DE19943786A1 - Antiviral agent, e.g. vaccine, antibody, agent that inhibits viral replication, transcription or translation, useful for preventing or treating tumors (or conditions which may become tumorous) associated with viral infections - Google Patents

Abstract

Antiviral agent (A) for preventing and/or treating alterations to tissues of mesenchymal origin (or derived tissue alterations), is new. Independent claims are also included for the following: (1) methods for identifying (A) and/or virus against which (A) is directed; (2) apparatus for detecting a virus involved in pathogenesis of tissue alterations comprising a product of a gene of the HMGI(Y) family (undefined), or its fragment or derivative, immobilized on a support; and (3) method for diagnosing tissue alterations by detecting, in a body fluid, antibodies against, or antigens of, a virus implicated in the alterations.

Description

The invention relates to means for the prevention and / or treatment of a tissue change, wherein the tissue change comprises tissue of mesenchymal origin, use of the Means, methods for determining for the production of an agent for prevention and / or Treatment of tissue changes of mesenchymal origin and / or detection of viruses against which the agent according to the invention is directed and uses of the Method, apparatus for the determination of a pathogenesis of tissue alteration mesenchymal origin and methods of diagnosing a tissue alteration,  wherein the tissue change mesenchymal a tissue change Origin is.

The treatment of tissue changes such as tumors and carcinomas is intense despite The efforts of modern medicine are still relatively limited to Che Mother therapy in its most varied modifications and surgical procedures. By far pro more problematic is the prevention of such tissue diseases. As a rule, it is the case that factors responsible for tissue change for the individual area of life to exclude, which is not always possible.

A special problem area is the prevention and treatment of tissue changes with mesenchymal origin. To this day, it is the one of the most diverse tumors such as leiomyoma, endometrial polyp, endometriosis, hamartoma of the lungs and the breast, Prostate adenoma, atheroma and many more, underlying aetiology unknown what As a result, only symptomatic therapy remains for this type of disease. Un In these circumstances, prevention is especially difficult, as the individual knows not, as by his own behavior, the risk of such a tissue change to reduce it.

As an example, reference should be made to the leiomyomas of the uterus. These are, even if they are are benign, a health problem. Thus, studies have shown that in the Western European States every third woman has uterine leiomyomas and, for example, in the Every fifth visit to the gynecologist for fibroids (Morton, C. C .; At the. J. Pathol. 1998; 153 (4): 1050-20). If these leiomyomas manifest themselves symptomatically, can this z. B. with significant bleeding and thus health risks, pain and urinary incontinence. In addition, these leiomyomas may contribute to infertility the affected women.

Despite many efforts, the aetiology / pathogenesis of uterine leiomyomas has been so far unclear (Morton loc. cit.). Various possible causes of uterine leiomyomas will be  for example, by Cramer, S.F. et al. (Cramer S.F., J. Reprod. Med. 1995, 40 (8): 595-600), for example, injury and repair of the endometrium. Also, the involvement of estrogen and / or progesterone and estrogen and / or progesterone receptors in the development of Neoplasms of smooth muscle of the uterus were discussed (=) in the literature, such. B. Tiltman A.J. (Tiltman A.J., Curr. Opin. Obstet., Gynecol., 1997; 9 (1): 48-51 However, various studies have suggested that Mutatio genes of the HMGI (Y) family are involved (see Schoenmakers E.F. et al., Nat. Genet. 1995, 10 (4): 436-44), it is still unclear whether the said Mutations are primary or secondary events.

Despite this finding, the fibroids currently only have two therapeutic approaches available On the one hand the surgical removal of the uterus (hysterectomy), so alone in the Approx. 200,000 hysterectomies per year (Morton, loc. Cit.), Or myoma nucleation, d. H. the "peeling" of the tumors, at uterus-preservation. In the case of myoma nucleation can be induced preoperatively a drug-based myoma reduction under Ver use of hormone antagonists, however, to the extent undesirable side effects associated with it as causing menopausal symptoms.

It thus exists for leiomyomas, especially those of the uterus; as well as endometrium poly penis and endometriosis an urgent need for new concepts for therapy and prevention tions and the appropriate means.

It is thus an object of the present invention to provide means for prevention and treatment tissue changes, where the tissue change is tissue reading of chymal origin.

Furthermore, it is an object of the present invention to provide a method with which can be determined those essential components which are used to produce the inventions The agents are suitable or required.  

Finally, it is an object of the invention to provide a device for determining a to provide the agent involved in the pathogenesis of tissue alterations, wherein the Tissue modification includes tissues of mesenchymal origin.

Furthermore, the invention has for its object to provide a method for diagnosing a To provide tissue alteration, wherein the tissue change mesenchymal tissue Origin, and a kit suitable for this purpose.

The object is achieved by an agent for prevention and / or treatment a tissue change, wherein the tissue change me at least one tissue of senchymal origin and the agent comprises an anti-virally active agent which is effective against a virus whose nucleic acid is at least one binding site for a Gene product of genes of the HMGI (Y) family or their derivatives.

Furthermore, the object is achieved by a means for prevention and / or Treatment of a tissue change, wherein the tissue change at least one Ge of mesenchymal origin and the agent comprises an anti-viral agent which is active against a virus whose nucleic acid codes for a gene product, wherein this gene product with at least one gene product of genes of the HMGI (Y) family or whose derivatives interact.

In the inventive compositions can be provided that the binding site on the Nucleic acid of the virus, the structural and sequence feature of a first AT-rich sequence includes.

In one embodiment, it may be provided that the binding site on the nucleic acid of the virus in addition to the first sequence nor the structural and sequence features comprises that

• A second AT-rich sequence is present, and  
• - The first and second sequence arranged at a spatial distance from each other are.

In a preferred embodiment it is provided that the spatial distance is so out is selected, that the first sequence and the second sequence relative to each other in a plane the nucleic acid are arranged.

In the inventive compositions may further be provided that the genes of HMGI (Y) family MAG genes, HMGIC, HMGIY, aberrant transcripts of genes of HMGI (Y) family and derivatives thereof.

In one embodiment it is provided that the tissue of mesenchymal origin at least partially infected with a virus.

In a further embodiment it is provided that the tissue change as from final or obligatory component tissue, at least some of which Tissue-building cells are infected with any of the viruses described herein.

Furthermore, it can be provided that the tissue proliferation at least a proliferation a mesenchymal cell infected with any of the viruses described herein.

In a preferred embodiment, the proliferation is a clonal proliferation.

In the inventive compositions can be provided that the tissue proliferation a epithelial component.

In a preferred embodiment, the epithelial component has at least one Cell infected with any of the viruses described herein.  

Furthermore, it can be provided that infected with one of the viruses described herein Cell has a chromosomal change.

It is preferred if the chromosomal change at least one HMGI (Y) gene of infected cell.

In another preferred embodiment, the HMGI (Y) gene is selected from the group selected, the MAG genes, HMGIC, HMGIY, aberrant transcripts of genes of HMGI (Y) - Family and derivatives thereof.

In the inventive compositions can be provided that the tissue change from is selected from the group, the leiomyomas, in particular leiomyomas of the uterus; Endome triumpolypen; endometriosis; Fibroadenomas, in particular fibroadenomas of the breast; Phyl lodes tumors, especially the breast; Hamartomas, in particular the mamma; Prostate- adenomas; lipomas; aggressive angiomyomas; enchondromas; pleomorphic adenomas, esp especially the salivary glands; Colonic polyps, especially colon adenomas; hamartomas, especially the lungs; Atheroma and resulting carcinomas includes.

It is provided in one embodiment that the resulting carcinomas from the Group comprising colon carcinomas and prostate carcinomas.

In a further embodiment of the means according to the invention it is provided that the Virus is selected from the group containing DNA viruses, and in particular adenoviruses and Her pesviruses.

In the inventive compositions can be provided that the agent is selected from the group, the vaccines; Antibody; Means that replication, transcription or Inhibit translation of viral, especially adenoviral genes; Means with viruses, in particular  Adenoviruses, recognize and / or destroy infected cells; and means by their Effector cell stimulating effect to achieve an antiviral effect includes.

In a preferred embodiment, the vaccine comprises an antibody which is resistant to the Virus or part of it.

In an alternative preferred embodiment, the vaccine comprises a virus particle, as described herein, or a part thereof.

In a further embodiment of the agents according to the invention the antibody is out selects from the group containing monoclonal antibodies, polyclonal antibodies, polyvalent An antibodies, antibody fragments and derivatives thereof.

The object is also achieved by the use of the agent according to the invention Immunization against viruses that interfere with the pathogenesis and / or etiology of tissue dispositions ments as described herein.

Furthermore, the object is achieved by a use of the agent according to the invention for the preparation of a pharmaceutical composition comprising the agent according to one of the preceding claims and a pharmaceutically acceptable carrier for prevention and / or treating the tissue changes according to any one of the preceding claims or for immunization against the viruses involved in the pathogenesis and / or etiology of Tissue modifications are connected according to one of the preceding claims.

It may be provided in one embodiment that the immunization an active Immunization is.

Finally, the object is also achieved by a method for determining the preparation of an agent for the prevention and / or treatment of tissue changes, as described herein, suitable viruses and / or for detecting viruses, against which the inven tion proper means is directed, which the steps include:

• a) transfection of a normal karyotype cell culture derived from one A tissue that converts the tissue according to any one of the preceding claims with an expression vector for a gene of the HMGI (Y) family or its Deri vat,
• b) Comparison of the RNA pattern of the transfected cells with that of control cultures, and
• c) Expri in the transfected cultures over control cultures mated or amplified expressed RNA (s) by sequence homology to the Vorhan of viral elements.

The object is also solved by a method for determining from to Her providing a means of preventing and / or treating tissue alterations, such as described herein, suitable viruses and / or for detecting viruses against which the inventions directed means of the invention, which comprises carrying out a PCR test, wherein the primers (pairs) used for the PCR correspond to the sequence of viral nucleic acid.

