CA2388974A1 - 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

Medicament for inducing tolerance Description The invention relates to a medicament for inducing tolerance, for immunomodulation or/and for inhibiting inflammation, comprising inhibitors of 11-j3-hydroxy-steroid dehydrogenase (11(3-HSD), where appropriate in combination with an antigen.
The immune system is distinguished by the property of being able to differentiate between hazardous, disease-promoting endogenous and/or exogenous and nonhazardous antigens.
The state referred to as tolerance in this connection is one distinguished by systemic "passivity" or else "ignorance" of the immune system in relation to a specific antigen. It is immaterial in this connection whether this antigen is endogenous (self-antigens) or exogenous. Collapse of tolerance leads, if endogenous antigens continuously maintain an immune defense, to autoimmune diseases. Overreactions to environmental antigens which are not disease-promoting per se are embraced by the term allergies. In the area of trans-plantation medicine, when there are unwanted immune responses there is said to be a rejection response against the transplant or, in the case of a defense response of the transplanted material against the recipient, graft versus host disease (GVHD). The term tolerance includes in particular desensitization, so that exogenous substances are tolerated, and mechanisms leading to a reduction in immune responses to endogenous substances.
The nature of the immunological tolerance depends on the type of antigen and on the form and dose in which it is presented to the immune system.

