EP1223974A2 - Medicament in order to induce tolerance - Google Patents

Abstract

The invention relates to a medicament comprising 11- beta -hydroxysteroid dehydrogenase inhibitors combined with an antigen in order to improve and optimize tolerance induction.

Description

Medicines for tolerance induction

description

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). 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.

It is believed that tolerance can be based on at least three different mechanisms. On the one hand, 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.

In the case of an immune reaction when eliminating a virus, for example, or in the case of non-specific inflammations, 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.

Autoimmune diseases represent a situation in which tolerance has broken down in whole or in part. They are usually chronically degenerative in humans. Remission, spontaneously or under immunosuppressive therapy, has so far been observed only rarely. The longer the disease process lasts, the more difficult it seems to break the vicious circle of chronic degenerative inflammation. Mechanisms such as epitope spreading seem to be important Role (Craft and Fatenejad 1 997; Moudgil 1 998; Vaneden, Vanderzee et al. 1 998).

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).

In medicine, tolerance induction is playing an increasingly important role, especially in the fight against autoimmune diseases, in desensitization to environmental antigens, such as in the treatment of hay fever and other allergies and asthma (Tsitoura et al. 1 999; Tsitoura et al. 2000)

The latest findings also attribute importance to the induction of tolerance in the field of classic vaccination (McSorley et al. 1 999).

However, modern immunosuppressive therapies still have significant side effects and are insufficient if the disease has already started, i.e. they do not cure.

According to current knowledge, the success of tolerance induction or immune modulation depends both on the way in which the antigen is presented and on the immunological milieu of the tissue / organism in which the desired immune reaction is to take place. With regard to the immunological processes that lead to the induction of tolerance in vivo, various theories are in some cases discussed very controversially.

So far, it has been assumed that tolerance and, in particular, orally induced tolerance are associated with certain cytokine patterns. This

Cytokine patterns in turn suggest different T helper cell populations. A distinction is made between Th 1, Th2 and recently also Th3 cells.

It is generally assumed that autoimmunity is mainly dominated by Th 1 cells and tolerance is more dominated by Th2 cells. However, it could be shown that immunological tolerance can be maintained in the animal model even in the absence of functional Th 1 and Th2 cells.

Some experts assume that at high doses of a mucosal antigen, autoreactive T cells that recognize the respective antigen are selectively eliminated (clonal elimination) (Gutgemann, Driver et al. 1 998). When using low antigen doses, this theory is based on the induction of regulatory T cells, which actively suppress the pathological immune response (bystander suppression). These T-cells, which are also antigen-specific, are assigned to the Th2 or Th3 type or T cell classes which are not characterized in detail (Weiner 1 997; Mason and Powrie 1 998; Seddon and Mason 1 999). The pathological situation is often defined so that it is generally caused by Th 1 -T 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). Within the framework of the theory, which is based on the counterregulation between Th 1 - and Th2 / 3 cytokines, 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).

The term "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.

According to the current state of the art, the therapeutic induction of tolerance in advanced stages has been an insurmountable problem, e.g. in rheumatoid arthritis. This new therapy approach currently only seems to be successful with a disease duration of less than 2 years. Thereafter, mechanisms such as epitope spreading and also non-specific inflammatory reactions are likely to complicate oral tolerance induction (Albani, UCSD, personal communication).

WO98 / 21 951 (Haas et al.) Discloses general methods for oral tolerance induction using an antigen with a derivatized amino acid as an adjuvant. In 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.

Attempts have also been made to modify the immunological milieu, among others. towards a presumably protective environment that promotes the proliferation of regulatory Th-2/3 by means of various auxiliary substances such as cytokines or antibodies against cytokines (Patent No. WO95 / 27500, WO98 / 1 6248). 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.

However, there are very few studies that try to control the immunological processes that are necessary for targeted tolerance induction via the body's own mechanisms.

Due to the complex functions of the cytokines in immune regulation and the possible uncontrollable side effects, manipulation of cytokines is highly problematic as a way of optimizing immune reactions and thus for clinical use in inducing tolerance. It has been shown that interventions in the cytokine network are often accompanied by dangerous side effects and incalculable risks. This is how the FDA recently got it pointed out that the administration of TNF antibodies as part of rheumatism therapy has already resulted in 1 0 deaths because an inflammatory reaction in the context of a disease other than the underlying disease rheumatism was no longer controllable and was therefore lethal. Similar fears also exist with regard to the use of IL-1 2 neutralizing antibodies, or with IL-4 because of known side effects.

