WO1987005703A1

WO1987005703A1 - Antiparatypical antibodies, their use for detecting and treating auto-immune diseases

Info

Publication number: WO1987005703A1
Application number: PCT/EP1987/000149
Authority: WO
Inventors: Klaus-Henning Usadel; Josef Volker Teuber
Original assignee: Boehringer Mannheim Gmbh
Priority date: 1986-03-19
Filing date: 1987-03-13
Publication date: 1987-09-24
Also published as: AU7160887A; DE3790139D2; JPS63502928A; EP0263135A1; DE3609271A1

Abstract

For the specific determination of auto-immune diseases, in particular auto-immune thyropathy, antiparatypical antibodies are employed for diagnostic purposes. These antiparatypical antibodies are, furthermore, used for the treatment of auto-immune diseases against autoreactive cells and relevant auto-antibodies.

Description

Antiparatypical antibodies, its use in the detection and treatment of autoimmune diseases.

The invention relates to a method and a reagent for the detection of autoimmune diseases as well as a medicament having an effect against autoimmune diseases and a method for its production, in which antiparatypical antibodies are used in each case.

The immune regulation by anti-idiotypic antibodies was described for the first time by Oudin and further by Jerne in his network theory. In contrast to the Burnett selection model, it represents a hypothetical basis for understanding specific immunosuppression in many respects and offers a realistic explanation for the genesis and pathomechanism of autoaggressive diseases.

There are two types of antibodies that can lead to antigen binding blocking:

1. Antibodies that bind to the idiotype of another antibody in an antigen-unspecific manner and thus possibly prevent the antigen binding of that antibody by diaster interaction. They are called anti-idiotypic antibodies.

2. Antibodies that attack the so-called paratope, ie at the trough-shaped transition point of the light and heavy chain, and are thus able to physically attract the antigenic epitopes with different affinity through van der Waalschen forces. Antibodies directed against this antigen binding site are called antiparatypical antibodies. Antiidiotypic antibodies are by definition antibodies that are directed against the idiotype of another antibody, ie against the so-called hypervariable part of an immunoglobulin, on which the specific part of the antigen binding site, paratype, is also located. This definition appears to be important because the antibody directed against the idiotypic part - antiidiotypic antibody - which includes the paratype, is able to displace the antigen binding or the antiparatypic antibody from its paratypical binding site by steric hindrance. The mechanism of action of the anti-idiotypic antibody is therefore based on an unspecific steric blocking of more or less all antigens, while the antiparatypic antibody has a high selectivity. The paratope recognizes the corresponding epitope by the specific steric arrangement of its amino acids, which it can only detect if the epitope structure and the paratope structure are mirror images. This mechanism is comparable to a highly differentiated lock (paratope) key (epitope) principle. If an antiparatypic antibody with the corresponding paratype is to react, the mirror structures of both reactants must be present. It follows that the antiparatypic antibody has an identical formation with the corresponding epitope which is bound by the paratope.

Immunization with antigen-specific antibodies purified and isolated on columns can induce anti-idiotypic antibodies in animal experiments. The antigen-specific selectivity of this anti-idiotypic antibody is usually detected in the literature by two methods.

1. by the precipitation of the anti-idiotypic antibody after reaction with the isolated iodine-labeled antibody.

2. in the form of a radio-ligand test by the displacement of the antigen binding to the antibody by the specific idiotypic-antiidiotypic reaction. Since antiidiotypic antibodies are generally able to block both the antigen binding and the binding of the antiparatypic antibody, this detection method is unsuitable for the detection of paratypical antibodies. The reaction of both antibodies with each other and the resulting antigen blocking in no way justify the conclusion of an antibody / antigen-specific anti-idiotypic response, as supposedly assumed from the literature. This reaction product can be produced without the involvement of antiparatypic antibodies alone by idiotypic-antiidiotypic compounds or also from the combination of aniidiotypic idiotypic and antiparatypical bonds. The identity with a pure paratypical-antiparatypical reaction is not guaranteed. Because the detection methods based on this are therefore not sufficiently specific, the supposedly antigen-specific anti-idiotypic antibodies isolated according to these methods also lack the right to selectivity and specificity with regard to the resulting results for further diagnostic and therapeutic use.