s CA 02388974 2002-04-25 w It is assumed that tolerance can be based on at least three different mechanisms. Firstly, dangerous, poten-tially autoreactive T cells which react in the thymus with antigens present therein are negatively selected, i.e. they are killed (deletion). Another mechanism is clonal anergy. This entails T cells which recognize an antigen on an antigen-presenting cell but not if costimulatory signals are present simultaneously being deactivated and being no longer able to elicit an immune response against this antigen later either. The third component of tolerance is assumed to be regulatory T cells, called suppressor T cells, which can have immunomodulatory effects on immunological processes which have already been initiated.
In the case of an immune response in the elimination for example of a virus or else in nonspecific inflam-mations, regulatory T cells contribute to restoring an immunological balance and to terminating the immune response. A deficiency of self-regulation of unexplained cause or prevention thereof for example by medicaments may lead to a pathological state such as autoimmunity and allergies, or to an unwanted immune response in the area of transplantation medicine.
Autoimmune diseases represent a situation in which tolerance has wholly or partly collapsed. In humans, they generally have a chronic degenerative course.
Remission, spontaneous or under immunosuppressive therapy, has to date been observed only rarely. The longer the disease process lasts, the more difficult it appears to be to break the vicious circle of chronic degenerative inflammation. Mechanisms such as so-called epitope spreading appear to play an important part in this (Craft and Fatenejad 1997; Moudgil 1998; Vaneden, Vanderzee et al. 1988).
Oral tolerance is based on the fact that antigens taken by mouth usually elicit no immune responses and moreover prevent the same antigen being followed by an immune response when it gets into the body at a later time via a route which normally produces immune responses . This has led to vigorous attempts to modify or to restore through presentation (in particular by mucosal administration) of a suitable specific antigen or of another antigen which brings about an immune response similar to that of the disease-relevant antigen (Liblau, Tisch et al. 1977; Weiner 1997; Bonnin and Albani 1998; Strobel and Mowat 1998).
Tolerance induction is becoming increasingly important in medicine, especially in the control of autoimmune diseases, also in desensitization against environmental antigens such as, for example, in the treatment of hay fever and other allergies and of asthma (Tsitoura et al. 1999; Tsitoura et al. 2000).
Very recent findings also ascribe importance to the induction of tolerance in the area of conventional vaccination (McSorley et al. 1999).
Modern immunosuppressive therapies still display considerable side effects, however, and are inadequate if the onset of the disease has already taken place, i.e. they produce no cure.
According to the current state of knowledge, the success of tolerance induction or immunomodulation depends both on the mode of presentation of the antigen and on the immunological milieu of the tissue/organism in which the desired immune response is to proceed.
Various theories have been suggested about the immuno logical processes leading to tolerance induction in vivo, and some of them are very controversial.
It has to date been assumed that tolerance, and in particular orally induced tolerance, is connected with certain cytokine patterns. These cytokine patterns in turn suggest various T-helper cell populations. A
distinction is made between Thl, Th2 and, recently also, Th3 cells. Thus, it is generally assumed that autoimmunity is dominated mainly by Thl cells and tolerance more by Th2 cells. However, it has been possible to show that immunological tolerance in animal models can be maintained even in the absence of functional Thl and Th2 cells.
Some specialists assume that with high doses of a mucosally administered antigen there is selective elimination of autoreactive T cells which recognize the particular antigen (clonal elimination) (Gutgemann, Fahrer et al. 1998). On use of low antigen doses, this theory starts from the induction of regulatory T cells which actively suppress the pathological immune response (bystander suppression). These likewise antigen-specific T cells are assigned to the Th2 or else Th3 type or to T cell classes which have not been characterized in detail (Weiner 1997; Mason and Powrie 1998; Seddon and Mason 1999). The pathological situa-tion is moreover frequently defined in such a way that it is generally caused by Thl T cells. A further theory postulates a regulation which has not to date been characterized in detail and which depends on direct contact between individual T cells as possible mechanism a bystander suppression (Tsitoura, DeKruyff et al. 1999). Other hypotheses again postulate influences, which differ in each case, of different cytokines or mechanisms independent of cytokines for tolerance induction (Segal and Shevach 1998; Lundin, Karlsson et al. 1999; Rizzo, Morawetz et al. 1999;
Seddon and Mason 1999).
Within the theory based on counter-regulation between Thl and Th2/3 cytokines, it appears that the cytokine milieu in which the immune responses proceed has crucial importance in the induction of active bystander i suppression; i.e. the proliferation mainly of presumably protective Th2/3 T cells can take place only in a suitable milieu (Liblau, Tisch et al. 1997; Weiner 1997; Strobel and Mowat 1998).
"Milieu" means in this connection in immunology the combination of various purely immunological factors which determine the direction of an antigen-induced immune response. Hormones and other factors influencing the immune system are, however, not included in this classically immunological concept.
The aim in developing novel substances and methods is to optimize this milieu. The intentions in this connec-tion are firstly to allow the desired immune response to proceed reliably and in a targeted manner, and secondly to minimize the required amount of antigen.
In the current state of the art, therapeutic induction of tolerance in advanced stages is a problem, for example in cases of rheumatoid arthritis, which has not yet been mastered. Thus, this new therapeutic approach appears to be successful only if the duration of the disease is less than 2 years. Thereafter mechanisms such as epitope spreading and also nonspecific inflammatory reactions presumably make oral tolerance induction difficult to make difficult (Albani, UCSD, personal communication).
W098/21951 (Haas et al.) discloses general methods for oral tolerance induction using an antigen with a derivatized amino acid as adjuvant.
In US patent No. 5,935,577 of Weiner et al. it was attempted to improve tolerance induction by administer-ing a bystander antigen in combination with methotrexate. One aim was to reduce the amount of methotrexate which is associated with serious side effects because of its toxicity. However, the current view is that it is desirable to be able to dispense entirely with substances such as methotrexate because methotrexate has a cumulative toxicity, i.e. liver damage occurs above a certain amount.
Attempts have also been made to modify the immuno-logical milieu inter alia in the direction of a presumably protective milieu which favors the proliferation of regulatory Th-2i3 by means of various auxiliary substances such as, for example, cytokines and antibodies against cytokines (patent No. W095/27500, W098/16248). W095/27500 discloses a method for oral tolerance induction using a bystander antigen together with cytokines, in particular IL-4, which directs the immune system toward a response which is dominated more by T-helper cells of type 2 (Th2).
W098/16248 uses inhibitors of IL-12 for oral tolerance induction.
However, there have been only a very few studies attempting to control via endogenous mechanisms the immunological processes necessary for targeted tolerance induction.
However, because of the complex functions of cytokines in immunoregulation and thus possible uncontrollable side effects, there are great problems in manipulating cytokines as a possible way of optimizing immune responses and thus for clinical use in the induction of tolerance. It has emerged that interventions into the cytokine network are frequently accompanied by hazardous side effects and incalculable risks. Thus, the FDA has recently drawn attention to the fact that there have already been 10 deaths associated with administration of TNF antibodies for rheumatoid therapy because an inflammatory reaction associated with a disorder other than the basic rheumatoid disorder was no longer controllable and thus had a fatal cutcome.
Similar worries relate also to the use of IL-12 _ 7 _ neutralizing antibodies and with IL-4 because of known side effects.
A further aspect associated with current therapeutic methods is the fact that oral tolerance induction in some cases encompasses therapy cycles in which the antigen must be taken every day for several weeks. It is to be assumed at present that these cycles must be repeated more than once because the tolerance status in some circumstances requires continuous presence of the antigen, at least until a complete cure has occurred.
It is not possible to deduce from the data published to date whether a complete cure is possible.
Strategies to date for tolerance induction are usually based on administration of supraphysiological amounts both of the antigen and of the adjuvants. The disadvantage associated with the use of high concentrations of the agents employed are high costs and, in some cases, serious side effects, as, for example, with methotrexate.
A further disadvantage of the studies of tolerance induction carried out and published to date is that there is use mostly of animal models in which induction of tolerance is shown by absence of initiation in the treated animals of the disease occurring in control animals. However, agents able to intervene also in the preexisting disease are of much greater importance.
Glucocorticoids are known for their antiinflammatory and immunosuppressant properties (Cupps and Fauci 1982;
Chrousos 1995; Marx 1995; Almawi, Beyhum et al. 1996, Wilckens and Derijk, 1997). They are therefore preferentially used for treating inflammatory disorders and also for treating autoimmune diseases.
It has been known for some time that glucocorticoids (GCs) are able to downregulate the production of -certain cytokines. The antiinflammatory effect of glucocorticoids is based not only on their ability to inhibit interleukin-2 (IL-2) and interferon-y (IFN-y) but also to downregulate IL-1, tumor necrosis factor a (TNF-a) and IL-6. The GC concentrations in tissues and plasma is in turn regulated by a plurality of mecha nisms, namely by cytokines, GC receptor expression and by certain enzymes, e.g. 11-~-hydroxysteroid dehydrogenase (11-a-HSD); Hult, Jornvall et al. 1998;
Krozowski 1999; Stewart and Krozowski 1999).
Whereas wide-ranging knowledge about the part played for example by cytokines has accumulated during research into tolerance induction, little or nothing is known about the influence of steroid hormones in general and of glucocorticoids in particular. It is of interest, however, that it has been demonstrated that estrogens classified as immunosuppressant in their effect on the immune system (Jansson and Holmdahl 1998) prevent the induction of tolerance (Mowat, Lamont et al. 1988). This is particularly remarkable inasmuch as estrogens per se promote a TH2 immune response which is said in some systems to assist oral tolerance (Weiner 1997). Combination of inactive or suboptimal concentra-tions, administered alone in each case, of estrogens together with glucocorticoids brings about synergistic immunosuppression (Carlsten, Verdrengh et al. 1996). It is concluded from this in general that glucocorticoids also inhibit tolerance induction.
No published data exist on the effect of glucocorti-coids on tolerance induction. However, it was found in a preclinical phase I study at the University of San Diego in California that a glucocorticoid therapy conflicts with an attempted therapy to induce oral tolerance. This is also reflected by the fact that patients treated with glucocorticoids are generally excluded from clinical studies on tolerance induction in autoimmune diseases. Administration even of low steroid concentrations blocks active induction of tolerance (S. Albani, University of California, San Diego and H. Weiner, Harvard University, Boston, personal communications, (Weiner 1997; Bonnin and Albani 1998)).
It is true that under certain conditions there may be a shift, under the influence of glucocorticoids, in the cytokine pattern in the direction of a Th2-like cytokine profile. However, the latter is inadequate as therapy of an autoimmune process also within the framework of measures to induce tolerance. Both administration of Th2 cytokines and transfer of Th2 cells is unable to completely prevent an autoimmune reaction (Mason and Powrie 1998; Segal and Shevach 1998 ) . In addition, it has been demonstrated in a very recent study that inhibition of 11-(3-HSD leads, just like glucocorticoid injection, to killing of immature T cells in the thymus (Gruber, Sgonc et al. 1994;
Horigome, Horigome et al. 1999). It is known that glucocorticoids have a similar effect on peripheral T cells and on undifferentiated, naive and immature T cells (Cupps and Fauci 1982). Induction of tolerance on the other hand promotes inter alia the activation and proliferation of these immature T cells, whereas tolerance apparently cannot be induced in memory cells (Chung, Chang et al. 1999). It is additionally assumed that glucocorticoids inhibit antigen presentation (Piemonti, Monti et al. 1999; Piemonti, Monti et al.
1999)), which additionally conflicts with assistance of tolerance induction by definition.
Thus, immunological therapeutic methods currently fail because of the deficient possibility of controlling the immune response and also because of the costs because very large amounts both of protein and peptide antigen and DNA must be used in order to induce relevant clinical effects in humans. Whereas considerable advances have been achieved in the identification of possible antigens, at present no methods suitable for use in humans and suitable for long-term use are available. Immunological approaches appear at present not to be very promising because of uncontrollable side effects.
The present invention was therefore based on the object of improving and/or optimizing tolerance induction through administration of particular antigens in combi nation with a novel adjuvant.
This object is achieved by a novel medicament compris-ing as active ingredient inhibitors of 11-(3-hydroxy-steroid dehydrogenase in combination with one or mare antigens and the use of the medicament for inducing tolerance.
11-~i-Hydroxysteroid dehydrogenase (11-(3-HSD) is an enzyme which is responsible for interconversion of biologically active forms of glucocorticoids into and out of their inactive forms. It has been found, surprisingly, that inhibitors of enzymes which regulate cortisol metabolism, in particular inhibitors of 11-(3-HSD, are able in combination with an antigen to induce tolerance. A particularly advantageous effect is achieved in this connection in combination with at least one antigen.
This is unexpected inasmuch as it is generally known that an increase in the cortisol level in the plasma (e.g. on administration of glucocorticoids) has an immunosuppressant effect. However, a distinction must be made between the cortisol concentration in blood plasma, which has systemic effects, and an increase in the cortisol level which is possibly confined only to very particular cells or tissues. The mechanisms applying on inhibition of 11-~3-HSD are apparently different from those resulting from systemic cortisol administration. It is evident that inhibition of a~