Another aspect of today's therapeutic methods is the fact that 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.

The previous strategies for tolerance induction are mostly based on the administration of supraphysiological amounts of both the antigen and the adjuvants. The disadvantage of using high concentrations of the agents used is high costs and sometimes serious side effects, such as methotrexate.

Another disadvantage of the previously carried out and published studies on tolerance induction is that animal models are mostly used, in which the induction of tolerance is shown by the fact that the disease occurring in control animals is not even triggered in the treated animals. However, means that are able to intervene in the existing disease are of much greater importance.

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.

It has long been known that glucocorticoids (GCs) are able to down-regulate the production of certain cytokines. In addition to their ability to inhibit interleukin-2 (IL-2) and interferon- ^ (IFN ~), the anti-inflammatory effect of glucocorticoids is based on the downregulation of IL-1, tumor necrosis factor (TNF-σ) and IL -6. 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).

While extensive research on tolerance induction has accumulated, for example, the role of cytokines, little or nothing is known about the influence of steroid hormones in general and glucocorticoids in particular. Interestingly, however, it has been shown that estrogens, which are classified as immunosuppressive in their effect on the immune system (Jansson and Holmdahl 1 998), prevent the induction of tolerance (Mowat, Lamont et al. 1 988). This is particularly noteworthy in that estrogens per se promote a Th2 immune response, which is said to support oral tolerance in some systems (Weiner 1 997). The combination of inactive or suboptimal concentrations of estrogens administered alone together with glucocorticoids brings about synergistic immunosuppression (Carlsten, Verdrengh et al. 1 996). From this it is generally concluded that glucocorticoids also inhibit tolerance induction. There are no published data on the influence of glucocorticoids on tolerance induction. However, a preclinical phase I study at the University of San Diego / California found that glucocorticoid therapy prevented an attempt to induce oral tolerance. This is also reflected in the fact that patients treated with glucocorticoids are generally excluded from clinical studies on tolerance induction in autoimmune diseases. The administration of even low steroid concentrations blocks the active induction of tolerance. (S. Albani, University of California, San Diego and H. Weiner, Harvard University, Boston, personal communications, (Weiner 1 997; Bonnin and Albani 1 998)).

Under certain circumstances, under the influence of glucocorticoids, the cytokine pattern may shift towards a Th2-like cytokine profile. However, the latter is 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). Furthermore, 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. 1 999) , It is known that 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, on the other hand, 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). In addition, it is assumed that 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.

This object is achieved by 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. Surprisingly, it was found that 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.

This is unexpected insofar as it is generally known that an increase in the cortisol gel in plasma (for example when glucocorticoids are administered) has an immunosuppressive effect. But you have to distinguish between the cortisol concentration in the blood plasma, which has a systemic effect, and an increase in the cortisol play gel, which may be restricted to very specific cells or tissues. When 1 1 - / .- HSD is inhibited, other mechanisms appear to work than those that are the result of systemic cortisol administration. Obviously, inhibition of 1 1 - 5 HSD causes immune stimulation to induce tolerance, possibly by activating suppressor T cells.

1 1 -? -HSD is a member of 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).

1 1 - /? - 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. At 1 1 - /. 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 -? -Hydroxysteroid, for example the active cortisol. The dehydrogenase activity converts the 1 1 -? -Hydroxysteroid into the 1 1 -ketosteroid. There are different isoforms of 1 1 - /? - HSD. For example, 1 1 -? -HSD type 1 is a bidirectional enzyme that mainly acts as a reductase in vivo. 1 1 -? -HSD type 2, on the other hand, 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.

On the one hand, 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.

However, 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. Typically, in a classic vaccination, a pathogen is administered to the patient intravenously, which causes protective immunity. However, it has now been found that 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.

Surprisingly, it was found that the induction of tolerance has a beneficial effect on a subsequent infection not only in autoimmune diseases but also in infectious diseases. It was found that infections could be resolved by inducing tolerance. It is believed that the following mechanism of action is based on vaccination protection through tolerance induction: Many infectious agents contain several antigens, some of which obviously cause an overreaction of the host. This overreaction can, for example, convert T cells into Th2 cells, where Th2 cells cannot fight the invading pathogen. In the case of an infectious disease, such antigens now cause the host's immune system to overreact in a harmful manner, while at the same time it does not effectively fight the infectious agent. By inducing 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. In the case of 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.

