EP1521588A2

EP1521588A2 - Use of alanyl-aminopeptidase inhibitors and pharmaceutical compositions containing said inhibitors

Info

Publication number: EP1521588A2
Application number: EP03762633A
Authority: EP
Inventors: Siegfried Ansorge; Janine Tadje; Uwe Lendeckel
Original assignee: IMTM GmbH
Current assignee: IMTM GmbH
Priority date: 2002-07-05
Filing date: 2003-07-04
Publication date: 2005-04-13
Also published as: EA008946B1; CN1665524B; US7425532B2; EP2085094A2; AU2003250892B2; AU2003250892A1; WO2004004750A3; US20060211602A1; CA2490714A1; CN1665524A; JP2005532380A; EA200500163A1; DE10230381A1; WO2004004750A2

Abstract

The invention relates to the use of one or several alanyl-aminopeptidase inhibitors and/or enzyme inhibitors which exhibit the same substrate specificity in order to stimulate the production of TFG-β 1 and the expression of TFG-β 1 in and/or on lymphocyte T regulators. The invention also relates to the use of said inhibitors for preventing and/or curing autoimmune, allergic and cardiovascular diseases and to preclude the rejection of transplants. In addition, said invention relates to applications in which peptidic fragments of pathogenic autoantigens or synthetic analogues and/or specific antigenic components of pathogenic microorganisms are used.

Description

Use of inhibitors of alanyl aminopeptidases and pharmaceutical compositions comprising them

The present invention relates to the use of one or more inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for inducing the production of TGF-β 1 and expression of TGF-β 1 in and / or on Treg cells and the use for the prevention and / or treatment of autoimmune diseases, allergies, arteriosclerosis and for the suppression of graft rejection. The invention further relates to uses in which peptide fragments of pathogenic autoantigens or synthetic analogs and / or specific antigenic components of pathogenic microorganisms are additionally used. The joint application of inhibitors against the above-mentioned enzymes with disease-specific antigens enhances the targeted action of the inhibitors against pathogenic T-cell clones and is suitable for the specific therapy of immunologically related diseases.

It is already known that in diseases with autoimmune pathogenesis such as type I diabetes mellitus or multiple sclerosis, an activation and proliferation of autoreactive, ie immune cells directed against the body's own antigens, in particular autoreactive T-lymphocytes, form the basis of the disease process or constitute it. Similar mechanisms come into play in the development of rejection episodes after organ transplantation, with the difference that it is not primarily "autoantigens" but "foreign antigens" from the donor organ that are responsible for the development of the fatal immune response. In both cases, ie both in autoimmune diseases and in rejection reactions, there is an undesirable break in the "tolerance" of the immune system against the body's own or transplant-derived antigens. The same applies to the excessive immune response in allergies.

The inhibition of autoreactive T cells via soluble (a) or membrane-bound TGF-ßl (b) is shown schematically in Fig. 5. The membrane-bound TGF-ßl on Treg has a direct inhibitory effect on autoreactive T cells by binding to their TGF-ßl receptor (cell-cell contact), which can be seen in Fig. 5 (b) above. This cell contact can be achieved through the simultaneous binding of both Treg and autoreactive T cells to an antigen-presenting cell (APC, in particular dendritic cells). On the other hand, as shown in Fig. 5 (b) below, previous binding of the Treg to the APC can change it (lack of costimulatory signals) so that a subsequently binding autoreactive T cell is not activated (anergy). In both cases, the Treg and autoreactive T cell are characterized by the same antigen specificity.

Findings in recent years show that this "tolerance" is actively maintained in a healthy organism by actively suppressing the function and growth of autoreactive T-lymphocytes. This is achieved through a special, suppressive T-Zcll population, the so-called natural regulatory T cells (Treg, CD4 ⁺ CD25 ⁺ cells). Treg cells arise in the thymus [Kawahata K. et al., J. Immunol. 168: 4399-4405, 2002] and account for 5-10% of the T cells in peripheral blood. They have an inhibitory effect on CD4 ⁺ T cells of the same antigen specificity via direct cell contact. This inhibitory effect is shown by a strong expression of TGF-ßl in the Treg reached. The TGF-ßl is presented on the surface of the Treg and binds to the TGF-ßl receptor on autoreactive T cells, which represents a completely new mechanism of action of this strong immunosuppressive cytokine [Nakamura et al., J Exp Med 194: 629- 644, 2001].

