Use of il-18 inhibitors for the treatment and / or prevention of heart disease

Description

The invention relates to the treatment and / or prevention of tuberculosis. The subject of the invention is the use of IL-1 for the treatment and / or prevention of tuberculosis. IA sstok® mwltekia 19-st <11-1b) «mtótífeg iatefete-y (kbN-y) iatoaló fetotkósA kzák fe [Natasám Ι and mmkatem. (1989)]. The IL-1 receptor is a signal for the development of type 1 T-helper cells (Tit cells). In contrast, IL-19, together with its 11-12 and 11-3 receptors, induces the production of IL-18. IL-18 is responsible for the induction of QM-0 and IL-1-2 and promotes the proliferation of T cells by activating CD4+ and CD8+, and also inhibits the cell-killing effect of killer cells (KCs). The food is TL-IŐ and appropriate precursors are fused to the 11-lp converting enzyme (ÍCB, caspase-1). The 11,-19 receptor consists of at least 10 subunits, which are key to the binding of ,iig«temk| boa, The 11,-19-stt binding kb and zagy affinity binding sites were found in stimulated T cells from 11-12 and | of these, the complex structure of the 11-1 protein is known (Voshkooto and (1988)). Two subunits are involved, both of which are capped by the 11-1 protein [Patto and Ssmkasfete (1990) and Kim and Mtetofeta (2001). The 11-1 protein is activated by the 11-1 protein [DiDeuato and Maarten (1997)]. The 11-1 protein consists of two subunits, one of which is the 11-1 protein chain, and the other is the 11-1 protein chain. 11-lffiffi is a signal carrier. The tt-llR lafiset was first detected by the ssjilblófeb groíefet bound to IL-i 9 labeled with the fadioskOv isotope, The poAefet was tested and the amisxmtwímía of the tstótatanzziák. and It was thus revealed that the earlier ?L-líUe tótő gwehmek {Ik-lÜsp} called ''orva (otpim) ttógtemal fTongee et sosotlíspartasag (1999)1. Recently, a novel protein has been isolated from human urine that has a high affinity for the 11-19-binding protein and can thus bind to DNA and other target proteins (Feovlek and Mnakatami <1999) and is published in German patent application WO 99109043. This protein was isolated from the 11-19 binding protein (11-19BF). IL-1SBF is not a novel R.-1 receptor agonist, but rather a protein selected in the stomach, which is bound to the surrounding tissues, which belongs to a family of proteins that are encoded by the phospholipids (Nnvíck and Ostakfersai, 1999). The urine and the tt-lSÖP are also spsxffikosao, bind lt-19 with high affinity and thereby modify the 11.,-10 biological subTssitáSiik The oldest, the mountain is located in the rain in the llgi3 cemetery: the á,3 kb getsas szskveoeiabi® eagle was found to be a bommfefaa demmn ezeo tasting. Four alternative sffiAS agital álstl geoseáb wkbssát or izefasoja (variant) of IL-i 9BP have been identified, Eaeket the IL-iOBF g„ ó, g and B tewel saw ek ffifetl the sésy szolbnosak (váhs>zstsak) azteos sz N-végesoportja. ős skáfé the C-vegesepostfe [tásvisfe and mostesiámi, {1999)), First ax IL-1Ó binding abilities is. The ségy szolet® hózill the «mberi 11.-1 ÓBB It is known from ΦΦ 56 * « and g ixoriji-mia that they have neutralizing capacity for ΪΕ-18-a. The human It-188P isoform « cross-reacts with mouse II -18-cat Heart diseases are disorders that affect the heart muscle or the blood vessels of the heart (The Merek Mannal Home Edition, www.rn.erek.com). Vascular disorders are disorders of the blood vessels, such as inadequate blood circulation caused by stenosis. Heart diseases are also called cardiovascular disorders. Ischemic heart disease is the usual cause of heart failure; it is the most common cause of death in Western countries. It is most often caused by fatty plaques (atherosclerosis) in the coronary arteries. Damage to the heart muscle includes ischemic infarction and acute infarction. In a healthy heart, the blood flow in the coronary arteries is just sufficient to meet the metabolic needs of the heart muscle. Ischemic heart disease occurs when the blood supply is inadequate, either because the blood supply itself is pathologically insufficient or because a greater blood supply is required due to myocardial hypertrophy. In a healthy heart, blood flow in the coronary arteries is independent of the pressure in the aorta because there is an effective self-regulating mechanism to regulate the blood flow through the coronary arteries. If a narrowing develops in a coronary artery - usually due to atherosclerosis or arteriosclerosis - the blood flow in the coronary arteries is first obstructed because the distal peripheral resistance decreases as a result of the narrowing. If the vessel diameter (cross-section) decreases by more than ?5%, ischemia develops, especially if the coronary circulation is insufficient. The metabolism of the heart muscle is particularly active, with mitochondria accounting for more than 30% of each heart muscle cell. Aerobic metabolism is essential because the reserve of high-energy phosphates is very small. Myocardial death occurs when the tissue ATP level is very low and anaerobic glycosyltransferases are apparently exhausted. As in other tissues, the exact cause of death is unknown, but fatal myocardial damage has been associated with membrane damage and the sudden entry of calcium into the cell cytoplasm. After brief periods of ischemia, blood flow to the heart is reduced (called perperfusion). After a critical period of ischemia, however, reperfusion is impossible, probably because of swelling of the capillary endothelial cells, The most common coronary artery disease is atherosclerosis. Ischemic heart disease is caused by insufficient blood flow in the coronary arteries. A common cause of this is blockage by clots, especially blood clots. As previously noted, ischemic heart disease is caused by an imbalance between myocardial blood flow and its metabolic needs. Blood flow can be impeded by events such as spasm, thrombosis, and circulatory changes that reduce flow. The pressure gradient in the coronary arteries depends on the pressure difference between the systolic (aortic diastolic pressure) and the coronary sinus (right atrial pressure). During systolic pressure, coronary artery blood flow is reduced by the reduction in the force of the contraction of the heart and the compression of the myocardium during ventricular contraction. Factors that reduce blood flow in the coronary arteries include reduced aortic diastolic pressure, increased cardiac output, coronary artery stenosis, aortic valve stenosis and regurgitation, and increased right atrial pressure. φ.