The object is also achieved according to the invention by a method for determining viruses suitable for producing an agent for the prevention and / or treatment of tissue changes as described herein and / or for detecting viruses against which the agent according to the invention is directed, comprising the steps comprising:

• a) Creating a cDNA library from a tissue that changes the tissue according to any one of the preceding claims, which comprises activation of a gene of HGMI (Y) family or a derivative, and  
• b) screening the cDNA library with a virus-specific probe or
• c) Analysis of the cDNA clones for viral sequences or
• d) Comparison with a normal myometrium cDNA library.

In one embodiment of the method according to the invention it can be provided that the The gene of the HMGI (Y) family is selected from the group consisting of HMGIC, HMGIY, MAG, but transcripts of the genes of the HMGI (Y) family and derivatives thereof.

In a further embodiment, the virus, the viral element or the virus-specific a probe selected from the group of viruses comprising viruses as described herein are written, d. H. those viruses whose nucleic acid has at least one binding site for a Gene product of genes of the HMGI (Y) family or derivatives thereof or such viruses, whose nucleic acid codes for a gene product, said gene product being at least ei encoded gene product, said gene product with at least one gene product of Genes of the HMGI (Y) family or their derivatives interacts. To those described above Viruses also include those belonging to the group of DNA viruses, in particular those adenoviruses, herpesviruses and papovaviruses, at least one of the above have mentioned features.

The object is also achieved by the use of one of the methods according to the invention for detecting viruses against which for the prevention and / or treatment of tissue alter can be immunized as described herein.

Finally, the object is also achieved by a device for determining an the pathogenesis of tissue alterations as described herein, virus, wel a gene product of genes of the HGMI (Y) family or a part thereof or its De which is bound to a carrier.  

In one embodiment, it is provided that the viral nucleic acid in addition to the first sequence still includes the structural and sequence features that

• A second AT-rich sequence is present and
• - The first sequence and second sequence in a spatial distance to each other are orders.

In a preferred embodiment it is provided that the spatial distance is so out is selected, that the first sequence and the second sequence relative to each other in a plane the nucleic acid are arranged.

The object is further achieved by a method for diagnosing a tissue change change, wherein the tissue change comprises such a tissue change as herein described, wherein a body fluid on the presence of antibodies against Viruses as described herein.

The object is also achieved by a method for diagnosing a tissue change, wherein the tissue change comprises such a tissue change as described herein ben, wherein a body fluid on the presence of antigens of viruses, such as described herein.

Furthermore, the object is achieved by a method for diagnosing a tissue change change, wherein the tissue change describes such a tissue change as described herein ben, wherein a tissue sample is reacted with an agent selected from the group the antibodies selected with viruses as described herein, especially DNA viruses and especially adenoviruses and / or herpesviruses or parts thereof; Antigens those of viruses as described herein, especially DNA viruses, and more particularly adenoviruses and / or herpesviruses or parts thereof, and nucleic acid containing nucleic acid  of viruses as described herein, especially DNA viruses and more particularly adenoviruses and / or herpesviruses, in the case of the presence of viruses, as herein described, especially DNA viruses and especially adenoviruses and / or herpesviruses a complex of the agent and the virus forms and the complex is detected.

Before the invention is explained in more detail below, Be used herein Be In addition to the general understanding of the skilled person on the Ge be defined.

In particular, benign tumors of smooth muscle should be described herein as leiomyomas (Definition according to Baltzer, J. et al .; Gynecology - A Short Textbook, 5th ed., 1994, Thieme Verlag).

Among endometrial polyps herein are particularly hyperplasia and polypous wax Forms of endometrium with stromal and glandular (epithelial) or exclusively stromal component understood.

By endometriosis, it is intended in particular to include endometrial foci elsewhere than in the uterine cavity (definition according to Baltzer loc. cit.).

In particular, fibroids are to be understood here as meaning leiomyomas (definition according to Baltzer, loc. Cit.).

The invention is based on the surprising finding that tissue changes, the comprise a tissue of mesenchymal origin, a common pathogenicity is underlying. This pathogenicity mechanism is associated with the presence of a Virus in the tissue of mesenchymal origin, the virus being one, whose nucleic acid has at least one binding site for a gene product of genes of HMGI (Y) family or derivatives thereof, or the virus is one whose nucleus acid for a gene product, said gene product being at least one gene product  of genes of the HMGI (Y) family or their derivatives interacts. These viruses will be Also referred to herein as "the viruses described herein" or incorporated by reference Term "as described herein". In other words, these types of viruses are a factor in triggering tissue changes that involve tissues that are mesenchymal Origin is.

The tissue changes may include tumors and / or carcinomas. respect The histological structure of said tissue changes can be that these may consist entirely of such tissue which is under the influence of said virus has changed, or a part of the tissue change having Tissue consists of such tissue, which changes under the influence of said viruses Therefore, this part of the fabric has only one, but an obligatory part of the Ge web variation or tumor is.

The tissue change may further be one in which the change to a Attributed proliferation of mesenchymal cells infected with said viruses is. At the same time, the tissue change may also have an epithelial component. By epithelial component herein is meant a part of the tissue alteration (eg of the Tu mors or carcinoma), which in terms of its histological origin can be assigned to the epithelium. This histological assignment is done on the Based on generally accepted criteria of histopathology.

In the tissue changes may also be the situation that the proliferation is a clonal proliferation, i. H. the proliferation to a single infection event too thus, a single cell transfor. as a result of infection with said viruses is being mingled. As a result of the transformation of this single cell, the behavior of the Cell, in particular their differentiation state and / or their growth behavior, resulting in the Tissue change leads. Does the tissue change on a single, with the said Viruses infected cells back, it is called a monoclonal tumor, goes the tissues change to several but few cells infected with the said viruses,  This is called an oligoclonal tumor. Both clonalities are open to those herein back through the said virus mediated pathogenicity mechanism.

With the infection of the mesenchymal cell component of tissue by said viruses, which finally shows the tissue change or trains it, as a universal pathogen A number of different infection scenarios are possible. So can, z. B. in one case, the primary infection in a tissue of mesenchymal origin and be limited to this. This can lead to further tissue changes, wherein an epithelial proliferation occurs, the direct or indirect consequence of the virus infectious on the mesenchymal component. Examples of this are hamartomas and endomes However, it is also possible that the primary infection on other tissue parts expands. In this case, for example, epithelial tissue can also be infected, whereby it is is a secondary infection and this secondary infected epithelial tissue just if it can proliferate. It is further conceivable that epithelial tissue first, i. H. pri mär, infected by the said viruses and starting from a secondary infection tion of the mesenchymal tissue or tissue portion of the - later - tissue change results, which can then lead to a proliferation of mesenchymal tissue. An example for the last described scenario represents the colon adenoma.

The viruses described herein may be present during or after infection in the cell in ir exist in a form. So the virus can be episomal in the infected cells or in the Host genome integrated. It can go through a lytic cycle, into the environment be released and infect other cells, as stated above. The virus may also be present in epithelial cells either episomally or integrated into the genome.

As a result of this particular in humans, with regard to tissue changes, the tissues, which is of mesenchymal origin include, in the current opinion of the inventor, uni general pathogenicity mechanism based on the involvement of said, d. H. herein be written viruses, it is thus possible, means or therapy concepts for  To provide treatment of all those tissue changes that mesenchymal tissue Origin. The same applies to the diagnosis of such tissue changes.

Moreover, knowing this pathogenicity mechanism now also a prevention be operated using the means according to the invention. The implementation of this fundamental finding is antiviral means of treating such tissues to use changes. These remedies can also be known antiviral so far Active agents, as appropriate, include the activity of those described herein To influence viruses. As a possible target for such impairment of the viral activity, all sub-steps or sub-aspects are conceivable, including Ab Sorptionsvorganges, Internalisierungsvorganges, integration of the viral DNA in the Wirtsge nom or stabilization in the cytoplasm of the host cell, replication, transcription and Translation, assembly of the viral capsid and release of the viral capsid. Next to it Especially vaccines against these viruses are both for therapy, but especially for the prevention of such tissue changes, as explained in more detail below will be.

By way of example, in the following Table 1, tissue changes are listed for which the agents according to the invention can be used in each case or for their therapy and Prevention of the already known antiviral agents, as shown for example in Table 2 are, can be used.  

Table 1

Table 2

Overview of various antiviral compounds that can be used in the present invention

In addition to the above-described universal pathogenicity mechanism, the inventor has Furthermore surprisingly found that the emergence of tissue changes, the Ge mesenchymal origin include or corresponding tumors, building on the above-described infection with said viruses by an additional event in sy nergistically encouraged. This additional event is chromosomal alterations, especially those involving HMGI (Y) genes, d. H. Breakpoints in structural chromosome aberrations are either within the genes or at a distance from these, so that it can be determined by the structural chromosomes transcriptional de-regulation of HMGI (Y) genes. As a result of this Chromosomal change results in the expression of now altered cellular gene products that interact with certain viral sequences, causing the observed sy nergistic effect on the genesis of tissue changes. The concept of HMGI (Y) genes will be referred to hereinafter as agents according to the invention disclosed vaccines will be further elaborated.

Examples of tissue changes in addition to the infection of the mesenchymal tissue still have a chromosomal change of HMGI (Y) result from the Table 1 above, with exemplification of endometrial polyps, Endometrioseherde, Hamarto lungs, lipomas, breast fibroadenomas, and salivary pleomorphic adenomas is referred to glands. As can also be seen in particular from Table 1, the proportion of tissue changes that, in addition to the viral infection, a chromosomal Ver change the HMGI (Y) genes, fluctuate. The detection of chromosomal changes For example, in Kazmierczak et al. al., Oncogene 12: 515-521.

As mentioned above, the prevention and therapy of mesenchymal tissue continues Changes involving tissues of mesenchymal origin in an antiviral The on. The tissue changes, however, can chromo in addition to the viral infection have somale change regarding the HMGI (Y) genes. Also such Gewebever Changes, because they are ultimately based on a viral activity, with the treated or prevented herein means. This will also be the  Schoenmakers (loc. cit.) studies on mutations described above of the genes of the HMGI (Y) family to uterine leiomyomas, although from the therein described findings, the technical teaching disclosed herein could not be derived. The pathogenesis of the leiomyomas is based not only on mutations, especially Chro mosomic aberrations in the loci of members of the HMGI (Y) gene family, son at least some of these cases are d. H. Tissue change under Be participation of a tissue of mesenchymal origin with a mutation in the region of the genes of the HMGI (Y) genes to produce a consequence of the interaction of mutational events of the Members of the HMGI (Y) gene family and a virus, in particular a transforming one Virus, or infection with such acts, the viral infection itself already out is enough to trigger a Myomentstehung whose growth potential through a - possibly subsequent mutation of genes of the HMGI (Y) family is enhanced.