Treg cells inhibit autoimmunity more efficiently than the immune response to "foreign" antigens [Romagnoli P et al., J hnmunol 168: 1644-1648, 2002]. Therefore, restrictions or losses in the functioning of Treg cells are of particular pathogenetic importance in the development of autoimmune disorders. A direct relationship between the number / function of Treg cells and the manifestation of autoimmune diseases is for type I diabetes [Boudaly S et al., Eur Cytokine Netw 13: 29-37, 2002; Gregori S et al., Diabetes 51: 1367-1374, 2002], autoimmune encephalomyelitis (animal model of multiple sclerosis) [Furtado GC et al., Hnmunol Rev 182: 122-134, 2001; Muhallab S et al., Scand J Hnmunol 55: 264-273, 2002; Hamilton NH et al., Scand J hnmunol 55: 171-177, 2002], for the "autoimmune ovarian disease" (AOD) [Tung KS et al., Hnmunol Rev 182: 135- 148, 2001], and for the disease Crohn [Neurath MF et al., J Exp Med 195: 1129-1143, 2002].

In addition, Treg cells are also responsible for suppressing intestinal or pulmonary inflammation [Singh B et al., Hnmunol Rev 182: 190-200, 2001; Hori S et al., Eur J Hnmunol 32: 1282-1291, 2002]. The role of Treg cells in suppressing rejection episodes after allogeneic (foreign) organ transplantation is also clearly demonstrated [Kingsley CI et al., J hnmunol 168: 1080-1086, 2002; Taylor PA et al., Blood 99: 3493-3499, 2002; Chiffoleau E et al., Jnnmunol 168: 5058-5069, 2002]. All of these immunosuppressive functions of the Treg cells have in common that they are distinguished by a high antigen specificity, ie each Treg cell clone is directed against a specific antibody and inhibits autoreactive T cells of the same antigen specificity under normal physiological conditions, in the case of Autoimmune diseases lose this Treg function and auto-reactive T cell clones, such as those used in type I diabetes against proteins of the pancreatic beta cell, lead to the outbreak of the autoimmune disease. On the other hand, this antigen specificity can also be used therapeutically, by increasing or increasing the number / function of these cells through targeted "antigen-specific" activation in vivo or ex vivo of Treg cells (or of denritic cells activating these cells) getting produced. Oral application of "antigens" is also suitable for this [Zhang et al., J hnmunol 167: 4245-4253, 2001]. However, the production of such antigens is technically extremely time-consuming and expensive and is restricted to antigen-specific T cell clones.

The special role of TGF-ßl for the regulation of immunological hyperreactivity is underlined by two recent publications, which show that the overproduction of TGF-ßl in CD4 ⁺ cells caused by genetic manipulation can suppress the disease process. Since in the case of asthma Th2 cells are crucially involved in the pathogenesis, the function of pathogenic Th2 cell clones can accordingly be effectively inhibited by transgenic overproduction of TGF-β1 [Hansen G et al., J Clin ivest 105: 61-70 , 2000; Thorbecke GJ et al., Cytokine Growth Factor Rev 11: 89-96, 2000]. The disadvantage of these methods for inducing the production of TGF-β1 in CD4 ⁺ or Treg cells is that they make it necessary to carry out a genetic manipulation, which is very complex on the one hand and is unsuitable for pharmacological use on humans or animals on the other.

The present invention has for its object to provide an efficient method for the induction of production and expression of TGF-ßl in and / or on Treg cells, which is also for the prevention and / or treatment of autoimmune diseases, allergies, arteriosclerosis and the suppression of Graft rejection on humans or animals is suitable. Another object is to provide corresponding pharmaceutical preparations with which these objects can be achieved.