11-~i-HSD causes immunostimulation progressing to tolerance induction, possibly through activation of suppressor T cells.
11-~i-HSD is a member of the short-chain dehydrogenases/reductases (SDR). 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 agreement of from 15 to 30~ between the individual members. The enzymes of the SDR family encompass a wide range of specific substrates, including steroids, alcohols and aromatic compounds (Jornvall et al., 1999; Oppermann et al., 1996).
11-(3-Hydroxy-steroid dehydrogenase is the key enzyme in the extrahepatic conversion of 11-(3-hydroxysteroids such as, for example, cortisol and prenisone into their inactive metabolites. 11-(3-hydroxysteroid dehydrogenase is a bidirectional enzyme which displays a reductase or/and a dehydrogenase activity depending on the environment and the isoform. The reductase activity of 11-(3-hydroxysteroid dehydrogenase converts an 11-ketosteroid, for example the inactive cortisone, into an 11-~3-hydroxysteroid, for example the active cortisol. The dehydrogenase activity converts the 11-(3-hydroxysteroid into the 11-ketosteroid.
Various isoforms of 11-(3-HSD exist. For example, 11-(3-HSD of type 1 is a bidirectional enzyme which acts mainly as reductase in vivo. 11-(3-HSD of type 2, by contrast, is a unidirectional enzyme in vivo and acts exclusively as an NAD-dependent dehydrogenase. The 11-(3-hydroxysteroid dehydrogenase inhibitor used herein is preferably an inhibitor of the reductase activity and particularly preferably an inhibitor of 11-~i-HSD-1.
The medicament of the invention comprises as active ingredient a combination of two or more substances which may be present both as mixture or formulation and separately, e.g. as kit.
On the one hand, the medicament comprises one or more antigens which serve to induce a specific immunological tolerance response.
The substances suitable as antigens of this type are all those which elicit unwanted immune responses, such as, for example, those associated with autoimmune diseases, e.g. rheumatoid arthritis including juvenile forms, lupus erythemadotes, multiple sclerosis, uveitis, diabetes of type I (autoimmune diabetes), and those associated with allergies or/and asthma.
However, it is also possible to use as antigens substances which bring about an infection, in which case the medicament of the invention is able to induce a tolerance which can diminish or eliminate disadvantageous or pathological responses to the infec-tious pathogen. Examples of infectious pathogens are, for example, bacteria, viruses or other microorganisms.
The medicament of the invention may include specific epitopes or antigens of such infectious pathogens, but it is also possible to use the whole microorganism or parts thereof.
Classical vaccination normally entails intravenous administration of a pathogen to the patient, eliciting a protective immunity. However, it has now been found that vaccine protection can be achieved not only in a conventional way but also through tolerance induction through mucosal administration of antigens (McSorley, 1999). The medicament combination of the invention further enhances such an effect, so that a combination of 11-(3-HSD inhibitor and antigen can advantageously be employed as tolerogenic oral vaccine.