Without being limited in the following by these assumptions, in particular not in the Detail, it seems currently to be that as a result of infection with a transforming Virus and its subsequent persistence, presumed to be integrated into the cellular genome, in cells without further mutation of genes of the HMGI (Y) family, the transforming vi rales expressed, possibly weak, and therefore the resulting tumors grow very slowly and stay small. As a result of a mutation-induced re-activation of genes of the HMGI (Y) family, e.g. B. by displacement of enhancers in Juxta position to the genes, there is an increased activation of the genes of the transforming Proteins and an overall increased expression thereof. Those in the cell are more common existing transforming proteins lead to a significantly higher growth activity the corresponding tumors and thus to increased tumor growth.

Specifically, it has been found that the gene products of the members of the genes of HMGI (Y) - Family that can typically bind to nucleic acids, such as described by French, S.W. et al. (French, S.W., et al., Mol. Cell Biol., 1996; 16 (10): 5393-99; Yie, J. et al .; Mol. Cell Biol., 1997, 17 (7): 3649-62), also on nucleic acid of transforming viruses when binding in the region of the regulatory regions of the nucleic acid (eg.  Promoters and enhancers) the gene products of the genes of the HMGI (Y) family on the Tran scripting rate of the viral transforming proteins influence.

Furthermore, it has been found that the gene products of the members of the genes of HMGI (Y) - Family can also interact with a gene product of a viral nucleic acid.

This interaction may occur in a direct interaction of the two gene products, i. H. the gene product of the viral nucleic acid and that of a gene of the HMGI (Y) family, consist. Another form of interaction may be that these by a further component is mediated, d. H. no direct interaction between the two gene pro is present. This mediating further component can, for example, a nucleic acid and, in particular, such a nucleic acid which is a binding site for a gene product of genes of the HMGI (Y) family as described above.

As a result of this interaction of gene products of the genes of the HMGI (Y) family with Nucleic acid of transforming viruses, in particular the regulatory regions of Nucleic acid (eg, promoters and enhancers) of these viruses may prevent the genesis of tissues changes with tissue of mesenchymal origin, as exemplified in Table 1 are counteracted by an antiviral agent against the Virus is used. As stated above, such antiviral agents are generally suitable for this purpose, against the viruses causally involved in the tissue change directed, d. H. are active. The viruses are the viruses described herein. One - preferred - Subgroup of the viruses described herein are those viruses in which the single virus has or encodes a nucleic acid which has at least one binding site for a nucleic acid Gene product of genes of the HMGI (Y) family or their derivatives comprises or for a Gene product encoded, wherein the gene product with at least one gene product of genes of HMGI (Y) family or their derivatives interacts, and those to the group of DNA viruses belong.  

In connection with this, within the group of DNA viruses, in particular the Adenoviruses for this to be of particular importance. Another group of DNA viruses, for the tissue changes described herein comprising a tissue, the me is of senchymal origin, of particular importance are viruses of the herpes group, the hereinafter referred to simply as herpesviruses. Furthermore belong to the Grup Of the DNA viruses that are important for the tissue changes described herein are the papova viruses. The present invention is furthermore based on the knowledge that that for the tissue changes described herein various viruses, in particular DNA viruses, can act synergistically.

By adenovirus, it is intended to mean, in general, any member of the Adenovi group be understood as described, for example, in Fields Virology, 3 rd Edition, Raven Publisher, Philadelphia, 1996 and that has the properties described there. sliding This applies to viruses from the group of herpesviruses, d. H. Herpesvirus is to be referred to herein In general, any virus from the group of herpesviruses are understood, for. B. also the cytomegalovirus, as in Fields Virology, a. a. O., described and that be there has written properties. Furthermore, the term adenovirus extends and / or herpesviruses herein in particular in the context of the adenovirus and / or herpesvirus-targeted vaccine, even on such viruses, the essential elements and / or properties of these viruses. These include, for example, also genetic engineering altered viruses.

The group of DNA viruses also includes the polyoma viruses, which in turn belong to the family of Papovaviridae, which include the papilloma viruses and Simian Vacuolating Virus 40 (SV 40) belong. The family is characterized by extreme heat stability. Papovaviridae are hül leneless cubic DNA viruses with a diameter of 45 to 55 nm, comprising 72 caps somere and a cyclic double-stranded DNA. This particular to or in Zu The same applies mutatis mutandis to adenoviruses and herpesviruses for this group the DNA virus.  

The antiviral agents of the invention directed against the viruses described herein or are effective, including those directed against these viruses vaccines, verhin Thus, that the corresponding tissues, are virally infected or it to a Vermeh tion of the viral material and thus the formation of the complex of viral Nu nucleic acid and gene products of the genes of the HMGI (Y) family is prevented, which is reflected in the Result leads to the formation of tissue changes is omitted.

In the pathogenesis of the tissue alterations described herein, a Binding of gene products of viral nucleic acid with gene products of genes of HMGI (Y) family and their derivatives, and consequently the influence of the increase viral transforming proteins. As a result of the different antiviral agents This interaction is ultimately prevented or at least reduced.

Herein, binding of a gene product of genes of the HMGI (Y) family or their deriva to viral nucleic acid or to the gene product of viral nucleic acid, in particular a include any interaction of the molecular species involved, which results in the components forming the complex no longer serve as individual components but the complex is the only perceptible component, but what does not exclude that individual components are still present in unbound form. Such a bond includes, for example, interaction by electrostatic attraction forces, van der Wals forces, hydrophobic interactions, hydrogen bonds and Disulfide bridges and combinations thereof. Such a complex comprises at least the both gene product species, d. H. a gene product of the viral nucleic acid and a gene pro can gene of the HMGI (Y) family, which can interact directly with each other but also additionally comprise a nucleic acid, wherein also in this case a direct Interaction of the two gene product species, but not necessarily two se must take place.  

In that regard, one aspect of the invention also relates to a vaccine against transforming Vi used in the prevention and / or treatment of the tissues described herein changes is suitable.

Basically, all of the agents disclosed herein are for both therapy and pre tion of tissue changes of the type described herein. Most notably beneficial for prevention are those agents which are a vaccine against the herein include described viruses, thus the previous unsatisfactory therapy and pre make obsolete concepts with their not inconsiderable risk potential. there It is especially noteworthy that the use of vaccines for the body especially Gentle, as usually associated with relatively fewer side effects.

The production of vaccines against viruses is well known in the art and, for example. described in Modrow, S .; Falcon, D .; Molecular Virology, Spectrum, Akad. Verl., 1997.

For vaccines, there are basically several types known, namely live vaccines, The virus capable of replication contain vaccines from inactivated virus, the viruses are in no longer replicable form, split vaccines, only from those for the Immunization consist of important components of the virus, also called subunit vaccine or Designated antigenic vaccines, and so-called "synthetic antigenic vaccines". All vorer Such vaccine forms may be used in the context of the present invention.

Live vaccines contain replicable virus strains that have specific protection but cause no disease in healthy animals. A live vaccine can either from homologous (similar) or heterologous (alien) virus strains herge be presented. As homologous vaccines can be naturally derived or artificially herge strains of a virus were used.

Naturally obtained vaccine virus strains originate from field strains that only have one have weak or no virulence more, so in healthy animals no disease  cause more, but increase in the host and promote the formation of immunity ken.

A subgroup of live vaccines concerns the artificially attenuated, attenuated Tribes. They are derived from well immunizing, fully virulent field viruses, that after a more or less large number of passages, preferably in cell cultures, be artificially cultivated, thereby giving their. Losing virulence for the natural host. The Virulence loss in such a passing virus population does not occur at all at the same time Virus particles. By certain selection methods but you can attenuated Viru spiegelgut isolated (eg plaque method, final dilution method, etc.).

Attenuation is a targeted weakening or abolition of virulence a replicable virus for a given host while preserving the Vermeh viability, antigenicity and immunogenicity, over a given generation The result remains constant.

Attenuation may be a modification or a mutation in terms of loss of the ill making properties, here in this case in particular with regard to the transfor mating properties. It is correspondingly more or less stable. While you are in the past for artificial attenuation of virulence mainly passages in animals or hatching eggs, attenuated strains are mainly obtained from cell cultures over permanent passages.

Live vaccines from heterologous virus strains can then provide immune protection, if there are very close immunological relationships between species-different viruses exist. You can then as a vaccine strain the related heterologous and therefore not use pathogenic virus strain.

Live vaccines have advantages and disadvantages. On average, a better and better will be with them achieved longer-lasting immunity. A well attenuated vaccine virus can enhance the mechanism of immunity  stimulate only when administered in sufficient concentration. The determination of a corresponding sufficient concentration can be achieved by simple routine tests are carried out within the skill of the average person skilled in the art lie. The vaccine protection usually starts after a few days after vaccination. Responsible for this are several processes: interference, interferon formation, fast Ent development of cellular immunity. Another advantage of live vaccines is that they can be applied very easily locally, z. B. orally or by aerosol. This is special In view of the comparatively easy accessibility of the affected tissues or Organ in the case of the tissue changes described herein advantageous because in a sol In this case, end-users can apply a corresponding

Furthermore, according to the present invention ver vaccines from inactivated viruses be used. Virus inactivation is generally the abrogation of the infectiousness of a Virus particle called. In vaccine production specifically, inactivation is meant tion that viruses are artificial, with chemical-physical processes, the ability to multiply is taken without the other activities, in particular the antigenic and immunogenic ability to be adversely affected. For vaccines from inactivated viruses the term "antigenic vaccine" is sometimes found in the literature.