Surprisingly, it was found that inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity induce the production of TGF-ßl and expression of TGF-ßl in and / or on Treg cells and thus for the prevention and treatment of Autoimmune diseases, allergies and arteriosclerosis are suitable and can serve to suppress transplant rejections.

The invention therefore relates to the use of one or more inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for inducing the production of TGF-β1 and expression of TGF-β1 in and / or on Treg cells.

The relationship between the inhibition of alanyl aminopeptidases and / or the inhibition of enzymes of the same substrate specificity and the inhibition of the production and surface expression of TGF-β1 in and / or on Treg cells has not been known to date.

All inhibitors of alanyl aminopeptidases and all inhibitors of enzymes of the same substrate specificity come into consideration as inhibitors. Preferably come actinonin, leuhistine, phebestin, amastatin, marvel, probestin, arphamenin, MR 387, ß-aminothiols, -aminophosphinic acids and their esters and salts, α-aminophosphonates, α-aminoboronic acids, α-aminoaldehydes, hydroxamates of α-amino acids, N. - Phenylphthalimide, N-phenylhomophthalimide, α-ketoamides, thalidomide and their derivatives are used. Particularly preferred among these are α-ketoamides, α-aminophosphinic acids, N-phenylhomophthalimides, α-aminophosphonates and phebestin, 3-amino-2-oxo-4-phenylbutanoic acid amides being particularly preferred as α-ketoamides, D-Phe- as α-aminophosphinic acids γ [PO (OH) -CH ₂ ] -Phe-Phe, as N-phenylhomophthalimide PAQ-22, as α-aminophosphonates RB3014 and / or phebestin, and very particularly preferably PAQ-22, RB3014 and / or phebestin.

The advantages of the preferred and the particularly preferred inhibitors are in particular the simple accessibility, the low price and the simple pharmaceutical processing.

As an enzyme with the same substrate specificity as the alanyl aminopeptidases, cytosolic alanyl aminopeptidase may be mentioned here by way of example. PAQ-22 is specific for the cytosolic alanyl aminopeptidase. As a preferred inhibitor of the cytosolic alanyl Aminopeptidase is therefore used PAQ-22, or a mixture of several inhibitors comprising PAQ-22.

The inhibition of the enzymatic activity of the membrane-bound alanyl aminopeptidase (APN, CD 13, EC 3.4.11.2) or the inhibition of enzymes with the same substrate specificity and inhibitor sensitivity (such as eg the cytosolic alanyl aminopeptidase, zAAP, PSA, EC3.4.11.14) increases the gene expression of TGF-ßl in Treg cells and the expression of the immunosuppressive cytokm TGF-ßl ("transforming growth factor ßl") in / on regulatory cells. This induction of the production and in particular the surface expression of TGF-ßl selectively strengthens or restitutes the function of Treg cells and is due to the above-mentioned relationships between the expression of TGF-ßl on the Treg cells and the inhibitory effect on autoreactive T-lymphocytes are suitable to overcome the functional deficits of Treg cells existing in autoimmune diseases and inflammatory diseases, in allergies and in rejection episodes after organ transplantation and thus to allow the prevention of these diseases and / or to improve the course or the severity of these diseases and / or cure these diseases. All of these diseases and the rejection episodes after organ transplantation are due to the lack of a sufficiently effective natural immunosuppressive principle, i.e. H. insufficiently functioning immunoregulatory cells, including deficient production of TGF-ßl. The induction of TGF-β1 according to the invention is not restricted to individual antigen-specific T cell clones.

The invention therefore also relates to the use of one or more inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for the prevention and / or treatment of autoimmune disorders. The use according to the invention is preferred for the prevention and / or treatment of rheumatoid arthritis, lupus erythematosus, multiple sclerosis, IDDM, Crohn's disease, ulcerative colitis, psoriasis, neurodermatitis, glomerulonephritis, interstitial nephritis, vasculitis, autoimmune ScMeldhdämämischendiseases chronic anemia, autoimmune diseases with an inflammatory genesis such as arteriosclerosis. The use for the prevention and / or treatment of multiple sclerosis or arteriosclerosis is particularly preferred. According to the invention, an inhibitor or several inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity are also used for the prevention and / or treatment of type I allergies according to Gell and Coombs or allergies of the type π, HI or IV. The use for the prevention and / or treatment of bronchial asthma or hay fever as type I allergy according to Gell and Coombs and / or contact allergies as type π, DI or IV allergies is preferred.