The physiological importance of idiotypic-antiidiotypic or paratypical-antiparatypic antibodies lies in their functional property of maintaining the immune balance. The termination of an antibody response or cellular reactions with specific receptors against an antigen is mediated by the anti-response of anti-idiotypic antibodies which are directed against the antigen-specific antibodies or the antigen-specific receptors of these lymphocytes. In order to prevent this antigen-specific immunosuppression from generally suppressing the immune system after each sensitization with an antigen, the presence of an anti-response with highly selective properties towards the antigen-induced antibody is necessary. The balanced interaction of different antibodies may therefore protect our organism from the development of autoagressive diseases. Not only in the patient with autoimmune disorders, but also in the healthy organism, autoreactive cells, ie lymphocytes that are directed against the body's own substances, were discovered. This autoreactive cell population is likely to be caused by the blocking of their specific antigen receptors by certain antibodies or also by lymphocytes with antibody receptors prevents the destruction of the body's own tissue. A congenital or acquired antigen-specific defect eliminates the selective suppression of the corresponding lymphocytes, which then results in an inhibited autoagression disease. These autoimmune diseases are essentially of the following forms: autoimmune thyroid diseases, type I diabetes mellitus, myasthenia gravis, Crohn's disease, ulcerative colitis, autoimmune hepatitis, autoimmune diseases of the hemopoietic system, uveitis, immune vasculitis, autoimmune nephropathy disorders and other generalized autoimmune diseases Connective tissue diseases.

The autoimmune thyroid diseases are in particular the following two forms:

1. Chronic thyroiditis Hashimoto, which is based on chronic autoagressive inflammation, whereby the self-destructive process of the thyroid ends in a clear underactive thyroid.

2. Autoimmune thyroid dysfunction, which either stimulates the thyroid to grow or over-produce hormones. For this endogenous antibodies, which are directed against a receptor on the thyroid membrane, are discussed as the cause. They mimick the uncontrolled and non-suppressable effects of TSH, which has both growth and hormone-inhibiting properties on this TSH receptor.

These two diseases are serologically impressive, for example, through the appearance of high-titre antibodies either against thyroglobulin and / or thyroid microsomes or against the TSH receptor. The previous detection methods for thyroid diseases use the antigen as a detector. An immunological detection method which carries out the detection with the aid of anti-antibodies is not known.

The known detection methods, in particular the immune-related functional disorders of the thyroid gland, are extremely complex. Their diagnostic accuracy and prognostic significance are partially of uncertain relevance. This discrepancy is essentially caused by the weaknesses of the known detection methods. Although numerous methods are being propagated that more or less correlate with thyroid growth stimulation or with hyperthyroidism, in many cases there are positive results that have no clinical correspondence or also laboratory-negative results in which the full picture of goiter or autoimmune hyperthyroidism is clinically impressive. This phenomonology can be explained by the non-specificity of the antigen used for autoantibody detection. Pure isolation of TSH receptors is difficult. Antibody binding at different receptor sites produces a differentiated functional effect in vivo, which cannot be discriminated by the in vitro detection of binding. Especially for the differential diagnosis of hyperthyroidism or goiter growth, which is an indispensable prerequisite for the decision of a differential therapy strategy, a reliable diagnostic parameter must be required. The autoantibody not only has to be able to be detected specifically in terms of quality, but in particular also has to be quantitatively measurable and thus relatable to the extent of the in vivo malfunction.

The therapeutic influencing of thyroid diseases has so far been carried out by treatment with thyroid drugs. Therapy on an immunological basis is not yet known. The conventional treatment methods have disadvantages in that significant side effects such as damage to the blood picture and severe allergic reactions are not uncommon. The invention is therefore based on the object of eliminating these disadvantages and of creating methods and reagents which enable rapid and simple detection of autoimmune diseases and to provide medicaments for the effective treatment of autoimmune diseases.

This object is achieved according to the invention by a method for the detection and a method for the therapy of autoimmune diseases, which are characterized in that at least one paratypical antibody is used. The autoimmune diseases are essentially the forms mentioned above. These are antiparatypical antibodies that are directed against autoreactive cells and autoantibodies.

In the case of thyroid disorders, these are in particular antiparatypical antibodies which are directed against the clinically relevant epitopes of antibodies against thyroglobulin, the thyroid microsomes or the TSH receptor.

The detection method according to the invention is based on the surprising finding that antibodies can be obtained which have such a high selectivity that a detection method can be made available by which the prognosis of the treatment with regard to the duration and dose of therapy and the expectation of remission in thyroid diseases also Use of thyrostatics, is calculable.