The starting material for these vaccines are virus-containing organs or tissues, but today primarily from cell cultures, purified and highly concentrated Virus suspensions of fully virulent well-immunized virus strains. These are concentrated trated virus suspensions are then inactivated gently by suitable methods. operating room Timal are chemical or physical treatments that use the virus nucleic acid as a carrier proliferation and infectivity, but destroy the protein components of the virus effective components are fair antigenicity and immunogenicity, as little harm as possible, denature or change. Well-proven means are z. As formaldehyde and certain Deter genzien. The physical components are heat and radiation.  

Furthermore, in connection with the present invention, split vaccines can be used used, the antigenic and immunogenic by splitting of viruses Virus components contained in, usually, purified form.

In the enveloped viruses, these are the virus-specific glycoproteins of the lipid-containing envelope len. Specific antibodies against these antigens bind in vivo to the glycoproteins of the Virus, thereby blocking their adhesion function to the cells and thus the infectivity.

The immunizing glycoproteins of enveloped viruses can be detected by the chemical Aufspal Release the virus envelope (certain lipid-dissolving detergents). The virus is losing by spontaneously and completely its infectious properties and then the ge wanted glycoprotein from unwanted components like nucleoprotein, capsid enzyme, Lipids etc. of the decomposed virus material by physico-chemical methods gerei nished, concentrated and processed into a vaccine.

For non-enveloped, nude viruses, split vaccines are important for immunization co-capsid proteins can be developed by those skilled in the art.

Finally, synthetic antigenic vaccines can also be used by genetically engineered processes. About isolation and identification of relevant genes of the virus genome, for example, the capsid protein of the corre sponding viruses are produced by genetic engineering. It is within the capabilities the expert, the corresponding nucleic acid or resulting proteins so far to shorten that only the antigenic determinant or the corresponding epitope as Vaccine component remains. In this sense, the device according to the invention is also to use. The tRNA attached to the gene product of genes of the HMGI (Y) family Germaterial-bound viral nucleic acid can be used, usually after elution be determined to determine which virus, or its nucleic acid, in the training of for the formation of the complex of cells responsible for the tissue changes described herein from viral nucleic acid and gene product of a gene of the HMGI (Y) family.  

After this identification, the inventive device but also for the ready one for the preparation of a composition of the invention for prevention and / or Treatment of the tissue changes described herein essential component ver be used. In this case, a viral nucleic acid or a pool of viral nucleic acids to the device according to the invention, whereupon that viral nucleic acid to the Device or to the bound in this to a carrier gene product of a gene the HMGI (Y) family binds the at least one binding site for the gene product of a Gene of the HMGI (Y) family. Unbound or unspecifically bound viral Nucleic acid is removed, for example by washing the support material with a ge suitable washing solution. Subsequently, the specifically bound viral nucleic acid from Carrier eluted. The nucleic acid thus obtained can then be used to form a viral component used in the compositions of the invention becomes. For example, the viral nucleic acid can be cloned into an expression vector and the expressed viral peptide or protein can be used as a vaccine. alternative For example, the thus-expressed viral peptide or protein, possibly after further intermediate steps known to those skilled in the art for preparing anti bodies are used, which in turn as a vaccine in Mit mit can be used. Related to this is the expressed viral peptide or protein or antibodies directed against it for the production of an agent for Prevention and / or treatment of the tissue changes described herein essential Component.

The same applies to the case of the binding of a gene product of the viral nucleic acid a gene product of a gene of the HMGI (Y) family. In this case, instead of the viral Nucleic acid The gene products of viral nucleic acid, in particular nucleic acid of Kandi data viruses, d. H. those viruses suspected of being causally involved in the development of the herein written tissue changes are added. The specific bin tion and subsequent elution of gene products encoded by viral nucleic acid can then be used directly as a vaccine or further modification or wide ren processing steps are subjected. It can also be provided that the  Vaccines are further purified or mixed with appropriate adjuvants or for the intended use will be handled or prepared in a suitable manner.

Adjuvants may be added to the vaccines, such as complete or untreated complete Freund's adjuvant. Further additives are the experts in this field known.

In general, the agents according to the invention can be present as a pharmaceutical preparation, in addition to at least one of the various agents according to the invention also a suitable Neten pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable Carriers are known to those skilled in the art.

The compositions according to the invention may contain further additives, for example, the stabilization of the co which serve preservation, the modification of the properties of the agent itself, as well as Substances that modify the properties of the agents of the invention include.

Such substances, which themselves modify the properties of the agent according to the invention, For example, in the case of vaccines, adjuvants, such as incomplete or full Constant Freund's adjuvant, his.

The compositions of the invention may further comprise components which they in a for convert the respective desired application form preferred form. So z. In the Case of the formation of the agents according to the invention as aerosols in addition to the actual Means be provided for the aerosol formation required carrier material.

The agent according to the invention can, for example, in the form of a solution or emulsion for intraderm oral, intravenous or subcutaneous injection. Liquid solutions of the invention appropriate means may also be present in infusible form.

Furthermore, the agents according to the invention can be present in lyophilized form.  

Moreover, the agents according to the invention can in principle be used in any phar in pharmaceutically suitable form, including, for example, tablets, dragees, supposito rien, gels, powders.

In the event that the agent includes a vaccine, the vaccine itself may be a complete be virus particles live or attenuated, as well as inactivated or parts thereof, wherein the parts thereof typically have the antigenic and immunological properties of the jewei carry a dead virus. It may be provided that the vaccine a variety verschie or virus particles or antigenic or immunogenic effective parts. The virus party The parts as well as the parts may themselves be in modified form. Such modifications may be formed by, as generally for peptides, proteins that may be glycosylated are known.

The virus particles or parts thereof may be produced by genetic engineering. It is not him Required that the virus particles or parts thereof with the for the emergence of herein be described tissue changes responsible or at least associated viruses is identical. It is crucial that those used in the vaccine or for its production used viruses, including parts thereof, are suitable for the Erkran kung causal agent, d. H. Virus to generate directional immune response and thus the trans verhin forming properties of the agent or virus involved in the pathogenesis countries.

The above applies mutatis mutandis in the event that the vaccine is an antibody includes.

It has been found that the binding site for a gene product of genes of HMGI (Y) - Family or their derivatives on the nucleic acid of the virus a number of structural and Sequence features includes. Basically, for the binding of gene products the HMGI (Y) family, parts thereof and their derivatives, the presence of a - first - AT- rich sequence of importance. AT-rich sequence is not to be understood as  that this forms an exclusive sequence consisting of AT dimers. Rather, it can this sequence can comprise any order of the two bases, which are represented by single or several nucleotides can be interrupted. In addition to this first structure and sequence feature of the said binding sites of the gene products of the HMGI (Y) family still a second AT-rich sequence, which may be similar to the first AT-rich Sequence. Both AT-rich sequences are at a spatial distance relative to each other arranged. This spatial distance results from the spatial dimensions and thus from the secondary and tertiary structure of the HMGI (Y) proteins, d. H. the gene products of genes the HMGI (Y) family. As a result of this secondary and tertiary structure is for a binding of the HMGI (Y) gene product required that the first sequence and the second sequence be relative to each other in a plane on the viral nucleic acid are arranged. Looking at the DNA as a three-dimensional model, so are in the pre-pictorial arrangement as Binding sites acting AT-rich sequences on the viewer respectively turned page. This arrangement is also referred to as "same face". Are these three Structure or sequence features of the viral nucleic acid before, it comes to a special sustained binding of the gene product to the viral sequence, especially in regulatory Regions of the nucleic acid (eg., Promoters and enhancers), there preferably the said Has structural and sequence features. Missing one or more of these sequence or Structural features, binding of a gene product of the genes of the HMGI (Y) family will only weak or not at all.

Conversely, if one looks at the secondary or tertiary structure of the gene products of the gene HMGI (Y) family, there exist three regions, or domains, in a defined Distance apart, the AT-rich sequences have a high affinity have. Successful binding to a nucleic acid thus requires that the AT-rich sequences are arranged at a distance corresponding thereto. These Removal results from the pitch of the nucleic acid, which is usually about 10 base pairs is, with the result that the distance of the AT-rich sequences is usually 10 bases pairs as well as integer multiples up to ≦ 3 of them.  

According to the present invention, in addition to vaccines in general, especially such vaccines substances against the viruses described herein, such vaccines for the invention Means which are directed against a virus mentioned above, the nucleic acid at least one binding site for at least one gene product of genes of HMGI (Y) - Family or their derivatives. Genes of the HMGI (Y) family are good in the art known. The genes of the HMGI (Y) family represent a family of genes that, among others rem, HMGIC, HMGIY and MAG genes. An example of this is the international one Patent Application PCT / EP96 / 00716 and PCT / DE96 / 02494, the disclosure of which content is incorporated herein by reference. It is noteworthy that the binding site on the viral nucleic acid for any of the aforementioned genes or its Gene product is suitable. Herein the term gene product is also intended to designate parts thereof as long as these parts are still suitable to bind a viral nucleic acid. Likewise should the term gene product encompasses the respective derivatives of the gene product which have a modifi cation, as is customary for peptides and proteins, and, for example, deletions and exchanges of the carboxy-terminal portions of the proteins. In particular, the term derivatives of the genes of the HMGI (Y) family also includes those in PCT / DE96 / 02494 described aberrant transcripts and their translation products, as long as they are still able to bind to the viral nucleic acid, especially in re gulatory regions of the nucleic acid (eg, promoters and enhancers) thereof the. The characterization of such aberrant transcripts is described, for example, by Kazmierczak, B. et al. At the. J. Pathol., 1998; 153 (2): 431-5 and their structure, for example, from Schoenmakers, E.F. et al. op.

In an alternative embodiment of the inventive means can be provided that the vaccine is an antibody directed against the virus. It is exhausted if the antibody is not primarily against the virus or a corresponding part directed thereof, but by means of a corresponding cross-reactivity its effect satisfied and accordingly ensures that there is no interaction between the vira len nucleic acid with the gene product of the genes of the HMGI (Y) family comes. It can be provided that the antibody directed against any component of the virus  is, d. H. it may be directed against or interacting with proteins or protein fragments of the viral capsid, the optionally present glycopeptide or else with the corresponding viral nucleic acid or fragments thereof.