It has surprisingly been found that induction of tolerance has an advantageous effect on a subsequent infection not only in cases of autoimmune diseases but also in cases of infectious diseases. Thus, it was possible to establish that it was possible to resolve infections through induction of tolerance. It is presumed that a vaccine protection through tolerance induction is based on the following mechanism of action: many infectious pathogens comprise a plurality of antigens, and evidently some of these antigens produce an overreaction in the host. This overreaction may bring about, for example, conversion of T cells into Th2 cells, although Th2 cells are unable to control the invading pathogen. In the case of an infectious disease, such antigens bring about an overreaction of the host's immune system in a harmful manner, while it is unable at the same time to control the infectious pathogen effectively. It is possible by inducing tolerance, for example by mucosal administration of the antigen and simultaneous administration of an 11-(3-HSD inhibitor, to eliminate the disadvantageous effect of the antigens producing an overreaction, so that the remainder of the immune system can perform its protective function. In tolerance induction to protect from or cure infectious diseases, it is normally preferred to promote a Thl-like response and eliminate a Th2-like response.
Accordingly, it is advantageous to generate a tolerance for antigens which elicit a Th2-like response.
It is possible in principle, by suitable choice of the antigen in accordance with the instructions given herein, to provide vaccination protection through tolerance induction for virtually all infectious diseases. The antigen chosen is preferably one which is associated with a bacterial or viral infection, for example influenza, leishmania, fungal infections, cytomegaly, pneumonia, streptococci B, chlamydias, helicobacter, hepatitis C, herpes, human papilloma virus, mycobacteria tuberculosis and others.
The antigen employed according to the invention may moreover preferably be a natural or synthetic protein, protein constituent or peptide, in particular also a so-called altered peptide ligand (APL), but carbo-hydrates including polysaccharides and lipopoly-saccharides are likewise suitable, as well as antigens from biological resources. The latter comprise antigens which play a part in the development and/or cure of autoimmune diseases, allergies, or wanted and unwanted immune response within the framework of transplantation medicine. Tolerance induction brought about according to the invention may thus be advantageous in trans plantations too.
The antigen may moreover be one against which an immune response is produced directly. However, it may also be a so-called bystander antigen which elicits an (auto)immune response to related or adjacent epitopes on a protein.
Altered peptide ligands (APLs) are peptides which essentially correspond to an antigen against which an immune response is induced. However, individual amino acids [lacuna] APLs have been exchanged. It has been found that little or no additional adjuvant is neces-sary on administration of APLs within the framework of oral tolerance induction.
In the area of allergy prevention it is possible in principle to use all nontoxic environmental antigens as antigens suitable according to the invention.
Preference is given to benzylpenicilloyl, insulin, ovalbumin, lactalbumin, but also various pollens, food antigens, house dust mites and constituents thereof, excreta thereof and the like.
Further suitable antigens comprise endogenous and other heat shock proteins (Prakken .et al. (1997); prakken et al. (1998)), thyroglobulin, cellular constituents of the uvea, of the skin, of various epithelial tissues, of the thyroid, of the basement membrane, of the muscles, of the myelin sheaths, of the nerve cells, of the thymus, red blood corpuscles, further blood constituents and cells, proteolipid, myelin basic protein (MBP), myelin-oligodendrocyte glycoprotein (MOG), or other constituents of normal or diseased body tissue.
Preference is further given to a combination which comprises a vaccine as disclosed by Rock et al. (2000), in particular a bacterial vaccine.
The antigen may be present in the medicament of the invention also as nucleic acid or oligonucleotide. It is moreover possible on the one hand for the nucleic acid or the oligonucleotide itself to represent the antigen. On the other hand, the nucleic acid may code for a particular peptide antigen. It can be given by various routes of administration, e.g. by injection, intravenously, intramuscularly, subcutaneously or with the aid of a gene gun.
Antigen presentation can be effected preferably also by dendritic cells. Dendritic cells are the most important cells in the immune system for the presentation of endogenous and foreign antigens. They are therefore very potent stimulators of an immune response.
Dendritic cells can be cultured for example from monocytes or bone marrow cells in the manner known in the prior art (D. Rea et al. (2000); E. Dejong et al.
(1999); M. Mathiszak et al. (2000)). Dendritic cells can be employed for antigen-specific immunotherapy (Fairchild et al. (2000); Reid et al. (2000);
Kapsenberg et al. (1998)). For this purpose, they are either pulsed in vitro with the required antigen, i.e.