The invention further relates to the use of one or more inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for suppressing graft rejection, preferably in kidney or bone marrow transplants.

In the prevention and / or treatment of autoimmune diseases, allergies and hay fever and in the suppression of transplant rejections, all inhibitors of alanyl aminopeptidases and all inhibitors of enzymes of the same substrate specificity come into consideration as inhibitors. Preferred are actinonin, leuhistin, phebestin, amastatin, bestatin, probestin, arphamenin, MR 387, β-aminothiols, α-aminophosphinic acids and their esters and salts, α-aminophosphonates, α-aminoboronic acids, α-aminoaldehydes, hydroxamates of α-amino acids, N-phenylphthalimide, N-phenylhomophthalimide, α-ketoamides, thalidomide and their derivatives are used. Among these, α-ketoamides, α-aminophosphinic acids, N-phenylhomophthalimides, α-aminophosphonates and phebestin are particularly preferred, 3-amino-2-oxo-4-phenylbutanoic acid amides being particularly preferred as α-ketoamides, D-Phe- as α-aminophosphinic acids γ [PO (OH) -CH ₂ ] -Phe-Phe, as N-phenylhomophthalimide PAQ-22, as α-aminophosphonates RB3014 and / or phebestin, and very particularly preferably PAQ-22, RB3014 and / or phebestin

Because of the high antigen specificity of the Treg cell clones, the joint application of aminopeptidase inhibitors with the antigens causing the respective disease, for example antigenic peptides of the "myelin basic protein" in multiple sclerosis, appears to be particularly suitable for therapy because In this way, the inhibition of the pathogenic T cell clones is specifically and specifically effected. Antigen-specific immunosuppression is practically free of side effects [Zhang et al., J hnmunol 167: 4245-4253, 2001].

The invention therefore also relates to the use of inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for the induction of production of TGF-β1 and expression of TGF-β1 in and / or on Treg cells and for the prevention and / or treatment of Autoimmune diseases, allergies, hay fever, arteriosclerosis and to suppress transplant rejection, in which peptide fragments of pathogenic autoantigens or synthetic analogues and / or specific antigenic components of pathogenic microorganisms are additionally used. The inhibitors listed above and the preferred and particularly preferred inhibitors as well as the preferred and particularly preferred diseases are also preferred for use in which peptide fragments of pathogenic autoantigens or synthetic analogs and / or specific antigenic components of pathogenic microorganisms are additionally used. Preferred peptide fragments of pathogenic autoantigens in multiple sclerosis are MBP (myelin basic protein), MOG (myelin oligodendrocyte glycoprotein), MAG (myelin associated glycoprotein) and PLP (proteolipid protein), preferred specific antigenic components of pathogenic microorganisms are coat proteins or membrane glycolipid complexes.

The invention therefore also relates to the use of one or more inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for the manufacture of a medicament or a pharmaceutical preparation for inducing the production of TGF-ßl and expression of TGF-ßl in and / or on Treg cells.

All inhibitors of alanyl aminopeptidases and all inhibitors of enzymes of the same substrate specificity come into consideration as inhibitors. Actinonine, leuhistine, phebestine, amastatin, bestatin, probestin, arphamenine, MR 387, β-aminothiols, α-aminophosphinic acids and their esters and salts, α-aminophosphonates, α-aminoboronic acids, α-aminoaldehydes, hydroxamates of α-amino acids are preferred. N-phenylphthalimide, N-phenylhomophthalimide, α-ketoamides, thalidomide and their derivatives are used. Particularly preferred among these are α-ketoamides, α-aminophosphinic acids, N-phenylhomophthalimides, α-aminophosphonates and phebestin, 3-amino-2-oxo-4-phenylbutanoic acid amides being particularly preferred as α-ketoamides, D-Phe- as α-aminophosphinic acids γ [PO (OH) -CH ₂ ] -Phe-Phe, as N-phenylhomophthalimide PAQ-22, as α-aminophosphonates RB3014 and / or phebestin, and very particularly preferably PAQ-22, RB3014 and / or phebestin.