The new antibodies used for the detection and therapeutic treatment of thyroid diseases can be obtained according to the invention by adsorbing autoantibodies either on thyroid cell membranes or on TSH receptors, which are obtained in the conventional manner by membrane fractionation, and then these antigen-antibody complexes blows up. The antibodies are purified using methods such as ultracentrifugation using density gradients, electrophoresis and HPLC. The selected antibody fractions are used for immunization. From the spleen cells of the sensitized animals, a monoclonal antiparatypic antibody is obtained by fusion with mouse myeloma cells, the specificity of which in the paratypical-antiparatypical reaction is essentially due to TSH displacement at its specific receptor and / or the receptor antibody is detected at its functional binding site. Another specificity test is a displacement assay in which monoclonal starting antibodies used for sensitization have been coupled to a solid phase.

In another method, antigen-sensitized lymphocytes are isolated using a rosette technique (Hammelerythrozyten with fixed TSH) and used for fusion with human myeloma cells. After hybridization, the individual monoclonal antibodies obtained in this way are tested for their functional properties on thyrocyte monolayer cultures for further use.

In the immunizations mentioned above, the immunogen is administered in a conventional manner, for example in combination with an adjuvant. Aluminum hydroxide is preferably used as an adjuvant together with Bordatella pertussis or Freund's adjuvant. The immunization is preferably carried out over several weeks with at least four immunizations every 2-3 weeks (injection intraperitoneally). B-lymphocytes are obtained from animals immunized in this way and are fused with a permanent myeloma cell line. The fusion takes place according to the well-known method of Köhler and Milstein. The primary cultures of hybrid cells formed here are in the usual manner, for. B. cloned using a commercially available cell sorter or by "limiting dilution".

The monoclonal antibodies as such or fragments thereof which have the corresponding immunological properties, for example Fab fragments, can be used for these determination methods. The term “monoclonal antibodies” is therefore understood to mean both the complete antibodies and the fragments. The antibodies according to the invention are outstandingly suitable for detecting thyroid diseases in the form of a reagent in a sample, for example serum or plasma. The test is carried out using the ELISA or RIA technique. In the context of this reagent, the monoclonal antibody, both in its complete form and in the form of the fragments, can also be fixed on a solid support, for example on immunosorptive paper or the surface of plastic tubes or tubes.

For the production of medicaments, the antibodies are mixed in a manner known per se with suitable pharmaceutical carriers, flavorings, flavors and colors and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, such as, for. B. olive oil, suspended or dissolved.

The antibodies can be administered orally and parenterally in liquid or solid form. Water is preferably used as the injection medium, which contains the stabilizers, solubilizers and / or buffers customary for injection solutions. Such additives are e.g. B. tartrate or borate buffer, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation or polyethylene derivatives of sorbitan hydrides.

Solid carriers are e.g. B. starch, lactose, mannitol, methyl cellulose, talc, highly disperse silica, higher molecular weight fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats or solid high molecular weight polymers (such as polyethylene glycols). Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.

Cytostatics, complement and isotopes can be considered as tracers of the antiparatypical antibodies. After application, the medicaments according to the invention are unerringly able to recognize the corresponding autoreactive lymphocytes and specifically block these clones.

The invention is illustrated by the following examples.

A) Evidence of immune regulation on thyroglobulin antibody and TSH receptor antibody mode11

a) It was found that patient sera with high thyroid antibody titers after 1: 1 mixing with a serum from the same patient with a low antibody level, which are determined with the haemagglutination technique, are again below the expected arithmetic mean after redetermination with this method . It follows from this that the sera with low antibody titer have formed antiidiotypic antibodies in the course of the disease, which enter into an idiotypic-antiidiotypic binding with this thyroglobulin antibody after mixing the serum at a time with a high thyroglobulin antibody level. As a result, the free antibody content from the serum with the high thyroglobulin antibody concentrations is reduced and is no longer available for the subsequent reaction in the hemagglutination technique.

b) Agargel diffusion methods were carried out to rule out interference with thyroglobulin antigen in the serum with low thyroglobulin antibody titers, which can also lead to a reduction in free thyroglobulin antibodies in the serum with the high thyroglobulin antibody titers. First, using an Ouchterlony technique, thyroglobulin was added to the agar gel in various concentrations. Sera from the patients and thyroglobulin antibody negative sera were filled into the punched holes. Precipitation rings were found compared to sera positive for thyroglobulin antibodies. In a further approach, the agar gel was purified using columns purified human Thyreoglobulin antibody-containing serum added. Thyreoglobulin-containing human serum, thyreoglobulin and thyroglobulin antibody-negative control sera and thyroglobulin antibody-positive sera were filled into the templates as reaction samples this time. Precipitation rings appeared in this experiment in the human sera spiked with thyroglobulin as well as in some patients with sera containing thyroglobulin antibodies in low concentration, which had previously been autoimmunological due to high anti-Tg at the time of the disease

Had activity. This result points to the

Formation of either a thyroglobulin antibody-thyroglobulin compound or thyroglobulin antibody anti-idiotypic

Connection.