In principle, it is possible to provide vaccination protection by tolerance induction for practically all infectious diseases by suitable selection of the antigen according to the instructions given here. 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. 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 (APLs) are peptides that essentially correspond to an antigen against which an immune response is triggered.

However, APLs have been replaced with individual amino acids. One has found that no or little additional adjuvant is required when APLs are administered as part of an oral tolerance induction.

In the field of allergy prevention, in principle all non-toxic environmental antigens can be used as 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.

Other 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.

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. On the other hand, 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. For example, 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)). For this purpose, they are either pulsed in vitro with the desired antigen, ie incubated with the antigen until they have taken it up and express it on the surface. 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. A 1 1 - /? - HSD inhibitor can then be combined with these dendritic cells in order to further support the effect. By treating dendritic cells with glucocorticoids, for example with 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.

This is presumably due to the fact that the combination according to the invention of a 1 1 - /? - HSD inhibitor with the antigen-presenting dendritic cells in the lymph node creates an environment in which the dendritic cells are more stable.

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)).

In a further preferred embodiment, 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.

In principle, 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. Examples of 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. Examples of exogenous inhibitory substances are glycyrrhetic acid (3 /? - hydroxy-1 1 -oxoolean-1 2-en-30-acid) and derivatives thereof, such as 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 (GA) 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. Furthermore, the term inhibitor of 1 1 - /? - HSD, as used herein, also includes substances that regulate the transcription of 1 1 - / J-HSD.

By using such transcription regulators, 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%. However, it can be advantageous to use substances which inhibit the in vivo 1 1? HSD activity by at least 90%, preferably by at least 95%. The inhibitors preferably have IC ₅₀ values, as determined in placental microsomes or MCF-7 cells, of <100 μM, preferably <30 μM, particularly preferably <1 μM. 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 μM, more preferably <100 μM and particularly preferably <1 μM. Possible dosages of the inhibitors, in particular of GA and derivatives, are up to 1 g per dose unit in humans.

In addition to the use of the inhibitors mentioned, it is also possible, and in the sense of the invention, to use 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. However, the two components are preferably not administered as one formulation, but rather separately. In addition, 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.

There was also a need to provide means with which immune reactions, in particular autoimmune diseases, can be positively influenced. 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. Surprisingly, it has been found that by influencing the 11 - /? - HSD as a representative of the SDR family, immune diseases and in particular Autoimmune diseases can be positively influenced. In addition, allergies, graft rejection and GVHD can be treated therapeutically and / or prophylactically using 1 1 - / .- HSD. In particular, 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. In addition, it is possible to use 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. In contrast to the immunosuppressive effect of 1 1 - /? - HSD modulators described so far, it has surprisingly been found that the effects indicated above can be obtained even when 1 1 - /? - HSD modulators, in particular inhibitors, are used alone.

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. Surprisingly, it was found that the use of a 1 1 - /? - HSD inhibitor 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. Preference is given to using the medicament according to the invention, in particular the combination of inhibitor of the 1 1 - /? - HSD with one or more antigens for inducing tolerance, inhibiting inflammation and / or immunomodulating in a mammal, in particular humans. 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. In addition, 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. However, 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. Glycyrrhizinsäure or Glycyrrhetinsäure 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.

The invention is further illustrated by the attached figures and the examples below.

Figure 1 shows the course of an experimentally induced arthritis without

(blue) or with (red) treatment by a 1 1 - /? - HSD inhibitor. The inhibitor, here glycyrrhetinic acid (GRA), was observed on days 0, 2 and 4

Injection of Freund's complete adjuvant (CFA) at a dose of 2 mg into 200 μl olive oil intradermally at the base in the tail of Rats injected. CFA was administered intradermally at a dose of 0.4 mg. The combination of inhibitor and antigen (contained in the CFA as mycobacterium t.) Leads to a weakened course of the disease, and therefore has an immunomodulatory effect.

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.

Examples

Enhancing tolerance induction in the adjuvant-induced arthritis model

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 50μl 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 formation of this form of arthritis is interpreted as the result of a so-called cross-reaction of the immune defense against both antigens of the Mycobacterium (Heat Shock Protein 60, hsp 60) and articular cartilage (Vaneden, Vanderzee et al. 1 998). example 1

Prevention of disease:

The development or the course of the disease can be positively influenced or prevented. For this purpose, 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 μg intranasally).