incubated with the antigen until they have taken it up and express it on the surface. However, dendritic cells can also be stimulated by gene transfer to express the particular antigen, thus producing it themselves. It is additionally possible to stimulate proliferation ex vivo of cells already loaded with antigen and then reinject them into the body. Antigen presentation takes place by means of dendritic cells according to the invention particularly preferably by maturing dendritic cells in vitro with addition of glucocorticoids, for example of cortisone, to the medium to give a tolerance-inducing phenotype and then reinfusing them.
These dendritic cells can then be combined with an 11-(3-HSD inhibitor in order to assist the effect further. It is surprisingly possible by treating dendritic cells with glucocorticoids, for example with cortisone, to increase the tolerance in addition to the increase normally occurring in the immune response on antigen presentation by dendritic cells.
This is presumably attributable to the fact that the combination according to the invention of an 11-(3-HSD
inhibitor with the antigen-presenting dendritic cells creates in the lymph node a milieu in which the dendritic cells are more stable.
Besides genetic manipulation of dendritic cells to express required antigens, it is also possible to isolate dendritic cells with the required antigen from patients suffering from the corresponding disease.
Artificial antigen-presenting cells or/and artificial dendritic cells are preferably employed for antigen presentation (Falcioni et al. (1999); Latouche et al.
(2000); Wu et al. (2000)).
In another preferred embodiment, antigen presentation is effected by T cells. Regulatory or/and antigen-specific T cells can be generated for example in vitro s, (Ramirez et al. (2000); Shevach (2000)). In this case, the antigen is presented by T cells or/and it is possible for antigen-specific T cells to be influenced by regulatory T cells.
11-(3-Hydroxysteroid dehydrogenase inhibitors which are suitable in principle are all those disclosed to date but also, where appropriate, as yet unidentified inhibitors.
The inhibitors preferably inhibit all isoforms of 11-(3-HSD, but especially 11-(3-HSD-1, also preferably in addition other isoforms, as well as tissue-specific isoforms. An isoform which has not yet been unam-biguously identified and which is likewise preferably inhibited is 11-(3-HSD-3.
The inhibitors are preferably selected from endogenous and exogenous inhibitors. Examples of endogenous inhi-bitors are the following: substrates for 11-(3-HSD such as, for example, 11-OH-progesterone, 3-alpha,5-beta-tetrahydroprogesterone, 3-alpha,5-beta-tetrahydro-11-deoxycorticosterone, 11-epicortisol, chenodeoxy-cholic acid, cholic acid. Examples of exogenous inhibi-tors are glycyrrhetinic acid (3(3-hydroxy-11-oxoolean-12-en-30-oic acid) and derivatives thereof such as, for example, glycyrrhizin, glycyrrhizic acid and carben-oxolone; furosemide and derivatives thereof; flavonoids and derivatives thereof such as, for example naringenin; triterpinoids (e. g. CHAPS), ketoconazole, saiboku-to, gossypol, metyrapone, 11-epiprednisolone.
Other suitable inhibitors are steroid-like such as, for example, dexamethasone, budesonide, deflazacort and stanozolol. There are suspected to be unidentified derivatives among the ACTH-dependent inhibitors.
Particular preference is given to glycyrrhetinic acid and derivatives, in particular glycyrrhizic acid, glycyrrhizin, glycyrrhitic acid and derivatives thereof, and, in particular carbenoxolone.
Glycyrrhetinic acid (GA) is an extract from liquorice (Glycyrrhiza glabra) and inhibits the metabolism of endogenous glucocorticoids through blockade of the enzyme 11-~i-hydroxysteroid dehydrogenase.
Carbenoxolone is a GA derivative which has a higher affinity for 11-(3-HSD (Hult, Jornvall et al. 1998).
Carbenoxolone has, just like GA, been investigated in a large number of studies on the pharmacokinetics, toxicity and possible dosage regimens and mode of administration in humans and is already approved for human use, and possible side effects are not to be expected or are nonhazardous and reversible (Ulick, Wang et al. 1993; Bernardi, D'Intino et al. 1994;
Krahenbuhl, Hasler et al. 1994; Schambelan 1994).
It is also possible to employ antibodies against 11-(3-HSD or fragments thereof as inhibitors of 11-(3-HSD. Such antibodies against 11-(3-HSD can be produced in a manner known to the skilled worker, e.g.
as monoclonal or polyclonal antibodies. The term inhibitor of 11-(3-HSD as used herein additionally encompasses substances which regulate the transcription of 11-~i-HSD.
The amount of 11-(3-HSD available in the body can be controlled by using such transcription regulators.
Suitable transcription regulators for 11-~3-HSD are described for example in Williams et al. (2000) and include in particular members of the C/EBP family.
Preference is further given to choosing the antigen or/and the 11-(3-HSD modulator, in particular inhibitor, from low molecular weight substances which preferably have a molecular weight of <_ 500 Da, more preferably <_ 250 Da.

Said inhibitors of 11-(3-HSD, in particular glycyrrhetinic acid and its derivatives, are nontoxic even in higher doses and have no serious side effects.
The therapeutic use of GA or similar inhibitors of 11-~i-HSD is possible ad hoc. Combination of an inhibitor/method for inhibition of 11-~3-HSD with an antigen thus represents a novel therapeutic approach to curing various immunological disorders.
Possible dosages of the inhibitors, in particular of GA
and derivatives, for humans are up to 1 g per dose unit.
The inhibitors are preferably administered in an amount of at least 0.01, preferably at least 0.1 and particu-larly preferably at least 1, mg/kg of body weight and day and up to 100, preferably up to 50, particularly preferably up to 10, mg/kg per day. An inhibitor of 11-~i-HSD is regarded as being a compound which inhibits the in vivo 11-(3-HSD activity by at least 10%, preferably at least 30%, more preferably at least 50%, particularly preferably at least 70% and most prefer-ably at least 80%. However, it may be advantageous to use substances which inhibit the in vivo 11-~i-HSD
activity by at least 90%, preferably by at least 95%.
The inhibitors preferably have ICSO values as determined in placental microsomes or MCF-7 cells of < 100 ~M, preferably < 30 ~M, particularly preferably < 1 ~M.
Particularly potent inhibitors have ICSO values of < 100 nM, preferably < 10 n~.M and particularly prefer-ably < 1 nM.
The Ki values of the inhibitors employed according to the invention are preferably < 1 200 ~,M, more pre-ferably < 100 ~M and particularly preferably < 1 ~M.
Possible dosages of the inhibitors, in particular of GA
and derivatives, for humans are up to 1 g per dose unit.