The antibody as used in the invention may be a monoclonal antibody or polyclonal antibody. The term antibody herein may include a mixture of different monoclonal antibodies. Further, as used herein, the term antibody is intended to encompass any peptide or protein which has at least one antibody property, in particular binds to a suitable epitope, and does not cause the complex of antibody plus epitope or antigen to be present in any of the pathogenesis of the tissue changes described herein more accessible form is transferred or removed from the pathogenesis process. This can be done, for example, that an interaction of a gene product of a gene of the HMGI (Y) family with the viral nucleic acid or such with a gene product of a viral nucleic acid (the corresponding virus - causally - at the formation of the tissue changes described herein involved) lastly avoided, this prevention can be caused both directly and indirectly, indirectly, for example, by removing the corresponding virus or virus particles. The term antibody also includes antibody fragments and their derivatives, so in particular (Fab) 'or F (ab) ₂ fragments as well as single-chain antibodies and the like. Derivatives of these antibodies are also known to those skilled in the art and include, in particular.

The above applies mutatis mutandis in the event that a vaccine against a virus is intended, whose nucleic acid codes for a gene product, said gene product at least one gene product of genes of the HMGI (Y) family or their derivatives interacts.

The viruses against which a vaccine or an antibody in the compositions of the invention ent belong to the various groups of viruses described herein with theirs different types.  

In the inventive use of the immunizing agent according to the invention, and in particular active immunization, against the viruses involved in the pathogenesis and / or Etiology of the tissue changes described herein are preferred Viruses that are causally associated with the pathogenesis / etiology of the tissues described herein connected or associated.

In the methods of the invention cell cultures are used which are derived from a tissue change or parts of the tissue / tissue constituting it. The Preparation of such cell cultures is known to those skilled in the art and is described, for example, in Stern, C. et al .; Geburtsh. u. Frauenheilk. 52 (1992), 767-772.

Under normal karyotype is to be understood here the set of chromosomes, as he after Application of routine techniques is obtained, provided that in a representation of 500 gangs per haploid set no identifiable anomalies especially of the areas 12q14-15 and 6p21.

An expression vector for a gene of the HMGI (Y) family is characterized in that it belongs to its entirety leads to the expression of a gene of the HMGI (Y) family and thus to Her position of corresponding gene products. Typically, such an expression vector comprises an origin of replication that is responsible for a gene product of the HMGI (Y) gene family or Frag ment encoding nucleic acid, and appropriate transcriptional and translational regulation rende sequences. Such constructs are known in the art and described, for example, in US Pat Winnacker, E.-L .; From Genes to Clones; Weinheim; New York: VCH, 1987.

In principle, any transfection method is within the scope of the present invention applicable, which leads to a transfection of the corresponding cell cultures.

The production of cDNA is known to those skilled in the art. For the comparison of the RNA or cDNA pattern of the transfected cells or cultures with that of non- transfected cells or cultures is typically done as under the method  the so-called "differential display" (Diatchenko, L .; Proc. Natl. Acad. Sci. USA, Vol. 93, pp. 6025-6030, 1996).

When checking in the transfected cultures over control cultures expri mated or amplified expressed RNA (s) by sequence homology to the presence Viral elements is typically operated so that the sequence with the aid of from relevant databases, eg. B. BLAST, a database service of the National Center for Biotechnology Information (NCBI), reviewed or identified where appropriate.

It is within the scope of the process of the invention that also by the primary transcript Nucleic acids derived from it are the comparison of the RNA pattern of the transfi ornamented cultures can be used with that of control cultures. Ent speaking, it is possible to make this comparison on the basis of the cDNA pattern, wherein the cDNA is derived from the transcription products, i. H. the RNA species using known methods.

The control cultures are usually those with normal karyotype derived from a tissue or part of a tissue used in a tissue described herein change, which are transfected with an expression vector, however the gene of the HMGI (Y) family or its derivative, d. H. coding for a gene product Insert, missing. However, control cultures can also be those that do not have any expression vector are transfected.

In a further method according to the invention, in which the execution of a PCR Assays are provided, with the probe used for the PCR being a viral probe the PCR test according to the methods known in the art. Under PCR test, a poly merase chain reaction test understood in which at least one sequence-specific primer is used for selective amplification of the desired nucleic acid (fragments). (please refer Newton, C.R .; Graham, A .; "PCR"; 1994, Spektrum Akadem. Publisher, Heidelberg, Berlin, Oxford.  

By primer or viral probe herein are meant oligonucleotides and / or nucleic acid fragments understood to be directed to a detection of nucleic acids containing a Homology to the primer / probe. The preparation of such viral probes can be done in any way known to those skilled in the art, such as by organic chemi synthesis or using PCR or cloning techniques.

Is in the context of a method according to the invention a cDNA library of a Ge web variation, as described herein, or a part thereof, the one Activation of a gene of the HMGI (Y) family or a derivative, the Ak be identified by a corresponding chromosome aberration.

In the methods of the invention, screening is typically under conditions low stringency. Under conditions of low stringency should be understood be that by lowering, for example, the hybridization temperature or modification the washing conditions (eg increasing the salt concentration) also bind to such Nucleic acids are made whose homology to the sequence of the probe is markedly reduced where at first, a detection of false-positive nucleic acid sequences accepted will, as a final clarification whether it is a positive signal or result, by sequencing and sequence analysis of the identified sequences, and thus permits excretion of the false-positive sequences.

In the method according to the invention, by comparison of the RNA or cDNA pattern of transfected cell cultures with that of control cultures, or by a positive signal in a PCR test using primer (pairs), the Sequen viral nucleic acids, or by a positive signal when screening a cDNA library with a virus-specific probe, or by analysis of the cDNA clones on viral sequences or comparison with a normal mesenchy cDNA library or epithelial tissue if necessary, it has been found that viral elements are as described herein described tissue changes or derived therefrom cell cultures  are, further provided that the viral elements identified and / or classified and used exclusively for vaccine production.

The device according to the invention for determining a pathogenesis involved Virus comprises a gene product of genes of the HMGI (Y) family that bind to a carrier that is. In connection with the device according to the invention as well as their possible Uses, the term gene product also includes parts of the gene products or derivatives of Gene products. The definition of gene products is also defined above based on genes of the HMGI (Y) family.

The gene product is coupled to a support material, which is known to those skilled in the Ge area is selected accordingly. Suitable carrier materials are all those materials which allow binding of proteins or derivatives, either directly or indirectly. suitable Support materials are typically found in the field of chromatography materials. Such a bond may also be an adsorption or a reversible bond. Because it the gene products of the HMGI (Y) family are proteins which can be the subject In the art, methods and compounds for immobilizing Pro are known be used.

With regard to the design of the gene product bound to the carrier material or Genial products is essentially to pay attention that the area to the support material or is available for binding viral nucleic acid available for the Bin responsible for the viral nucleic acid. In that regard, the corresponding Genpro be shortened or, for example, be provided as a fusion protein. Anything Construct is conceivable, provided that the nucleic acid-binding part of the gene product or that part of the gene product of the genes of the HMGI (Y) family which is responsible for the binding of the Gen product of the viral nucleic acid is responsible, nor for a binding of a Nu is available.  

In the specific case, such a device may be designed so that it is at an affinity chromatographic column, corresponding to the column material at least one gene product of genes of the HMGI (Y) family, be it from a gene pro or different gene products, is immobilized and different approaches or also mixtures of viral nucleic acid or gene encoded by viral nucleic acid product are added to the carrier matrix. As a result of the interaction between the Gene product and the viral nucleic acid or the gene product of the viral nucleic acid it comes to the formation of a stable complex. Non-specifically bound viral Nu nucleic acid or unbound nucleic acid or non-specifically bound or unbound denes gene product of viral nucleic acid and other components of the applied Sample are washed from the column. By a suitable elution buffer so then - possibly specific - the interactions between the gene product and the to the Gene product bound viral nucleic acid or the bound gene product of the viral Nucleic acid is reduced so that the corresponding viral nucleic acids or those of these coded gene products can be eluted and further analyzed.

The invention will be elucidated by the following examples, experimental findings and figures further explained. It shows

Fig. 1 shows the size distribution of normal karyotype fibroids (gray columns) as well as 12q14-15 aberrations (black columns);

Fig. 2 is an overview of the vectors used in Example 4;

3a-c show a sequence comparison of different sequences from myoma tissue with ade noviralen sequences.

Figure 4a-b is a comparative analysis of various Se obtained from myoma tissue Se;

Fig. 5 HMGI (Y) binding sites in the promoter sequence of the adenoviral protein E1A; and

Fig. 6 shows the result of a PCR analysis, with the presence of an adenoviral DNA fragment was examined in various tissue changes.

example 1

The results of previous cytogenetic studies on uterine fibroids are contradictory regarding possible correlations between tumor size and the occurrence of clonal Chromosomal aberrations. The problem of these studies, however, is that the investigated Tumors possibly z. B. are selected by size. Since the question of a possible Kor relation but also depends on whether the chromosome aberrations secondary on and increase the growth potential of the affected tumors, was a study unselected fibroids performed. Only fibroids according to Hysterek were examined tomie, where all tumors were examined, which by palpation of the surgically ent distant uterus were detectable.

A total of 155 fibroids from 96 patients were cytogenetically examined. Showed 28% of myomas clonal karyotype changes. On the three main karyotype groups with normal karyotype, aberrations of the chromosomal region 12q14-15 and deletion of the lan Genes of chromosome 7 accounted for 72%, 12%, and 8%. The average tumor size Table 3 shows the groups.

Tab. 3 Average myoma size in the three major karyotype groups with 12q14-15 aberrations, deletions of the lye arm of chromosomes 7 and normal karyotype

Karyotype group average size [cm] ± standard deviation [cm] normal karyotype 3.4 ± 2.1 12q14-15 aberrations 8.9 ± 5.6 Deletion of chromosome 7 3.5 ± 2.0

The results clearly show that the occurrence of 12q14-15 aberrations, which correlate molecularly with mutations in or in the region of the HMGIC gene, is accompanied by a highly significant increase in the size of the corresponding fibroids when compared either with normal karyotype fibroids or with Deletions on the long arm of chromosome 7 are compared. The differences become clear not only when comparing the mean values, but also the distributions of the tumor sizes of the individual tumor groups, as shown in FIG. 1.