As an enzyme with the same substrate specificity as the alanyl aminopeptidases, cytosolic alanyl aminopeptidase may be mentioned here by way of example. PAQ-22 is specific for the cytosolic alanyl aminopeptidase. PAQ-22 is therefore used as the preferred inhibitor of cytosolic alanyl aminopeptidase, or a mixture of several inhibitors comprising PAQ-22 is used.

The invention also relates to the use of an inhibitor or several inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for the production of a medicament or a pharmaceutical preparation for the prevention and / or treatment of autoimmune disorders, of type I allergies according to Gell and Coombs, such as hay fever, π, HI or IV type allergies and the use in the manufacture of a medicament or a pharmaceutical preparation for suppressing transplant rejection. Preferred diseases and types of transplantation are listed in subclaims 26, 27, 29 and 31. Preferred inhibitors of alanyl aminopeptidases and enzymes of the same substrate specificity are mentioned in claims 32 to 35. When using one or more inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for the manufacture of a medicament or a pharmaceutical preparation for the prevention and / or treatment of autoimmune diseases, of type I allergies according to Gell and Coombs, such as hay fever, of allergies of the type π, HI or IV and when used to produce a medicament or a pharmaceutical preparation for suppressing transplant rejection, peptide fragments of pathogenic autoantigens in multiple sclerosis or synthetic analogues and / or specific antigenic components of pathogenic microorganisms may additionally be used, MBP (myelin basic protein), MOG (myelin oligodendrocyte glycoprotein), MAG (myelin associated glycoprotein) and / or PLP (proteolipid protein) and / or as specific antigenic components are more pathogenic as preferred peptide fragments of pathogenic autoantigens Microorganisms coat proteins or membrane glycolipid complexes are used.

Furthermore, the present invention relates to a pharmaceutical preparation comprising an inhibitor or more inhibitors of alanyl aminopeptidases and / or enzymes of the same substrate specificity and one or more pharmacologically acceptable carriers, additives and / or auxiliaries. The invention also relates to a pharmaceutical preparation containing an inhibitor or several inhibitors of alanyl aminopeptidases and / or enzymes of the same substrate specificity and peptide fragments of pathogenic autoantigens or synthetic analogs and / or specific antigenic components of pathogenic microorganisms, and one or more pharmacologically acceptable carriers, additives - And / or auxiliary substances.

The invention shows that for the treatment of inflammatory diseases and autoimmune diseases as well as allogeneic rejection reactions and allergies, for the development of which the proliferation and activation of pathogenic T cell clones play a central role, the application of inhibitors of the abovementioned enzymes or appropriate preparations and dosage forms are suitable. The simultaneous application of disease-specific antigens further increases this therapeutic effect and narrows the effect on the pathogenetically relevant process. The application of aminopeptidase inhibitors to induce TGF-β1 expression in / on Treg cells and thus to increase the immunosuppressive function of this pathogenetically important inhibitory T cell population provides a novel method for the diseases mentioned and a supplementary one in the central one is a form of therapy that intervenes.

The inhibitor or the several inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity can be used in pharmaceutically acceptable formulation complexes as inhibitors, substrates, pseudo-substrates, inhibitory peptides and peptide derivatives and as antibodies of this enzyme. Preferred inhibitors are Bestaun, Phebestin, Probestin, Actinonin, Leuhistin, RB3014, PAQ-22 and their derivatives, Phebestin, RB3014 and / or PAQ-22 are particularly preferred.