In a third experiment both antibody precipitation and column chromatographic purification of the

Thyroglobulin spiked sera as well as Tg-AK positive sera were performed. The samples thus prepared were reinserted in an agar gel mixture containing thyroglobulin antibody. This time there was only one precipitation ring in the sera to which thyroglobulin was added. The disappearance of the initially positive reaction in the second approach of some patient sera, which have a low thyroglobulin antibody level, after immunoglobulin extract ion indicates an idiotypic-antiidiotypic thyroglobulin antibody reaction.

To characterize this idiotypic-antiidiotypic binding, numerous lymphocyte cultures were set up by the patients who had obviously developed anti-idiotypic thyroglobulin antibodies. The lymphocytes were stimulated in a sterile incubator with Pokeweedmitogen and LPS for 14 days to produce antibodies. In another approach, lymphocytes after rosetting on tannic sheep erythrocytes, which were infected with thyroglobulin antibodies, were isolated by density centrifugation and also using B-cell stimulators for antibody production cultivated for 14 days. In three patients from the non-selected lymphocyte culture and in six batches in patient lymphocytes, which could be isolated by rosette formation, thyroglobulin was detected in the medium using the RIA and ELISA technique, which was negative after renewed immunoglobulin extraction. A control medium spiked with thyroglobulin, from which immunoglobulin elimination was also carried out, remained thyroglobulin positive. These studies indicate the appearance and production of antiparatypical thyroglobulin antibodies of the patient's lymphocytes in the human system.

TSH receptor autoantibodies were initially usually determined using the radio ligand test. In order to obtain information about their functional importance, in the nu / nu mouse system after transplantation of thyroid surgery preparations, the growth stimulation via the ³ H-thymidine incorporation in the thyroid nucleus and the hormonal activity via the iodine up-take were both morphologically based on autoradiographic investigations as well as quantified by scintillation in the borehole. These investigations indicate the predominantly heterogeneous antigen binding of the polyclonal antibodies to the TSH receptor, which in no case correlated with the level of the measured value in the radio ligand test.

If the Basedow immunoglobulins were mixed 1: 1 in the individual analogously to the thyroglobulin antibody tests and specifically with samples which were obtained at a time of high autoimmunological activity and in the later course of the disease, significantly lower activity, an antibody titer could be determined this time in the radio ligand test which essentially corresponded to the arithmetic mean of this mixture. In the stimulation experiment in the nu / nu mouse assay, however, the mixed Graves' immunoglobulin preparations were within the values of the negative control sera according to the criteria for assessing the core volume size, while the use of the original antibody preparations individually a de Clinical function correlation showed. These results also demonstrate the presence of anti-idiotypic antibodies in remission, which result in idiotypic blocking of the free TSH receptor antibodies in the highly active serum. This reaction is obviously of diagnostic importance without the complex formation being detectable in the radio ligand test.

The further experimental approaches were used to characterize and purify the idiotypic-antiidiotypic or paratypical-antiparatypical antibodies. It was carried out both via guinea pig fat cell membrane preparations according to the Endo method and human membrane thyrocyte preparations according to the Smith and Hall method by column absorption. The wash solution was adjusted to a constant immunoglobulin concentration, which was determined by laser nephelometry, and the decrease in binding to receptors of iodine-labeled TSH was compared to an autoantibody-negative sample (normal assay) as an expression of the displacement potential of antiparatypical antibodies in a displacement assay. The deviations from the normal assay (= 100%) were between 15 and 27%.