In summary, the appearance of chromosome aberrations of the chro 12q14-15, associated with enhanced expression of HMGIC gene or ex associated with altered transcripts of this gene, to an enhanced tumor wax tum.

Example 2

Mutations in the region of the HMGIC or HMGIY gene manifest themselves cytogenetically by chromosome aberrations of the region 12q14-15 and 6p21, respectively. At least theoretically but it is quite conceivable that the cytogenetically recognizable aberrations are only "the tip of the Iceberg "and represent a much larger part of the mutations of the two Gene is associated with cytogenetically avenceable chromosomal alterations. Would this In the case, it could be a key role of the said aberrations in the tumorent overall as a primary mutation. A method for after One of the "hidden" rearrangements is fluorescence in situ hybridization (FISH). It was tested on a series of 40 fibroids with an apparently normal karyotype FISH- Carried out experiments using cosmid and PAC probes carrying the Lo coverage of the HMGIC or HMGIY gene. The probes were chosen  a range of about 150 kb 5 'to 40 kb 3' from the HMGIC gene and from 30 kb 5 'to 40 kb 3 'from the HMGIY gene. All myomas were using the probes for both Genes examined; at least 20 metaphases were analyzed. In no case erga there is evidence of conventional cytogenetics unrecognizable, ver revealed chromosomal rearrangements of the examined areas.

Considering the frequency of fibroids without apparent cytogenetic changes conditions (see Example 1) and the results of the studies presented in this example, It is likely that the mutations of the genes of the HMGI (Y) family in the majority the uterine fibroids plays no key role.

Example 3

Regardless of whether these changes are primary or secondary, molecular assumed genetic basis of 12q14-15 and 6p21 aberrations in uterine fibroids, that it is due to the chromosomal rearrangements to an expression / enhanced expression or an expression of aberrant transcripts of the HMGIC gene or HGMIY gene, which is absent in normal uterine tissue. For the HMGIC gene is by means of an RT-PCR in nor Malignant uterine tissue usually no HMGIC gene expression detectable. There were investigated with this method 40 myoma tissue with apparently normal karyotype. aim The investigation was again to determine whether in these fibroids, as in those with 12q14-15 changes, evidence of HMGIC gene expression.

In none of these fibroids were indications of expression found, so that out From these results it can be concluded that in the formation of these fibroids HMGIC gene expression is not the primary event.

Example 4

To study the effect of HMGIC on the SV 40 promoter, two vector systems are transfected into a cell. These are the expression vector H ₃ H _x for HMGIC and the "pGL3 luciferase reporter vector" from Promega. The complete "pGL3 Luciferase Reporter Vector" system from Promega comprises 4 different vectors that allow DNA sections to be examined for promoter or enhancer regions. These vectors are shown in FIG . To study promoter sections, the vector "pGL3 enhancer" is needed. The vector "pGL3 promoter" is intended for the study of enhancer elements. Furthermore, the vector "pGL3 promoter" is used in this experiment to test the mode of action of HMGIC on an SV40 promoter or promoters of other polyomaviruses. For this purpose, the vector H ₃ H _{x is} cotransfected with the vector "pGL3 promoter".

The vector "pGL3-Control" serves as a positive control for the system, a transfection finally with the vector "pGL3 promoter" as a negative control.

The individual vectors have the same except for promoter and enhancer elements Basic structure. They have a modified coding region for fireflies Luciferase (Photinus pyralis) (luc +), which is used to study transcriptional activity in transfected eukaryotic cells. Furthermore, they contain a pro karyotic origin of replication for propagation in E. coli, an ampicillin resistance gene for the selection, an origin of replication of filamentous phage (fl ori) for the products single-stranded DNA (ssDNA) and a multi-cloning site (MCS) 3 'and 5' of Lucife rase gene.

The "pGL3 promoter" vector is 5010 base pairs in size and contains in contrast to "pGL3 enhancer" an SV40 promoter and no enhancer. DNA fragments ver contain apparent enhancer sequences, 3 'or 5' of the luciferase gene can be used and thus lead to reinforcement. Furthermore, the SV40 promoter can by replaced by the polyomavirus promoters.

The vector "pGL3-Control" (5256 base pairs) contains an SV40 promoter and an En hancer sequence, which leads to a high expression of luc + in most mammalian cells.  

This vector is used to control transfection efficiency and sets the internal standard for the promoter and enhancer activity of the other vectors.

For the study, HeLa cells have proved to be suitable because they are very easy to handle the process of transfection with virtually no damage and no Expression of HMGIC (which was the absence of HMGIC expression detected by "Northern Blot"). The cells are transfected into plates with 6 Wells used.

For the process of transfection, 2 μg DNA with cell medium (TC 199), excluding calves serum and antibiotics, mixed (both can interfere with complex formation), final volume 100 μl.

10 μl of "SuperFect" are added to the DNA mixture. After mixing, incubate for 10 min at room temperature, with complexes of the DNA and the "SuperFect" form.

During the incubation the old medium is aspirated from the cells and the cells are rinsed with 1 × PBS. The mixture of "SuperFect" and DNA is mixed with 800 μl of cell medium containing 20% calf serum, which is then added to the cells. After incubation (in the incubator at 37 ° C. and 6% CO ₂ ) for 16-18 hours, fresh medium (20%) is added and the mixture is incubated for a further 8-32 hours.

The evaluation of the experiment is carried out with the "Luciferase Assay Kit" from Stratagene (see below).

Luciferase extraction and determination of luciferase concentration

After incubation of the transfected cells, the medium is aspirated and 500 μl 1 × Cell lysis buffer added. After 15 minutes incubation, at room temperature on a  Shakers, lysing the cells. The cell lysate is transferred to Eppendorf cups. This is for for a short time at 4 ° C storable. For a long time it can be stored at -80 ° C, this however, up to 50% of the luciferase activity is lost.

For the determination of the luciferase concentration, 20 μl of cell lysate are mixed with 100 μl of "luciferase assay reagent" (LSA) (both should be at room temperature). The luciferin in the reaction mixture is reacted under ATP consumption to produce light quanta.

Luciferase substrate (luciferin) + ATP + O ₂ → light (560 nm) + oxyluciferin + AMP + PP _i

The emitted light quanta can be measured with a photocell of a luminometer become. The values determined are in relative light units (RLU) given and convey in relation to other values information about the educated Amount of luciferase.

Results

So far, two separate series of measurements were performed. Further measurements, before all things with promoter regions of the BK and JCV viruses can be made easily be in the present test system by cloning the corresponding promoter regions into the test vectors.

The results of the first 2 series of measurements are summarized in Table 4.  

Table 4

Results of transfection experiments

The measurement results are above those of the negative control and among those of the positive con troll with a very strong promoter, indicating a slight regulation of the viral promoter region occupied by HMGIC.

This demonstrates the involvement of viruses in the genesis of Leiomyomas, endometrial polyps and endometriosis.

The features disclosed in the foregoing description and in the claims Invention can be used individually as well as in any combination for the realization be essential to the invention in its various embodiments. The Offenba content of the claims is hereby incorporated by reference.  

Example 5

This example shows the results of a PCR test that was performed de to search for adenovirus-specific DNA sequences in myoma tissues. there are for all 6 subgenera of the adenovirus specific oligonucleotides for amplification of viral DNA sequences available.

Using the PureGene kit (Gentra company, German sales Biozym) was DNA isolated from 16 fibroids, 6 cell cultures of fibroids, 1 myometrium and 2 blood samples.

DNAs from 8 fibroids, all 6 cell cultures, myometrium and blood samples were used in a PCR. The oligonucleotide pairs HsgA1 (SEQ ID No. 1: aaggtgtcaatyatgtttg) / HsgA2 (SEQ ID NO: 2: acggttacttkttt) and HsgB1 (SEQ ID No. 3: tctattccctacctggat) / HsgB2 (SEQ ID No. 4: actcttaacggcagtag) were used. from the sequence of the hexon gene, each amplifying adenovirus DNA of group A or B (Pring-Akerbol et al., J. Med. Virol. 58, 87-92, 99). The oligonucleotide pair HsgA amplifies a fragment of 299 bp, the oligonucleotide pair HsgB a fragment of 465 bp. The positive controls used were virus DNA samples of the adenovirus subgenera A (Ad18) and B (Ad7), which were used by Dr. med. Patricia Pring-Akerblom, Hannover Medical School, Institute of Virology and Disease Hygene, 30623 Hannover. The following PCR approach was used:
500 ng of DNA (myomas / blood) or 50 ng of viral DNA
1.5 mM MgCl ₂
0.5 μM each primer
5 μl 10 × PCR buffer without MgCl ₂ (Sigma)
200 μM dNTP
2.5 U Taq polymerase (Sigma).

Each batch contained 50 μl total volume. The following cycles were carried out:
1 × 6 min 95 ° C
40 × 40 sec. 92 ° C
30 sec 41 ° C
40 sec 72 ° C
1 × 5 min 72 ° C.

The entire batch was applied in a 1% agarose gel.

Fig. 6 shows the result of the PCR analysis for testing for possible DNA sequences of adenoviruses with consensus primers of group B. With the exception of the virus control DNA could be detected with primer pair HsgA no amplification of the 299 bp fragment who the. With primer pair HsgB, four DNA fragments of uterine leiomyomas (My178.1; My174.3; My174.4; My161.7) (cell culture and primary tumor tissue) and control viral DNA (human adenovirus 7) amplified the 465 bp fragment detected. Neither from blood DNA nor from DNA from normal myometrium from a uterus myomatosus (My187.6) or the investigated lung hamartomas (H) a corresponding product was amplified. M5 denotes a marker (DNA standard V, Roche, Penzberg), arrow: position of the specific 465 bp fragment. Thus, the detection of viral DNA sequences of the adenovirus type B could be clearly demonstrated in the myoma tissues.