The administration can take place in all suitable forms, for example as a topical application in the form of creams, ointments, pastes, gels, solutions, sprays, liposomes, shaking mixtures, hydrocolloid dressings or other dermatological bases / vehicles including instillative application or as a systemic application oral, transdermal, intravenous, subcutaneous, intracutaneous, inhalative, intramuscular use in suitable formulations or in suitable galenics or in connection with or incorporation into microparticles to overcome the blood-brain barrier. At the same time, the application of "disease-specific" antigens (petid fragments, lipopolysaccharides, etc.) in appropriate dosage forms can increase the success of the therapy.

The invention is explained in more detail with reference to the following examples, without being restricted to these.

example 1

Induction of surface expression of TGF- / 31 on human regulatory T lymphocytes (CD4 ⁺ CD25 ⁺ ) after incubation with the inhibitor phebestin. The T cells were incubated with phebestin for 24 hours without addition (control), with addition of PHA and PMA and with simultaneous addition of PHA / PMA. PHA (phythema agglutinin) and PMA (phorbol myristate acetate) were used as mitogens and agents that stimulated proliferation. The surface expression of TGF-ßl was then measured using flow cytometry using the commercially available polyclonal anon-TGF-ßl antibody (chicken anti-human; R&D Systems). The results are shown in Figure 1.

Example 2

Induction of gene expression of TGF-ßl in human regulatory T lymphocytes (CD4 ⁺ CD25 ⁺ ) after incubation with the inhibitor phebestin.

The T cells were incubated for 24 hours without addition (control), with addition of PHA and PMA or with simultaneous addition of PHA PMA with phebestin. PHA (phythema agglutinin) and PMA (phorbol myristate acetate) were used as mitogens and agents that stimulated proliferation. The content of TGF / 31 mRNA was then determined by means of quantitative RT-PCR using the i-cycler. The results are shown in Figure 2.

Example 3

Induction of gene expression of TGF-β1 on human regulatory T lymphocytes (CD4 ⁺ CD25 ⁺ ) after incubation with the inhibitor PAQ-22.

The T cells were incubated with PAQ-22 for 24 hours without addition (control), with addition of PHA and PMA or with simultaneous addition of PHA / PMA. PHA (phythema agglutinin) and PMA (phorbol myristate acetate) were used as mitogens and agents that stimulated proliferation. The content of TGF / 31 mRNA was then determined by means of quantitative RT-PCR using the i-cycler. The results are shown in Figure 3. Example 4

Induction of gene expression of TGF-β1 on human regulatory T lymphocytes (CD4 ⁺ CD25 ⁺ ) after incubation with the aminopeptidase inhibitor RB3014.

The T cells were incubated with RB3014 for 72 hours without addition (control), with addition of PHA and PMA or with simultaneous addition of PHA / PMA. PHA (phythema agglutinin) and PMA (phorbol myristate acetate) were used as mitogens and agents that stimulated proliferation. The content of TGF-β1 mRNA was then determined by means of quantitative RT-PCR using the i-cycler. The results are shown in Figure 4.

Claims

claims

1. Use of an inhibitor or several inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for the induction of production of TGF-β1 and expression of TGF-β1 in and / or on Treg cells.

2. Use according to claim 1, in which the one or more inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity have at least one member selected from the group consisting of actinonin, leuhistin, phebestin, amastatin, marvel, probestin, arphamenine, MR 387, β-aminothiols, α-aminophosphinic acids and their esters and salts, α-aminophosphonates, α-aminoboronic acids, α-aminoaldehydes, hydroxamates of α-amino acids, N-phenylphthalimides, N-phenylhomophthalimides, α-ketoamides, thalidomide and their derivatives is.

3. Use according to claim 2, in which as the one or more inhibitors α-ketoamides, preferably 3-amino-2-oxo-4-phenylbutanoic acid amides, α-aminophosphinic acids, preferably D-Phe-γ [PO (OH) - CH ₂ ] -Phe-Phe, N-phenylhomophthalimide, preferably PAQ-22, α-aminophosphonate, preferably RB3014 and / or phebestin, particularly preferably PAQ-22, RB3014 and / or phebestin.

4. Use according to one of claims 1 to 3, in which cytosolic alanyl aminopeptidase is used as the enzyme of the same substrate specificity.