Subsequently, by titration of this constant antibody fraction with the autoreceptor antibodies, which this time were labeled with chloramine-T-iodine, the decrease in binding corresponding to titrated antiparatypic antibody TSH products was detected in a similar manner. By adding these antiparatypical immunoglobulins to a constant amount of receptor antibodies, both in the bioassay and through adenylcyclase activation or T3 release on thyroid sections and thyroid cell cultures, a concentration-dependent decrease in activity of these receptor antibodies, partly related to the growth-stimulating influence, partly with regard to stimulation, partly with regard to stimulation ascertain. B) Generation of antiparatypical antibody clones

Two animal experiments were established for this:

1. each Balb-C mouse group was sensitized with Freud's certificate adjuvant human TSH receptor preparations and purified TSH receptor antibody fractions.

a) after a sufficient rise in TSH receptor antibodies after 12 weeks by repeated immunization, the spleen cells were cloned and hybridized using the method of Koehler and Milstein (Nature 256, 1975, pp. 495-497). The clones that reacted positively to various human tissues (not thyroid) were discarded. Through numerous implementations it was possible to grow clones which produced monoclonal binding affinity both in the radio ligand test and in those for hormone stimulation and cufferent for thyrocyte growth in the test systems described in thyrocyte cultures and functional assay

b) Immunization with receptor antibodies led to similar ones

Way of cloning monoclonal. Antibodies that showed a binding to iodinated TSH aas could be counted in the pellet after precipitation with anti-mouse serum.

To ensure that antiparatypic antibodies were generated here, the monoclonal antibodies on mouse IgG-coated columns were freed from possible anti-idiotypic antibodies.

By adding these antiparatypical monoclonal antibodies to the already functionally characterized monoclonal TSH receptor antibodies, depending on the antiparatypical clones, either hormone stimulation or thyroid cell growth could be inhibited. The associated detection of functionally different antiparatop structures was used to derive their specific function-stimulating antibody properties from polyclonal antireceptor-containing human sera. characterize. For this purpose, the respective antiparatypical antibodies were "coated" on microtiter plates. incubated with the patient's serum samples, washed and specific binding detected in the form of an ELISA system with a conjugated anti-human antibody. For the quantitative determination of the autoantibody content, comparative tests were carried out with a monoclonal TSH-ELISA test, the binding activity of this monoclonal antibody being set in equivalence to the binding of the antiparatypic antibody with the paratype of the receptor antibody.

Another direct quantifiable measurement variant represented the binding ability of known b-TSH concentrations to the antiparatypical antibodies, to which the binding of the autoantibodies could then be related (unit of measurement: TSH binding equivalents).

The autoantibodies found in this RIA system correlate very well with the clinical appearance and the activity of the respective disease. An assay system is therefore available which not only allows the qualitative differentiation of TSH receptor antibodies, but also shows disease specificity and correlations with disease activity.

The extraction of these antiparatypic antibodies, which have a high degree of functional differentiation, can be used after appropriate labeling for specific eliminations of the aetiologically relevant lymphocyte clones detected by the antiparatypical ELISA assay, as corresponding animal experiments show.

2. The paratypical antibodies were obtained in a modified system. Guinea pigs were immunized with TSH receptors, which were processed with Freud's adjuvant. The TSH receptor antibody activity was again demonstrated in the radio ligand test and functionally. After reaching an appropriate antibody level after about 12 weeks, the animals were bled and the antibodies for action and guinea pigs against human tissue, not thyroid). The receptor antibodies separated from human thyrocytes were used for further immunization in the Balb-C model. After repeated boosters, the binding ability of the mouse immunoglobulins to TSH was tested. Analogous studies followed in the bioassay and in the radio ligand test by the ability of this antibody to inhibit TSH from its functional units.

After about 8 weeks, the spleen cells were hybridized again with mouse myeloma cells and cloned until they were unlimited. The monoclonal antibodies thus determined, which had no binding to rabbit immunoglobulin, were examined for their antigen-specific reaction. The displacement attempt of labeled TSH to TSH receptor was used again. Furthermore, the functional activity of these antibodies was tested by their ability to displace TSH in the functional and bioassays. In this context, by inhibiting the minimum TSH concentration with a constant amount of immunoglobulin, a unit corresponding to the TSH displacement could be determined (displacement% TSH). This made it possible to quantify this measuring system.

Here, too, the polyclonal patient receptor antibody could be measured quantitatively in TSH displacement units using different antiparatypical AKs on the monoclones with regard to its functional target.

The monoclonal antibodies provoked in this way were expanded in the same way to an ELISA system, which allows reliable detection of different TSH receptor autoantibody specificities, both qualitatively and quantitatively. By antibody absorption on eye muscle tissue or retroorbital tissue and subsequent immunoglobulin separation, an antibody can be produced experimentally by sensitization in animals, which, analogous to the preliminary experiments on the TSH receptor antibody and antiparatypical antibodies by antiparatypical-paratypical binding, has ophthalmopathy-antigen specificity.

This antiparatypic antibody produced in analogy steps can be used therapeutically and diagnostically in the same way.