Apart from the use of said- inhibitors, it is also possible and within the meaning of the invention to use as inhibitor an antisense nucleic acid which hybridizes with sequences which code for 11-(3-HSD. This may be advantageous in particular if it is intended speci-fically to inhibit an 11-~3-HSD in a particular tissue.
The ratio by weight of the inhibitor and antigen constituents is preferably from 0.1:99.9 to 99.9:0.1, particular preferably 90:10 to 10:90.
The medicament of the invention may be in the form of a mixture or formulation of the two components antigens) and inhibitor. However, the two constituents are preferably administered not as a formulation but separately. It is additionally possible for the medica-ment or the two active ingredient components to comprise pharmaceutically acceptable excipients and/or additives (e. g. suitable solvents or diluents) and/or adjuvants. These can easily be established by the person skilled in the art.
There was additionally a need to provide compositions with which immune responses, in particular autoimmune diseases, can be beneficially influenced. The present invention therefore relates further to the use of an 11-(3-hydroxysteroid dehydrogenase for obtaining a medicament for tolerance induction, inhibition of inflammation or/and immunomodulation. It has sur-prisingly been found that it is possible to influence beneficially immune diseases and in particular autoimmune diseases by influencing the 11-~i-HSD as representative of the SDR family. It is additionally possible for allergies, transplant rejection and GVHD
to be treated therapeutically or/and prophylactically by use of 11-(3-HSD. Immunomodulatory substances which can be employed are, in particular, modulators such as, for example, inhibitors or promoters of 11-(3-HSD in order to bring about tolerance induction, inhibition of inflammation or/and immunomodulation, in particular to control autoimmune diseases, allergies, transplant rejection or/and GVHD. Suitable immunomodulatory sub-stances which can be employed are known inhibitors of 11-(3-HSD, or substances which interact with 11-(3-HSD
and, for example, are found by screening or computer-assisted methods such as, for example, force field calculations. It is additionally possible to use substances which are known to be inhibitors of other members of the SDR family and to test these substances for their interaction with 11-(3-HSD by simple experiments. In contrast to the previously described immunosuppressant effect of 11-(3-HSD modulators, it has surprisingly been found that the effects indicated above can be obtained even on use of 11-(3-HSD modula-tors alone, in particular of inhibitors.
The present invention further relates to the use of an inhibitor of 11-(3-hydroxysteroid dehydrogenase for producing a medicament for tolerance induction, inhibi-tion of inflammation or/and immunomodulation. It has surprisingly been found that a tolerance induction, immunomodulation or/and inhibition of inflammation, not an immunosuppressant effect, can be achieved through use just of an 11-(3-HSD inhibitor. An inhibitor of 11-(3-HSD can be generally employed for inhibiting inflammation in acute or/and chronic inflammatory processes, including septic shock and sepsis. Advanta geous effects have been observed both with infectious and noninfectious inflammations.
The preferred use of the medicament of the invention, in particular of the combination of inhibitor of 11-(3-HSD with one or more antigens, is for tolerance induction, inhibition of inflammation or/and immuno-modulation in a mammal, in particular a human. Areas of application are for autoimmune diseases, e.g.
rheumatoid arthritis, including juvenile forms, lupus erythematodes, multiple sclerosis, uveitis, diabetes of type I, and for allergies and in transplantation medicine, in particular transplant rejection and GVHD.
Tolerance induction can, however, also be employed in immunization against pathogens of infection as stated above.
The medicament can be administered by various routes.
It is possible to administer the inhibitors) of 11-~i-HSD, preferably together with the antigens) and, where appropriate, additional adjuvants, it being possible for said components to be in the form of a formulation. The two active ingredient components and the optionally additional excipients or adjuvants may, however, also be given by various administration routes. Possibilities on the one hand are mucosal routes, e.g. intranasal, oral, sublingual or by inhalation, but also others such as, for example, intravenous, subcutaneous, intramuscular and intra-peritoneal. In addition, the gene gun is suitable for administering the nucleic acids.
Possibilities for administration suitable for presenta-tion of the antigen are, in particular, the following:
the so-called mucosal, i.e. oral or nasal tolerance induction and, recently, through administration of DNA
(Ragno, Colston et al. 1997; Lee, Corr et al. 1998;
Lobell, Weissert et al. 1999; McCluskie and Davis 1999;
McCluskie, Millan et al. 1999) which codes for the relevant antigen and is injected into the organism to be treated, e.g. a human.
Besides this it is also possible for antigen presenta tion to be effected by means of dendritic cells or T cells as described above.
The composition of the invention is preferably employed for mucosal tolerance induction. In this connection, mucosal means uptake through mucous membranes and encompasses administration of an antigen inter alia by oral intake or instillation into the nose, or inhala tion and absorption via the lungs. However, administra tion can also take place subcutaneously, intravenously and/or intramuscularly.
Inhibitor and antigen can be administered together or separately via different routes and also sequentially.
A particularly advantageous dosage form is represented by a capsule which consists externally of an 11-(3-HSD
inhibitor, e.g. glycyrrhizic acid or glycyrrhetinic acid, which envelopes an antigen inside.
The inhibitor can be administered by all known routes and is for this purpose converted into the appropriate form in each case, e.g. dissolved in a suitable solvent for injection. It is also possible in this connection to administer the inhibitor first, e.g. by intravenous, intramuscular or subcutaneous injection, and then the antigens) by mucosal routes. It may be advantageous to give the inhibitor in more than one dose.
The invention is explained further by the appended figures and the following examples.
Figure 1 shows the course of an experimentally induced arthritis without (blue) or with (red) treatment by an 11-(3-HSD inhibitor. The inhibitor, in this case glycyrrhetinic acid (GRA), was injected intradermally at the base of the tail of rats in a dose of 2 mg in 200 ~tl of olive oil on days 0, 2 and 4 after injection of complete Freund's adjuvant (CFA). CFA was adminis-tered intradermally in a dose of 0.4 mg. The combina-tion of inhibitor and antigen (present in CFA as Mycobacterium t.) leads to a milder course of the dis-order, that is to say has an immunomodulatory effect.
Figure 2 shows the enhancing effect of an 11-~i-HSD