Example 6

To further characterize the PCR products, they were transformed into a suitable vector cloned and sequenced from the vector from both sides. For this purpose, starting from the Results of the PCR analyzes (see Example 5) corresponding to the 465 bp amplificate DNA (6 fragments from 6 myoma DNA samples and 1 fragment from virus control DNA Ad7) using the QIAEX II kit (Qiagen, Hilden, Germany) according to the manufacturer (QIAX II Handbook Edition August 1996, p. 12-13) eluted from the agarose gel. Further  became a larger fragment amplified from the DNA My174.3 (Comp. Ex. 5), eluted. In the following step, the purified DNA was inserted into the vector pGEM-T Easy (Prome ga, Madison, USA) according to the manufacturer's instructions (Technical Manual pGEM-T and pGEM-T Easy Vector Systems, p. 11) and the vector construct is cloned in E. coli (Technical Manual pGEM-T and pGEM-T Easy Vector Systems, p. 12-13). Plasmid DNA positive bacteri Enclones were made by manufacturer using this QIAprep kit (Qiagen, Hilden, Germany) (QIAprep Miniprep Handbook, April 1998, p. 18-19). The sequence tion of the cloned inserts was carried out using the oligonucleotides M 13 universal and M 13 reverse and with the aid of an automatic sequencing unit (373 Applied Biosy stems, Weiterstadt, Germany). The comparative analysis of the sequences was done with Hil The information from the National Center for Biotechnology (NCBI) of the Na tional Institute of Health databases published on the Internet (access: http://www.ncbi.nlm.nih.gov/) and search methods (Advanced BLAST, database "nr" without Indication of a particular species).

Results: The amplified sequences from all tumors and tumor cell cultures correspond (with some deviations, see Fig. 3, Fig. 4 and Table 5) to the 465 bp PCR fragment of the positive control. The sequence obtained from the analysis of the larger fragment of the amplicon from My174.4 revealed no match to a viral sequence in the comparative analysis.

Table 5

Thus, it was shown that the viral sequences that amplify from the individual fibroids were most similar to the sequence of the adenovirus type 7 and to each other can be distinguished from point mutations.

Explanations to Fig. 3a-c, Fig. 4a-b and Table 5

The comparative analysis of the DNA and protein sequences revealed evidence of high homology of the sequences amplified from the myoma tissues to published sequences from the hexon region of the adenovirus type 7. The individual DNA sequences 10875 00070 552 001000280000000200012000285911076400040 0002019943786 00004 10756 have point mutations and differ among themselves. With the exception of a point mutation leading to an amino acid change in the protein sequence of M 8-2, all other mutations turn out to be so-called silent mutations. The sequence differences are each Weil in the figures Fig. 3a-c marked by boxes. Nomenclature used: X765551, AF 065068, AF 65065: published sequences of adenoviral hexon genes, M3-3P: positive control (see Example 5), M 2-3, M5-1, M6-1, M7-1, M8- 2, M 9-2: different sequences of amplicons from myoma tissue.

Figure 4a-b shows a comparative analysis of all DNA sequences obtained from the different myoma tissues. The distinctions are marked by boxes. The nomenclature used corresponds to that of Fig. 3a-c.

Example 7

HMGI (Y) proteins can influence the expression of viral proteins by binding to viral promoters. From the published sequence of the promoter of the gene E1a (accession number X03000 or NCBI database; E1a is an adenoviral gene whose gene product is assigned a transforming function) and by means of published data on the binding modality of HMGI (Y) to DNA sequences (cf. Yic et al., Molecular and Cellular Biology 17: 3649-3662, 1997) examined whether HMGI (Y) can bind to the promoter sequence. Proteins of the HMGI-Y group contain three binding domains, two of which can bind in parallel to DNA sequences consisting of a sequence of at least 4 adenines and thymidines. These DNA sequences are ideally 10 or 20 base pairs apart, since the binding HMGI-Y proteins can span 1-2 helical turns of the DNA due to the location of the binding domains (Yie et al., Molecular and Cellular Biology, 17: 3649 -3662, 1997). If HMGI-Y binds proteins to cellular or viral promoters in the manner described, the promoter-mediated effect is modified in terms of activation or inhibition. Sequence comparison using databases published via NCBI (see Example 6) identified the promoter sequence of the adenoviral protein E1A (accession number X03000, nucleotide 1-511, source: AD7). Numerous binding sites for HMGIY proteins were determined on the basis of the described criteria (cf. FIG. 5). By way of example, two of these identified binding sites, which can be bound in parallel by two binding domains of an HMGI-Y protein, have been joined by a clamp.

It was shown that HMGI-Y can bind proteins to the promoter sequence.

Example 8

Using the NCBI-published sequence of the left end of AD7 (accession number X 03000), the oligonucleotides ADE1Bg12S: (SEQ ID NO: 5): gaa gat ctt tat aga tgg aat ggt gcc aac at and ADE1Hi3AS (SEQ ID NO. NO 6): ccc aag ctt aaa act ctt ctc gct ggc agt c selected which can bind to the promoter sequence of the A1 adenovirus E1A gene. The oligonucleotide ADE1Bg12S contains a Bgl II site and the oligonucleotide ADE-Hi3AS contains a HindIII site. Both interfaces are underlined in the above sequence. Using the oligonucleotides, a 521 bp fragment from the AD7 promoter region was amplified and cloned via the BglI and HindIII sites by standard methods (Maniatis) into the luciferase reporter vector pGL3 enhancer (Promega) (pAD7PROM). The template (template) used was the AD7 DNA, which had already served as positive control in Example 5. The amplified fragment then functions as a promoter for the present in the vector Firefly luciferase gene, sen activity by a luciferase assay (dual-luciferase reporter assay system, Promega) is measurable. Co-transfection of the above construct with an HMGIC expression vector (H3HX) into both Hela cells and primary myometrium cells from the 1st passage of tissue culture revealed evidence of modification of E1A promoter function by HMGIC. All transfections were performed with the Superfect according to the protocol of Qiagen. In contrast to the original protocol, 1 μg of the respective constructs were used in each case and the cells were not washed with PBS. The incubation was prolonged from a few hours to an overnight incubation and after this wur de de superfect not removed, but added 3 mL of medium to the cultures. It was thus shown that the expression of the transforming adenoviral protein E1A is influenced by the binding of HMGIC proteins in the viral promoter region. As ne gativ controls two more co-transfections were performed, once the expression vector contained no cloned HMGIC sequence and in addition was transfek animals without the addition of the HMGIC expression construct. The positive control was the pGL3 control vector containing an SV40 promoter and SV40 enhancer. To rule out inaccuracies in cell culture, such. B. different number of cells per cell culture peel, different efficiency in transfection and cell lysis, the activity of experimental reporter construct (see above) by co-transfection with an internal pRL control vector (pRL-TK, Renilla luciferase) normalized. The Lucifera se measurements were carried out according to the protocol of the "Dual Luciferase Reporter Assay System" from Promega.

Example 9

Another example of the induction of tissue changes by the infection of the Tissue cells with adenoviruses are the pulmonary hamartomas. This example describes the Strategy for the verification and detection of adenoviral genomes in different Lungenhamartomgeweben.

Using the PureGene kit (Gentra company, German sales Biozym) was DNA isolated from 10 cell cultures of hamartomas.

DNAs from 7 cell cultures were used in a PCR. The Oligonu were used Nucleotide pairs HsgA1 / HsgA2, HsgB1 / HsgB2, HsgC1 [(SEQ ID NO: 7): acctttgactcttctgt)] / HsgC2 [(SEQ ID NO: 8): tccttgtatttagtatc], HsgD1 [(SEQ ID NO: 9): ccat catgttcgactcct] / HsgD2 [(SEQ ID NO: 10): aggtagccggtgaagcc], HsgE1 [(SEQ ID NO: 11): gactcttccgtcagctgg] / HsgE2 [(SEQ: ID: NO.12): gctggtaacggcgctct] and HsgF1 [(SEQ ID. No. 13): atttctattccttcgcg] / HsgF2 [(SEQ ID No. 14): tcaggcttggtacggcc], from the sequence of Hexon gene, which in each case amplify adenovirus DNA of groups A to F (principle Akerblom et al., J. Med. Virol. 58, 87-92, 99). Oligonucleotide pair HsgA amplifies Fragment of 299 bp, oligonucleotide pair HsgC of 269 bp, oligonucleotide pair HsgD of 331 bp, oligonucleotide pair HsgE of 399 bp and oligonucleotide pair HsgF of 586 bp. The Virus DNA samples used as controls were also analyzed by Dr. Ing. Pring- Akerbloom (see Example 5: Subgenus A: Ad18, Subgenus B: Ad7, Subgenus C: Ad1, Subgenus D: Ad17 :, Subgenus E: Ad4 :, Subgenus F: Ad41).

The following PCR approach was used:
500 ng DNA (tissue, cell culture) or 50 ng virus DNA
1.5 mM MgCl ₂
0.5 μM each primer
5 μl 10 × PCR buffer without MgCl ₂ (Sigma)
200 μM dNTP
2.5 U Taq polymerase (Sigma)

Each batch contained 50 μl total volume. The following cycles were carried out:
1 × 6 min 95 ° C
40 × 40 sec. 92 ° C
30 sec 41 ° C
40 sec 72 ° C
1 × 5 min 72 ° C.

The entire batch was applied in a 1.5% agarose gel. With the oligonucleo HsgA1 / HsgA2, HsgB1 / HsgB2, HsgC1 / HsgC2 and HsgF1 / HsgF2 did not become Frag ment of the expected length from the various lungharmartoma DNA samples be amplified, wherein the corresponding fragment of the viral control DNA ampli was fiked. DNA samples from 3 lung hamartomas were probed with the oligonucleotides amplified the HsgD1 / HsgD2 a 331 bp fragment. From 4 other pulmonary hamartoma DNA samples became a 399 bp product with the oligonucleotide pair HsgF1 / HsgF2 amplified.

Thus, it was clearly shown that an infection of the original cell with adenoviruses he Group D or E leads to the formation of lung hamartomas.

Example 10

To examine whether pulmonary hamartoma cells can be permissive in vitro Hela cells cocultivated with cells of a lung hamartoma. Hela cells are often used for the multiplication of adenoviruses used and show after infection cytopathological Ef fect.  