Claims

1. A method for the detection of autoimmune diseases, characterized in that at least one antiparatypic antibody is used.

2. The method according to claim 1, characterized in that the antiparatypic antibodies are directed against autoreactive cells.

3. The method according to any one of claims 1 and 2, characterized in that the antiparatypic antibodies against lymphocytes are directed with antibody receptors.

4. The method according to any one of claims 1 to 3, characterized in that the autoimmune diseases are the forms of autoimmune thyroid diseases, type I diabetes mellitus, myasthenia gravis, Crohn's disease, ulcerative colitis, autoimmune hepatitis, autoimmune diseases of the hemopoietic system, uveitis, Immune vasculitis, autoimmune nephropathies, generalized autoaggressive diseases such as collagenosis and other connective tissue diseases.

5. The method according to claim 4, characterized in that it is autoimmune hyperthyroidism or autoimmune orbithopathies in the thyroid disorders.

6. The method according to any one of claims 4 and 5, characterized in that the antiparatypic antibodies are directed against the clinically relevant epitopes of antibodies to thyroglobulin, the thyroid microsomes or the TSH receptor.

7. Reagent for the detection of autoimmune diseases, characterized in that it contains at least one antiparatypic antibody.

8. Reagent according to claim 7, characterized in that the antiparatypic antibodies are directed against autoreactive cells.

9. Reagent according to one of claims 7 and 8, characterized in that the antiparatypic antibodies against lymphocytes are directed with antibody receptors.

10. Reagent according to one of claims 7 to 9, characterized in that the autoimmune diseases are the forms of autoimmune thyroid diseases, type I diabetes mellitus, myasthenia gravis, Crohn's disease, ulcerative colitis, autoimmune hepatitis, autoimmune diseases of the hemopoietic system, uveitis, Immune vasculitis, autoimmune nephropathies, generalized autoaggressive diseases such as collagenosis and other connective tissue diseases.

11. Reagent according to claim 10, characterized in that the thyroid diseases are autoimmune hyperthyroidism or autoimmune orbitopathies.

12. Reagent according to one of claims IQ and 11, characterized in that the antiparatypical antibodies are directed against the clinically relevant epitopes of antibodies to the thyroglobulin, the thyroid microsomes or the TSH receptor.

13. Medicament with action against autoimmune diseases, characterized in that it contains at least one antiparatypic antibody.

14. Medicament according to claim 13, characterized in that the paratypical antibodies are directed against autoreactive cells.

15. Medicament according to one of claims 13 and 14, characterized in that the antiparatypical antibodies are directed against lymphocytes with an antibody receptor.

16. Medicament according to one of claims 13 to 15, characterized in that the autoimmune diseases are the forms of autoimmune thyroid diseases, diabetes mellitus

Type I, myasthenia gravis, Crohn's disease, ulcerative colitis, autoimmune hepatitis, autoimmune diseases of the hemopoietic system, uveitis, immune vasculitis, autoimmune nephropathies, generalized autoaggressive diseases such as collagenosis and other connective tissue disorders.

17. Medicament according to claim 16, characterized in that the thyroid diseases are autoimmune hyperthyroidism or autoimmune orbitopathies.

18. Medicament according to one of claims 16 and 17, characterized in that the antiparatypic antibodies are directed against the clinically relevant epitopes of antibodies of the thyroglobulin, the thyroid microsomes or the TSH receptor.

19. Use of one or more antiparatypical antibodies for the production of medicaments according to one of claims 13 to 18

20. Antiparatypical antibodies directed against autoreactive cells.

21. Antiparatypic antibodies according to claim 20, characterized in that they are directed against lymphocytes with antibody receptors.

22. Antiparatypical antibodies which are directed against the clinically relevant epitopes of antibodies of the thyroglobulin, the thyroid microsomes or the TSH receptor.

23. Antiparatypical antibodies, obtainable by the following process steps

a) sensitization of each Balb-C mouse group with a human TSH receptor preparation prepared by Freund's adjuvant and purified TSH receptor antibody fractions,

b) repeated immunization after sufficient TSH receptor antibody and Arcti-TSH receptor antibody increase, cloning and hybridization according to Köhler and Milstein,

c) rejection of the clones that react positively to human non-thyroid tissues,

d) cultivation of the clones which produce monoclonal binding affinity both in the radio ligand test and in the test systems circumscribed for hormone stimulation and difference for thyroid growth in thyrerocyte cultures,

e) Freeing the monoclonal antibodies obtained from anti-idiotypic antibodies on mouse IgG-coated columns.