5. Use according to approach 4, in which the one inhibitor PAQ-22 is used or which comprise several inhibitors PAQ-22.

6. Use of an inhibitor or several inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for the prevention and / or treatment of autoimmune disorders.

7. Use according to claim 6 for the prevention and or treatment of rheumatoid arthritis, lupus erythematosus, multiple sclerosis, IDDM, Crohn's disease, ulcerative colitis, psoriasis, neurodermatitis, glomerulonephritis, interstitial nephritis, vasculitis, autoimmune thyroid or other anemia, autoimmune, autoimmune chronic diseases with inflammatory genesis such as arteriosclerosis.

8. Use according to claim 6 or claim 7 for the prevention and / or treatment of multiple sclerosis or arteriosclerosis.

9. Use of an inhibitor or several inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for the prevention and / or treatment of type I allergies according to Gell and Coombs, hay fever or type π, m or IV allergies.

10. Use according to claim 9 for the prevention and / or treatment of bronchial asthma or hay fever as type I allergy according to Gell and Coombs and / or contact allergies as type π, HI or IV allergies.

11. Use of one or more inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity to suppress graft rejection.

12. Use according to claim 11 in kidney or bone marrow transplants.

13. Use according to one of claims 6 to 12, in which the one or more inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity have at least one member selected from the group consisting of actinine, leuhistine, phebestin, amastatin, Bestatin, Probestin, Arphamenin, MR 387, β-aminothiols, α-aminophosphinic acids and their esters and salts, α-aminophosphonates, α-aminoboronic acids, α-aminoaldehydes, hydroxamates of α-amino acids, N-phenyl-phthalimides, N-phenylhomophthalimides, α-ketoamides, thalidomide and its derivatives.

14. Use according to claim 13, in which as the one or more inhibitors α-ketoamides, preferably 3-amino-2-oxo-4-phenylbutanoic acid amides, α-aminophosphinic acids, preferably D-Phe-γ [PO (OH ) -CH ₂ ] -Phe-Phe, N-phenylhomophthalimide, preferably PAQ-22, α-aminophosphonate, preferably RB3014 and / or phebestin, particularly preferably PAQ-22, RB3014 and / or phebestin.

15. Use according to one of claims 6 to 14, in which cytosolic alanyl aminopeptidase is used as the enzyme of the same substrate specificity.

16. Use according to claim 15, in which the one inhibitor PAQ-22 is used or the plurality of inhibitors comprise PAQ-22.

17. Use according to one of claims 1 to 16, in which peptide fragments of pathogenic autoantigens or synthetic analogs and / or specific antigenic components of pathogenic microorganisms are additionally used.

18. Use according to claim 17, in which, as peptide fragments of pathogenic autoantigens, MBP (myelin basic protein), MOG (myelin oligodendrocyte glycoprotein), MAG (myelin associated glycoprotein) and / or PLP (proteolipid protein) ) are used.

19. Use according to claim 17 or 18, in which envelope proteins or membrane glycolipid complexes are used as specific antigenic components of pathogenic microorganisms.

20. Use of an inhibitor or several inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for the production of a medicament or a pharmaceutical preparation for inducing the production of TGF-β1 and expression of TGF-β1 in and / or on Treg cells ..

21. Use according to claim 20, in which the one or more inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity have at least one member selected from the group consisting of actinonine, leuhistine, Phebestin, Amastatin, Bestatm, Probestin, Arphamenin, MR 387, ß-aminothiols, α-aminophosphinic acids and their esters and salts, α-aminophosphonates, α-aminoboronic acids, α-amino aldehydes, hydroxamates of α-amino acids, N-phenylphthalimides, N- Phenylhomophthalimide, α-ketoamides, thalidomide and their derivatives.

22. Use according to claim 21, in which as the one or more inhibitors α-ketoamides, preferably 3-amino-2-oxo-4-phenylbutanoic acid amides, α-aminophosphinic acids, preferably D-Phe-γ [PO (OH) - CH ₂ ] -Phe-Phe, N-phenylhomophthalimide, preferably PAQ-22, α-aminophosphonate, preferably RB3014 and / or phebestin, particularly preferably PAQ-22, RB3014 and / or phebestin.