inhibitor on nasal tolerance induction by means of a peptide antigen. This entailed peptide 176 to 190 (Prakken et al. (1997)) being administered in 3% sodium bicarbonate solution intranasally on days -15, -11, -7 and -3 before induction of the pathological episode.
GRA was given intranasally in a dose of 0.5 mg in 25 ~.l per nostril, i.e. in total in an amount of 1 mg. The red curve shows a control group. The blue curve shows the course of the disorder during peptide treatment (antigen) without addition of GRA. The yellow curve shows the combination according to the invention of peptide (antigen) and GRA, which were administered intranasally.
Examples Enhancement of tolerance induction in the model of adjuvant-induced arthritis This animal model, in which an arthritis-like auto-immune disease can be induced, is known in the prior art (Leech, Metz et al. 1998; Prakken, Wauben et al.
1998; Vaneden, Vanderzee et al. 1998):
This entails rats receiving an injection of a suspension of oil and mycobacterium into the tail (150 ~,l of a 10 mg/ml suspension with Mycobacterium tuberculosis). After about 10-13 days, the animals develop joint inflammations which reflect certain characteristics of human rheumatoid arthritis. The development of this type of arthritis is interpreted as a result of a so-called cross-reaction of the immune defenses both against antigens of the mycobacterium (heat shock protein 60, hsp 60) and of the articular cartilage (Vaneden, Vanderzee et al. 1998).
Example 1 Prevention of the development of the disorder:
The development and the progress of the disorder can be i beneficially influenced or prevented. To do this, tolerance to particular antigens of mycobacterium is induced in the rats before inducing the experimental arthritis. This entails the antigen, e.g. hsp60 or a so-called altered peptide ligand being presented to the immune system as protein or peptides either orally or nasally (Prakken, Wauben et al. 1998), or administered as DNA (Ragno, Colston et al. 1997) before the sensiti-zation with the oil/mycobacterium mixture takes place.
For this purpose, the APL for example is administered on day -15, -10, -5 and on the day of sensitization ( 100 ~tg intranasally) .
The 11-(3-HSD inhibitor used in this example in each case was glycyrrhetinic acid (GA) and a water-soluble derivative thereof, namely carbenoxolone.
If the inhibitor is administered (e. g. 1-8 mg intra-peritoneally in oil or intranasally in saline solution) together with the antigen until the oil/peptide mixture is injected, i.e. before the sensitization, the effect of the latter is enhanced and the amount of antigen necessary for inducing tolerance is reduced. There is dose-dependent prevention or a diminution in the incidence and the severity of the course of the rat's disorder. It is additionally possible thereby to reduce the amount of peptide necessary for tolerance induction.
Example 2 Manipulation of the course of the disorder after induction of autoimmune arthritis and after onset of symptoms:
The induced autoimmune arthritis has a fulminant mono-phasic course after the onset of the inflammatory reaction 10 days after the injection of Freund's adjuvant with mycobacterium or hsp60, with a pathology peak around day 27; symptoms are no longer detectable i after 40 days.
The course of the inflammatory reaction can be beneficially influenced with altered peptide ligands (APLs), even after onset of the symptoms, if the treat-ment takes place within 24-48 hours after appearance of the first symptoms and is continued daily.
For this purpose, rats receive, simultaneously during the nasal administration of the protein antigen (hsp60) or of the APL, the inhibitor carbenoxolone by injection or instillation through the nose (concentrations as in example 1).
The increase in the from symptom incidence is in this case influenced significantly more favorably than without inhibition of 11-~i-HSD. Certain antigens such as the pathogenic hsp60, which have no effect without carbenoxolone, likewise lead in combination with carbenoxolone to an improvement in the course of the disorder. On use of carbenoxolone in combination with APLs, an alleviation and shortening of the course of the disorder can be achieved even with suboptimal peptide concentrations.
The fact that inhibition of 11-~3-HSD using the peptide (hsp60), which has not to date been suitable for thera-peutic use, permits to attenuation of the course of the disorder or reduces the amount of APL appears to be a strong indicator that it may be possible even in late stages to initiate successfully attempts at cure by means of oral tolerance induction. Thus the data from the animal experiment make an ad hoc attempt at cure possible to assist tolerance induction in humans.
Example 3 Alleviation of experimentally induced arthritis by treatment with an 11-(3-HSD inhibitor alone i An autoimmune arthritis was 'induced experimentally in rats by administering Freund's complete adjuvant (CVA;
0.4 mg intradermally). The rats were divided into two groups, and one group received intradermal injection of 2 mg of GRA (glycyrrhitic acid) in 200 ~.l of olive oil at the base of the rat' s tail on days 0, 2 and 4 after injection of CVA. The results for the two groups are depicted in figure 1, which shows the course of the experimentally induced arthritis without (blue) or with treatment by the 11-(3-HSD inhibitor (red). As can clearly be seen in figure 1, the combination of inhibitor and antigen (present as Mycrobacterium t. in CVA) leads to an alleviated course of the disorder.
Further experiments have shown that even the inhibitor alone brings about a milder course of the disorder, or weakens the disease-promoting effect of CVA and thus has an immunomodulatory effect.
Example 4 Improved efficacy through mucosal tolerance induction compared with systemic administration It has been found that a distinctly improved efficacy is to be observed on administration of an antigen plus an 11-(3-HSD inhibitor (e. g. glycyrrhetinic acid) intranasally compared with administration of the same antigen alone or of the antigen plus 11-(3-HSD inhibitor (e. g. glycyrrhizic acid) systemically (orally).
Figure 2 shows the enhancing effect of an 11-(3-HSD
inhibitor on nasal tolerance induction by means of a peptide antigen. For this purpose, the peptide 176-190 was administered intranasally to all the experimental groups on days -15, -11, -7 and -3 before induction of a pathological episode of experimentally induced arthritis (caused by CFA as described in example 3) in 3% sodium bicarbonate solution. GRA i.n. (intranasally) was added in a dose of 0.5 mg in 25 ~1 per nostril, i.e. in total a dose of 1 mg. The red curve shows a i control group with systemic administration of glycyrrhizic acid in drinking water. The blue curve shows the course of the disorder during peptide treatment without addition of GRA and the yellow curve shows the combination according to the invention of peptide (antigen) and 11-(3-HSD inhibitor (e. g. GRA), both of which were administered intranasally.

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Claims (34)

Claims

1. A medicament comprising as active ingredient an inhibitor of 11-.beta.-hydroxysteroid dehydrogenase in combination with an antigen.

