85, XP001002027 ISSN: 0960-0760 * |
HULT MALIN ET AL: "Selective inhibition of human type 1 11beta-hydroxysteroid dehydrogenase by synthetic steroids and xenobiotics." FEBS LETTERS, Bd. 441, Nr. 1, 11. Dezember 1998 (1998-12-11), Seiten 25-28, XP002167666 ISSN: 0014-5793 in der Anmeldung erwähnt * |
KROES B H ET AL: "Inhibition of human complement by beta-glycyrrhetinic acid." IMMUNOLOGY, Bd. 90, Nr. 1, 1997, Seiten 115-120, XP002167665 ISSN: 0019-2805 * |
RAO CHAVALI S ET AL: "AN IN VITRO STUDY OF IMMUNOMODULATORY EFFECTS OF SOME SAPONINS" INTERNATIONAL JOURNAL OF IMMUNOPHARMACOLOGY,US,ELMSFORD,NY, Bd. 9, Nr. 6, 1987, Seiten 675-683, XP000863703 ISSN: 0192-0561 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8048918B2 (en) | 2000-08-17 | 2011-11-01 | Vampex Limited | Treatment of hyperproliferative diseases |
WO2003086472A1 (fr) * | 2002-04-15 | 2003-10-23 | Keio University | Medicaments prevus pour etre utilises en therapie genique pour les maladies genetiques transmises de maniere recessive |
US7816336B2 (en) | 2002-04-19 | 2010-10-19 | Isis Pharmaceuticals, Inc. | Antisense modulation of hydroxysteroid 11-beta dehydrogenase 1 expression |
JP2006519187A (ja) * | 2003-02-28 | 2006-08-24 | アルカベロ アクチェセルスカプ | 糖類マトリックスを有する剤形 |
US8012505B2 (en) | 2003-02-28 | 2011-09-06 | Alk-Abello A/S | Dosage form having a saccharide matrix |
US7759339B2 (en) | 2005-03-31 | 2010-07-20 | Takeda San Diego, Inc. | Hydroxysteroid dehydrogenase inhibitors |
Also Published As
Publication number | Publication date |
---|---|
DE19951970A1 (de) | 2001-05-03 |
KR20020057986A (ko) | 2002-07-12 |
AU1997201A (en) | 2001-05-08 |
WO2001030383A3 (de) | 2001-11-08 |
JP2003512438A (ja) | 2003-04-02 |
NZ518567A (en) | 2004-09-24 |
AU784245B2 (en) | 2006-02-23 |
CN1391479A (zh) | 2003-01-15 |
EP1223974A2 (de) | 2002-07-24 |
CA2388974A1 (en) | 2001-05-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Bomstein et al. | Features of skin-coincubated macrophages that promote recovery from spinal cord injury | |
DE69836643T2 (de) | Zusammensetzungen für die zufuhr von genen an antigen-präsentierende zellen der haut | |
WO2001030383A2 (de) | Arzneimittel für die toleranzinduktion | |
DE69737969T2 (de) | Dns-impfung zur einleitung einer suppressiven t-zell-antwort | |
Hauben et al. | Sexual dimorphism in the spontaneous recovery from spinal cord injury: a gender gap in beneficial autoimmunity? | |
EP1734975B1 (de) | Pflanzliche therapie zur behandlung von nahrungsmittelallergien | |
US11944600B2 (en) | Use of cannabinoids in the treatment of a neurodegenerative disease or disorder | |
KR20100022022A (ko) | 자가면역 질환 및 암을 치료하기 위한 의약 및 방법 | |
DE69830900T2 (de) | Immunologische toleranz-induzierende zusammensetzungen enthaltend antigen und mucosabindungskomponente | |
Banerjee et al. | Recent developments in the pharmacological treatment and prevention of corneal graft rejection | |
DE69815840T2 (de) | Verwendung von tall-104 zellen in kombination mit adriamyzin oder cisplatin zur behandlung von malignen tumoren | |
Schwartz et al. | Does inflammation in an autoimmune disease differ from inflammation in neurodegenerative diseases? Possible implications for therapy | |
Shen et al. | Protective effect of norcantharidin on collagen-induced arthritis rats | |
DE10005643A1 (de) | Kombination eines Antigens mit einem Sulphatase-Inhibitor | |
DE60226126T2 (de) | Verwendung von gamma-gt inhibitoren zur behandlung von chronischen degenerativerkrankungen | |
WO2002012453A1 (de) | Verfahren zur reduzierung von spezifischen immunreaktionen | |
WO2005084137A2 (en) | Cd25 dna vaccines for treating and preventing t-cell mediated diseases | |
WO2002077208A1 (de) | Antigen-abhängige reduktion von spezifischen immunreaktionen durch beeinflussung der co-stimulation | |
US11471496B2 (en) | Compositions and methods for treating or ameliorating cocaine addiction | |
EP1179587A1 (de) | Verfahren zur Reduzierung von spezifischen Immunreaktionen | |
JP2009067792A (ja) | 使用 | |
EP3641805A1 (de) | Vakzine zur behandlung eines malignoms | |
Bhavani et al. | Underlying antioxidant activity in the anticonvulsant potency of polyherbal tonic | |
EP2822567B1 (de) | Hefeextrakt zur behandlung von allergien | |
Gruber et al. | Site-specific immunosuppression with topical agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2000983094 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 19972/01 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 518567 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2388974 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020027005465 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10110781 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 2001 532800 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 008159920 Country of ref document: CN |
|
WWP | Wipo information: published in national office |
Ref document number: 1020027005465 Country of ref document: KR |
|
WWP | Wipo information: published in national office |
Ref document number: 2000983094 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 518567 Country of ref document: NZ |
|
WWG | Wipo information: grant in national office |
Ref document number: 518567 Country of ref document: NZ |