23. Use according to one of claims 20 to 22, in which cytosolic alanyl aminopeptidase is used as the enzyme of the same substrate specificity.

24. Use according to claim 23, in which the one inhibitor PAQ-22 is used or the plurality of inhibitors comprise PAQ-22.

25. Use of an inhibitor or several inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for the manufacture of a medicament or a pharmaceutical preparation for the prevention and / or treatment of autoimmune diseases.

26. Use according to claim 25 for the prevention and / or treatment of rheumatoid arthritis, lupus erythematosus, multiple sclerosis, IDDM, Crohn's disease, ulcerative colitis, psoriasis, neurodermatitis, glomerulonephritis, interstitial nephritis, vasculitis, autoimmune thyroid diseases, autoimmune or other chronic hemolytic disorders Inflammatory diseases such as arteriosclerosis.

27. Use according to claim 25 or approached 26 for the prevention and / or treatment of multiple sclerosis or arteriosclerosis.

28. Use of an inhibitor or several inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for the manufacture of a medicament or a pharmaceutical preparation for the prevention and or treatment of type I allergies according to Gell and Coombs, hay fever or type H allergies, HI or IV.

29. Use according to approach 28 for the prevention and / or treatment of bronchial asthma or hay fever as a type I allergy according to Gell and Coombs and / or contact allergies as type H, HI or IV allergies.

30. Use of an inhibitor or several inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for the production of a medicament or a pharmaceutical preparation for suppressing graft rejection.

31. Use according to speech 30 for kidney or bone marrow transplants.

32. Use according to one of claims 25 to 31, in which the one or more inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity have at least one member selected from the group consisting of actinonin, leuhistine, phebestin, amastatin, bestatin, Probestin, Ai hamenin, MR 387, β-aminothiols, α-aminophosphinic acids and their esters and salts, α-aminophosphonates, α-aminoboronic acids, α-amino aldehydes, hydroxamates of α-amino acids, N-phenylphthalimides, N-phenylhomophthalimides, α-ketoamides , Thalidomide and its derivatives.

33. Use according to claim 32, in which as the one or more inhibitors α-ketoamides, preferably 3-amino-2-oxo-4-phenylbutanoic acid amides, α-aminophosphinic acids, preferably D-Phe-γ [PO (OH) - CH ₂ ] -Phe-Phe, N-phenylhomophthalimide, preferably PAQ-22, α-aminophosphonate, preferably RB3014 and or phebestin, particularly preferably PAQ-22, RB3014 and / or phebestin.

34. Use according to one of claims 25 to 33, in which cytosolic alanyl aminopeptidase is used as the enzyme of the same substrate specificity.

35. Use according to spoke 34, in which the one inhibitor PAQ-22 is used or the multiple inhibitors comprise PAQ-22.

36. Use according to one of claims 20 to 35, in which peptide fragments of pathogenic autoantigens or synthetic analogs and / or specific antigenic components of pathogenic microorganisms are additionally used.

37. Use according to approach 36, in which MBP (myelin basic protein), MOG (myelin oligodendrocyte glycoprotein), MAG (myelin associated glycoprotein) and / or PLP (proteolipid protein) are used as peptide fragments of pathogenic autoantigens become.

38. Use according to claim 36 or 37, in which envelope proteins or membrane glycolipid complexes are used as specific antigenic components of pathogenic microorganisms.

39. Pharmaceutical preparation, comprising an inhibitor or more inhibitors of alanyl aminopeptidases and / or enzymes of the same substrate specificity and one or more pharmacologically acceptable carriers, additives and / or auxiliaries.

40. Pharmaceutical preparation comprising an inhibitor or more inhibitors of alanyl aminopeptidases and / or enzymes of the same substrate specificity and peptide fragments of pathogenic autoantigens or synthetic analogs and / or specific antigenic components of pathogenic microorganisms and one or more pharmacologically acceptable carriers, additives and / or auxiliary substances.