In this example, glycyrrhetic acid (GA) and a water-soluble derivative thereof, namely carbenoxolone, were used as 1 1 - /? - HSD inhibitor.

If the inhibitor (e.g. 1-8 mg intraperitoneally in oil or intranasally in saline) 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. Depending on the dose, the disease of the rats is prevented or their incidence and the severity of the course weakened. Furthermore, the amount of peptide required for induction of tolerance can be reduced.

Example 2

Manipulation of the course of the disease after induction of autoimmune arthritis or after onset of symptoms:

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.

For this purpose, 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).

The increase in the incidence of symptoms is influenced significantly more favorably than without the inhibition of 1 1 - /? - HSD. Certain antigens such as the disease-causing hsp60, which remain ineffective without carbenoxolone, also lead to an improvement in the course of the disease in combination with carbenoxolone. With regard to the use of carbenoxolone in combination with APLs, a weakening and shortening of the course of the disease can already be achieved with suboptimal peptide concentrations.

The fact that the inhibition of 1 1 - /? - HSD by means of the peptide (hsp60), which has not hitherto been suitable for therapeutic use, allows the course of the disease to be weakened or the amount of APL to be reduced appears to be a strong indication that it can succeed. to successfully initiate healing attempts by means of oral tolerance induction even in late stages. Thus, the data from animal experiments enable an ad hoc healing experiment to support tolerance induction in humans.

Example 3

Attenuation of experimentally induced arthritis by treatment alone with a 1 1 -ff-HSD inhibitor Autoimmune arthritis was experimentally induced in rats by the administration of Freund's complete adjuvant (CVA; 0.4 mg intradermal). The rats were divided into two groups and one group was injected intradermally at the base of the rat tail on days 0, 2 and 4 after injection of the CVA 2 mg GRA (glycyrrhitic acid) in 200 μl olive oil. The results of the two groups are shown in FIG. 1, which shows the course of the experimentally induced arthritis without (blue) or with treatment by the 11 - /? - HSD inhibitor (red). As can be clearly seen in FIG. 1, the combination of inhibitor and antigen (contained in CVA as mycrobacterium T.) leads to an attenuated course of the disease.

Further tests have shown that the inhibitor alone causes a milder course of the disease, or weakens the disease-promoting effect of the CVA and thus has an immunomodulatory effect.

Example 4

Improved effectiveness through mucosal tolerance induction against systemic administration It was found that a significantly improved effectiveness when administering an antigen plus a 1 1 - /? - HSD inhibitor (eg glycyrrhetic acid) intranasally compared to administration of the same antigen alone or of the antigen plus 1 1 - /? - HSD inhibitor (eg glycyrrhizic acid) can be observed systemically (orally). FIG. 2 shows the reinforcing effect of a 1 1 - /? - HSD inhibitor on nasal tolerance induction by means of a peptide antigen. For this purpose, 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 μl 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.

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Claims

Expectations

1 . Medicament comprising as active ingredient an inhibitor of 1 1 - /? - hydroxysteroid dehydrogenase in combination with an antigen.

2. Medicament according to claim 1, characterized in that the inhibitor and the antigen are present separately.

3. Medicament according to claim 1 or 2, for tolerance induction.

4. Medicament according to claim 3 for mucosal tolerance induction.

5. Medicament according to one of the preceding claims for anti-inflammatory and / or immune modulation.

6. Medicament according to one of the preceding claims, characterized in that the inhibitor is specific for isoform 1 or 3 of 1 1 - /? -

Hydroxysteroid dehydrogenase.

7. Medicament according to one of the preceding claims, characterized in that the inhibitor is selected from endogenous and exogenous

Inhibitors of 1 1 - /? - hydroxysteroid dehydrogenase and antisense nucleic acids which hybridize with sequences which code for 1 1 -? -HSD, antibodies against 1 1 - ^ - hydroxysteroid dehydrogenase or / and transcription regulators for 1 1 - /? - Hydroxysteroid dehydrogenase.

8. Medicament according to claim 7, characterized in that the inhibitor is selected from glycyrrhetic acid and derivatives thereof, in particular glycyrrhizin, glycyrrhizic acid and carbenoxolone.

9. Medicament according to claim 7, characterized in that the inhibitor is selected from furosemide and derivatives thereof.