2. A medicament as claimed in claim 1, characterized in that the inhibitor and the antigen are present separately.

3. A medicament as claimed in claim 1 or 2, for tolerance induction.

4. A medicament as claimed in claim 3, for mucosal tolerance induction.

5. A medicament as claimed in any of the preceding claims for inhibition of inflammation or/and immunomodulation.

6. A medicament as claimed in any of the preceding claims, characterized in that the inhibitor is specific for isoform 1 or 3 of 11-.beta.-hydroxysteroid dehydrogenase.

7. A medicament as claimed in any of the preceding claims, characterized in that the inhibitor is selected from endogenous and exogenous inhibitors of 11-.beta.-hydroxysteroid dehydrogenase and antisense nucleic acids which hybridize with sequences which code for 11-.beta.-HSD, antibodies against 11-.beta.-hydroxysteroid dehydrogenase or/and trans-cription regulators for 11-.beta.-hydroxysteroid dehydrogenase.

8. A medicament as claimed in claim 7, characterized in that the inhibitor is selected from glycyrrhetinic acid and derivatives thereof, especially glycyrrhizin, glycyrrhizic acid and carbenoxolone.

9. A medicament as claimed in claim 7, characterized in that the inhibitor is selected from furosemide and derivatives thereof.

10. A medicament as claimed in claim 7, characterized in that the inhibitor is selected from flavonoids and derivatives thereof.

11. A medicament as claimed in any 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.

12. A medicament as claimed in claim 11, characterized in that it comprises the antigen in the form of a nucleic acid coding therefor.

13. A medicament as claimed in any of the preceding claims, characterized in that the antigen is a bystander antigen.

14. A medicament as claimed in any of the preceding claims, characterized in that the antigen is selected from antigens which are associated with the following disorders: rheumatoid arthritis, multiple sclerosis, uveitis, diabetes of type I, lupus erythematosus.

15. A medicament as claimed in any of the preceding claims, characterized in that the antigen is selected from endogenous and other heat shock proteins, proteolipid, myelin basic protein (MBP), myelin-oligodendrocyte glycoprotein (MOG) and cellular constituents of the uvea, of the skin, epithelial tissues, of the thyroid, of basement membrane, of the muscles, of the nerve cells, of the thymus or of the red blood corpuscles.

16. A medicament as claimed in any of the preceding claims 5 to 8, characterized in that the antigen is selected from benzylpenicilloyl, insulin, ovalbumin, lactalbumin, pollen constituents, food constituents and house dust mite constituents.

17. A medicament as claimed in any of the preceding claims, characterized in that it additionally comprises pharmaceutically acceptable excipients, additives or/and adjuvants.

18. A medicament as claimed in any of the preceding claims, characterized in that antigen presentation takes place by means of dendritic cells.

19. A medicament as claimed in any of the preceding claims, characterized in that antigen presentation takes place by means of T cells.

20. The use of an 11-.beta.-hydroxysteroid dehydrogenase for obtaining a medicament for tolerance induc-tion, inhibition of inflammation and/or immuno-modulation.

21. The use of an 11-.beta.-hydroxysteroid dehydrogenase for obtaining a medicament for the treatment or/and prophylaxis of autoimmune diseases, allergies, transplant rejection and graft versus host disease.

22. The use of an inhibitor of 11-.beta.-hydroxysteroid dehydrogenase for producing a medicament for tolerance induction, inhibition of inflammation and/or immunomodulation.

23. The use of inhibitors of 11-.beta.-hydroxysteroid dehydrogenase in combination with an antigen for producing a medicament for tolerance induction, inhibition of inflammation or/and immunomodula-tion.

24. The use as claimed in claim 20 to 23, characterized in that a substance which is specific for one or more isoenzymes of 11-.beta.-hydroxysteroid dehydrogenase is employed as inhibitor.

25. The use as claimed in any of claims 20 to 24, characterized in that endogenous or exogenous inhibitors of 11-.beta.-hydroxysteroid dehydrogenase or antisense nucleic acids are employed as inhibitor.

26. The use as claimed in claim 25, characterized in that glycyrrhetinic acid or derivatives thereof;

in particular glycyrrhizin, glycyrrhizic acid or carbenoxolone, is employed as inhibitor.

27. The use as claimed in any of the preceding claims 20 to 26, characterized in that an improve-ment in mucosal tolerance induction is achieved.

28. The use as claimed in any 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. The use as claimed in claim 28, characterized in that the antigen is a bystander antigen.

30. The use as claimed in any of the preceding claims 20 to 29, characterized in that the antigen is selected from antigens which are associated with the following disorders: rheumatoid arthritis, multiple sclerosis, uveitis, diabetes of type I, lupus erythematosus.

31. The use as claimed in any of the preceding claims 20 to 30, characterized in that the antigen is selected from endogenous and other heat shock proteins, proteolipid, myelin basic protein (MBP), myelin-oligodendrocyte glycoprotein (MOG) and cellular constituents of the uvea, of the skin, of various epithelial tissues, of the thyroid, of basement membrane, of the muscles, of the nerve cells, of the thymus or of the red blood corpuscles.

32. The use as claimed in any of the preceding claims 20 to 31, characterized in that the antigen is selected from benzylpenicilloyl, insulin, ovalbumin, lactalbumin, pollen constituents, food constituents and house dust mite constituents.

33. A method for inducing tolerance for controlling autoimmune diseases, allergies and transplant rejection and GVHD, comprising treatment of a mammal or of a human requiring such a treatment with an effective amount of an inhibitor of 11-.beta.-hydroxysteroid, dehydrogenase in combination with a mucosal administration of the antigen or an administration of a nucleic acid coding for the antigen.

34. The use as claimed in any of claims 20 to 31 for producing a medicament for immunomodulation for treatment of autoimmune diseases, allergies, transplant rejection or/and graft versus host diseases.