The hamartoma tissue used was from a tumor with a chromosomal translocation t (6; 14) (p21; q24). After surgery, it was stored in Hank's solution at room temperature for 26 hours and then shredded with scissors and scalpel into approximately 1 mm ³ cubes. After routine methods, further fragmentation with collagenase was then carried out enzymatically (Kazmierczak et al., Oncogene, 12: 515-521). The resulting cell suspension was distributed to four 25 cm ² cell culture flasks each prefilled with 5 ml of cell culture medium (medium 199 with 20% fetal calf serum with the addition of antibiotics). After three days of cultivation at 3 ° C, 5% CO ₂ , a confluent monolayer had formed in the bottles. The cells were then detached according to standard procedures with trypsin / EDTA solution and distributed in each case to two new culture bottles. After two hours, about 3 × 10 ⁵ Hela cells in 1 ml of culture medium were added to the culture bottles. After one day of culture, the bottles each contained about 50% of Hela cells and fibroblast-like hamartoma cells. The serum concentration in the medium was reduced to 10%. After two more days, the Hela cells showed changes in the cell morphology in several places and began to detach elliptical cells from the bottom of the culture vessels. After four days, only single groups of Hela cells were detected, but they proliferated.

The cytopathic effect that has occurred may be due to hamastoma permissive for adenoviruses cells that have infected Hela cells.

Those disclosed in the foregoing description, claims and drawings Features of the invention can be used individually as well as in any combination for the Implementation of the invention in its various embodiments essential.

Claims (37)

1. Means for the prevention and / or treatment of a tissue change, wherein the tissues Variation of tissues of mesenchymal origin and the agent has an anti-viral effect Sames agent which is active against a virus whose nucleic acid at least one Binding site for a gene product of genes of the HMGI (Y) family or their derivatives includes. 2. Means for the prevention and / or treatment of a tissue change, wherein the tissues Variation of tissues of mesenchymal origin and the agent has an anti-viral effect which is active against a virus whose nucleic acid is a gene product  coded at least with a gene product of genes of the gene product HMGI (Y) family or its derivatives interacts. 3. Composition according to claim 1, characterized in that the binding site on the nucleic acid of the virus comprises the structural and sequence feature of a first AT-rich sequence. 4. Composition according to claim 3, characterized in that the binding site on the nucleic acid of the virus in addition to the first sequence nor the structural and sequence features comprises that

• a second AT-rich sequence is present, and
• - The first and second sequence are arranged at a spatial distance from each other.

5. Means according to claim 4, characterized in that the spatial distance is selected is that the first sequence and the second sequence relative to each other in a plane on the Nucleic acid are arranged. 6. Composition according to one of claims 1-5, characterized in that the genes of HMGI (Y) family MAG genes, HMGIC, HMGIY, aberrant transcripts of genes of HMGI (Y) family and derivatives thereof. 7. Composition according to one of claims 1-6, characterized in that the tissue mesen of chymal origin is at least partially infected with a virus. 8. Composition according to one of claims 1-7, characterized in that the Gewebeverände as an exclusive or obligatory constituent of tissue, at least some of which  the tissue-building cells with a virus according to any one of the preceding Ansprü are infected. 9. Composition according to one of claims 1-8, characterized in that the Gewebproliferati on a proliferation of at least one mesenchymal cell with a virus after one of the preceding claims. 10. A composition according to claim 9, characterized in that the proliferation of a clonal Pro Liferation is. 11. Composition according to one of claims 1-10, characterized in that the tissue prolif ration comprises an epithelial component. 12. Composition according to claim 11, characterized in that the epithelial component min at least one cell containing a virus according to any one of the preceding claims is infected. 13. Composition according to one of claims 1-12, characterized in that with a virus according to any one of the preceding claims infected cell a chromosomal change having. 14. Composition according to claim 13, characterized in that the chromosomal change at least one HMGI (Y) gene of the infected cell. 15. Composition according to claim 14, characterized in that the HMGI (Y) gene from the Grup pe is selected, the MAG genes, HMGIC, HMGIY, aberrant transcripts of genes of HMGI (Y) family and derivatives thereof.   16. Composition according to one of claims 1-15, characterized in that the tissue structures is selected from the group, the leiomyomas, in particular leiomyomas of the uterus; endometrial polyps; endometriosis; Fibroadenomas, in particular fibroadenomas of Mam ma; Phyllodes tumors, especially mamma; Hamartomas, in particular the mamma; Prostate adenoma; lipomas; aggressive angiomyomas; enchondromas; pleomorphic adeno mem, in particular the salivary glands; Colonic polyps, especially colon adenomas; Hamartomas, especially the lungs; Atheroma and resulting carcinomas includes. 17. A composition according to claim 16, characterized in that the resulting carcinomas of the group comprising colon carcinomas and prostate carcinomas. 18. Composition according to one of claims 1-17, characterized in that the virus out is selected from the group comprising DNA viruses, and in particular adenoviruses and herpesviruses, includes. 19. Composition according to one of claims 1 to 18, characterized in that the agent of is selected from the group, the vaccines; Antibody; Agent replication, Tran inhibition of scripting or translation of viral, especially adenoviral, genes; Means that with Detect and / or destroy viruses, especially adenoviruses, infected cells; and means, which achieve an antiviral effect by their effector cell-stimulating effect summarizes. 20. Composition according to claim 19, characterized in that the vaccine is an antibody which is directed against the virus or a part thereof. 21. Composition according to claim 19, characterized in that the vaccine is a virus particle or part thereof according to any one of the preceding claims.   22. Composition according to claim 20, characterized in that the antibody is selected from the group containing monoclonal antibodies, polyclonal antibodies, polyvalent antibodies, Antibody fragments and derivatives thereof. 23. Use of the agent according to any one of claims 19 to 22 for immunization against Viruses that interfere with the pathogenesis and / or aetiology of tissue changes according to one of preceding claims are connected. 24. Use of the agent according to any one of claims 1-23 for the preparation of a pharma ceutical composition comprising the agent according to one of the preceding claims and a pharmaceutically acceptable carrier for the prevention and / or treatment of Tissue changes according to one of the preceding claims or for immunization against viruses that interfere with the pathogenesis and / or etiology of tissue alterations one of the preceding claims are connected. 25. Use according to claim 23 or 24, characterized in that the immunization is an active immunization. 26. A method for determining viruses suitable for the preparation of a composition for the prevention and / or treatment of tissue changes according to any one of the preceding claims and / or for detecting viruses, against which the agent is directed according to one of the preceding claims, comprising the steps :

• a) transfection of a normal karyotype cell culture derived from a tissue comprising the tissue alteration according to any one of the preceding claims with an expression vector for a gene of the HMGI (Y) family or its derivative,
• b) comparison of the RNA pattern of the transfected cells with that of control cultures, and
• c) Examination of RNA (s) expressed or amplified in the transfected cultures relative to control cultures by sequence homology to the presence of viral elements.

27. Method for determining for the production of an agent for prevention and / or loading Treatment of tissue changes according to one of the preceding claims suitable Viruses and / or for the detection of viruses against which the agent is after one of the preceding Claims, which comprises performing a PCR test, wherein the for the PCR used primer (pairs) correspond to the sequence of viral nucleic acid. 28. A method for detecting viruses suitable for the preparation of a composition for the prevention and / or treatment of tissue changes according to any one of the preceding claims and / or for detecting viruses, against which the agent is directed according to one of the preceding claims comprising the steps :

• a) applying a cDNA library from a tissue comprising the tissue modification according to any one of the preceding claims, which has an activation of a gene of the HGMI (Y) family or a derivative, and
• b) screening the cDNA library with a virus-specific probe or
• c) Analysis of the cDNA clones for viral sequences or
• d) Comparison with a normal myometrium cDNA library.

29. The method according to any one of claims 26 to 28, characterized in that the gene of HMGI (Y) family is selected from the group consisting of HMGIC, HMGIY, MAG, aberrant Transcripts of the genes of the HMGI (Y) family and derivatives thereof. 30. The method according to any one of claims 26 to 29, characterized in that the virus, the viral element or the virus-specific probe is selected from the group of viruses, which comprises the viruses of any one of the preceding claims. 31. Use of a method according to any one of claims 26 to 30 for determining Viruses used for the prevention and / or treatment of tissue changes after a of the preceding claims can be immunized. 32. Apparatus for determining a pathogenesis of tissue alterations one of the preceding claims, which is a gene product of genes the HGMI (Y) family or a part thereof or its derivative which is attached to a Carrier is tied. 33. The device according to claim 32, characterized in that the viral nucleic acid ne ben the first sequence nor the structural and sequence features comprises

• a second AT-rich sequence is present and
• - The first sequence and second sequence are arranged in a spatial distance from each other.

34. Apparatus according to claim 33, characterized in that the spatial distance so is selected such that the first sequence and the second sequence relative to each other in an Ebe ne are arranged on the nucleic acid.   35. A method of diagnosing a tissue change, wherein the tissue change is a Such tissue change according to one of the preceding claims, characterized ge indicates that a body fluid is due to the presence of antibodies to Vi ren, as described in any one of the preceding claims, especially DNA viruses and especially adenoviruses and / or herpesviruses is examined. 36. A method of diagnosing a tissue change, wherein the tissue change is a Such tissue change according to one of the preceding claims, characterized ge indicates that a body fluid is indicative of the presence of antigens of viruses, as described in any of the preceding claims, especially DNA viruses and whole especially antigens of adenoviruses and herpesviruses is examined. 37. A method of diagnosing a tissue change, wherein the tissue change is a Such tissue change according to one of the preceding claims, characterized ge indicates that a tissue sample is reacted with an agent selected from the group is selected, the antibodies containing viruses as described in any of the preceding Claims, especially DNA viruses and especially adenoviruses and / or herpesviruses or parts of it react; Antigens caused by viruses, as described in one of the preceding claims, especially DNA viruses and especially adenoviruses and / or herpes virus or parts thereof, and nucleic acid infected with nucleic acid from viruses, such as described in any one of the preceding claims, especially DNA viruses and very particular which interacts with adenoviruses and / or herpesviruses, in the case of the presence of Viruses as described in any one of the preceding claims, especially DNA viruses and especially adenoviruses and / or herpesviruses are a complex of the agent and the Virus forms and the complex is detected.