1 0. Medicament according to claim 7, characterized in that the inhibitor is selected from flavonoids and derivatives thereof.

1 1. Medicament according to one of the preceding claims, characterized in that the antigen is selected from synthetic and natural proteins, peptides, nucleic acids, altered peptide ligands (APL), carbohydrates, including polysaccharides, lipopolysaccharides, antigens from biological resources and low molecular weight

Substances.

1 2. Medicament according to claim 1 1, characterized in that it contains the antigen in the form of a nucleic acid coding therefor.

1 3. Medicament according to one of the preceding claims, characterized in that the antigen is a bystander antigen.

1 4. Medicament according to one of the preceding claims, characterized in that the antigen is selected from antigens associated with the following diseases: rheumatoid arthritis, multiple sclerosis, uveitis, type I diabetes, lupus erythematosus.

5. Medicament according to one of the preceding claims, characterized in that the antigen is selected from the body's own and other heat shock proteins, proteolipid, MBP, MOG and cell components of the uvea, the skin, epithelia, the thyroid, the basement membrane, the

Muscles, nerve cells, thymus or red blood cells.

6. Medicament according to one of the preceding claims 5 to 8, characterized in that the antigen is selected from benzylpenicilloyl, insulin, ovalbumin, lactalbumin, pollen components, food components and dust mite components.

7. Medicament according to one of the preceding claims, characterized in that it additionally comprises pharmaceutically acceptable auxiliaries, additives and / or adjuvants.

8. Medicament according to one of the preceding claims, characterized in that the antigen presentation takes place by means of dendritic cells.

9. Medicament according to one of the preceding claims, characterized in that the antigen presentation takes place by means of T cells.

20. Use of a 1 1 - /? - hydroxysteroid dehydrogenase for obtaining a medicament for tolerance induction, anti-inflammatory and / or immune modulation.

21. Use of a 1 1 - /? - hydroxysteroid dehydrogenase to obtain a medicament for the treatment and / or prophylaxis of autoimmune diseases, allergies, graft rejection and graft versus host disease.

22. Use of an inhibitor of 1 1 - /? - hydroxysteroid dehydrogenase for the manufacture of a medicament for tolerance induction, anti-inflammation and / or immunomodulation.

23. Use of inhibitors of 1 1 - /? - hydroxysteroid dehydrogenase in combination with an antigen for tolerance induction, anti-inflammatory and / or immune modulation.

24. Use according to claim 20 to 23, characterized in that the inhibitor used is a substance which is specific for one or more isoenzymes of the 1 1 - /? - hydroxysteroid dehydrogenase.

25. Use according to one of claims 20 to 24, characterized in that endogenous or exogenous inhibitors of 1 1 - /? - hydroxysteroid dehydrogenase or antisense nucleic acids are used as inhibitors.

26. Use according to claim 25, characterized. that glycyrrhetinic acid or derivatives thereof, in particular glycyrrhizin, glycyrrhizinic acid or carbenoxolone, are used as inhibitors.

27. Use according to one of the preceding claims 20 to 26, characterized in that an improvement in the mucosal tolerance induction is achieved.

28. Use according to one of the preceding claims 20 to 27, characterized in that the antigen is selected from synthetic and natural proteins, peptides, carbohydrates including polysaccharides, lipopolysaccharides and antigens from biological resources.

29. Use according to claim 28, characterized in that the antigen is a bystander antigen.

30. Use according to any one of the preceding claims 20 to 29, characterized in that the antigen is selected from antigens associated with the following diseases: rheumatoid arthritis, multiple sclerosis, uveitis, type I diabetes, lupus erythematosus.

31 Use according to one of the preceding claims 20 to 30, characterized in that the antigen is selected from the body's own and other heat shock proteins, proteolipid, MBP, MOG and cell components of the uvea, the skin, various epithelia, the thyroid, the

Basement membrane, muscles, nerve cells, thymus or red blood cells.

32. Use according to one of the preceding claims 20 to 31, characterized in that the antigen is selected from benzylpenicilloyl, insulin, ovalbumin, lactalbumin, pollen constituents, food constituents and dust mite constituents.

33. A method of inducing tolerance to control autoimmune diseases, allergies and graft rejection and GVHD, comprising treating a mammal or a human

Treatment requires an effective amount of a 1 1 - /? - hydroxysteroid dehydrogenase inhibitor in combination with a mucosal administration of the antigen or an administration of a nucleic acid encoding the antigen.