φφφ φ φ «· ΦΦ ΦΦ φφχ φφ φ φφ Sun Φ·φ· Φ φφ » φφφ φ· φφ « ΦΦΦ The relatively fresh trorobusok ttloltteo gysteso Aalmaxaak trmbolhS:os treatment, put swafeekhtexzai or tövet plaafeoogáo sktiváíösrsü ÓTA). .With the treatment resulting in the tesnfestt festéätt, the blood flow is restored in most cases. Ex sjäättää s sälyaa sttvleomkäostfeteok sälyaa, hs täytbea, ax säyttä Angina pectoris is a condition that occurs in the heart, characterized by chest pain, chest tightness, or tightness in the chest. Myocardial infarction is caused by a blockage in the heart muscle. It occurs suddenly, either from the heart muscle or from a blood vessel in the chest. It affects about 100,000 people per year. Other heart diseases include alcoholic cirrhosis, aortic valve prolapse, aortic valve stenosis, myocardial infarction, cardiogenic shock, hereditary heart diseases, dilated cardiomyopathy, heart attack, stroke, heart disease, stenosis of the coronary arteries, mitral valve prolapse, coronary artery disease, ischemic heart disease, aortic valve stenosis, aortic valve prolapse, aortic valve stenosis, and mitral valve prolapse. Ischemic heart disease is also known as myocardial infarction. In the event of a heart attack, the blockage of the coronary artery, the thrombus, or the narrowing of the coronary artery, plays a role as a precursor. The blockage that develops is caused by a thrombus that is acute, the entire myocardial tissue is affected. The precursor of the disease can be calcification of the coronary arteries and the formation of aggregates, but also their contents. In myocardial infarction, oofette can also occur. The appearance of the myocardium tendons is characterized by several types of wounds. The irassmurálls (this is the upper part of the heart) extend to the entire thickness of the ventricle. The tfevfelbttlytt)la fevbotökig. During the course of the ventricular septal defect, multiple necrosis develops, affecting up to one-third of the ventricles. The complications of the disease include cardiac arrest and conduction disturbances, the possibility of “sudden death,” the development of ventricular septal defects, the recurrence of ventricular fibrillation, congestive heart failure (cardiac oedema), cardiogenic shock, myocardial infarction, thrombosis occurring in the ventricles, which may be accompanied by death, rupture of the ventricle, which may cause tamponade, rupture of the popliteal fossa, which may be associated with preexisting ventricular dysfunction and the rupture of the ventricular septal defect (aortic stenosis). The perpetrator is {Ml} the victim of the crime, which is caused by the possession of the victim's property resulting from the act. Ax ate sxtvizom in&rfciasbaa suffering beieg.sk more miat Mteahl ste ostew tetei ki, which often plskk letetessl onet, and which eltejt the fcteotet ierteti ielt sitteat, smelyat previously a steeosekietetes gbte ste leteikkefi, Ax éttetmesebesos platt ttsl caused oteoteliaté vétet tea# telteik megváhoxoít tttloosette teltette Ibtehetteg sttkéo teattjántl a ttombŐM kttttuteáhox. The tetette a patients terbtete tttesiuttetol sgootes tetek, so 24 hours a kitektttt ote assgte a Bategek éttá-átti teilbte teosbtes, In some cases, the blood supply to the heart is compromised, for example, by the heart's pumping action or the aortic valve. The amount of cocaine in the blood can cause a stroke or myocardial infarction. Autopsy studies and coronary angiography have shown that cocaine-induced coronary thrombosis can occur in healthy coronary arteries or can be superimposed on existing atheroma. Myocardial infarction is primarily a disease of the ventricle, but damage may extend to the right ventricle (RV) and atrium. Right ventricular infarction is usually caused by stenosis of the right coronary artery or a left atrial septal artery, and is characterized by right ventricular filling pressure and is often severe, with regurgitation from the mitral valve prolapse and decreased outflow tract blood flow. Some form of right ventricular regurgitation occurs in approximately half of patients. Along with inferior-posterior infarction, it causes blood flow abnormalities in up to 15% of patients. Whether the heart can continue to function as a pump depends directly on the extent of damage to the heart muscle. A full-thickness myocardial infarction involves the entire thickness of the ventricular wall, from the pericardium to the endocardium (epicardial to occipital) and is usually characterized by an abnormal Q wave on the ECG. A non-thickness myocardial infarction does not involve the entire thickness of the ventricular wall and causes abnormalities only in the ST segment and T wave. A non-thickness myocardial infarction usually involves the inner one-sixth of the myocardium, where the developed wall pressure is greatest and where the myocardium is most sensitive to changes in blood flow and circulation. This may be followed by persistent hypotension. Because death from full-thickness myocardial infarction cannot be accurately determined clinically, infarctions are divided into Q-wave and non-Q-wave infarctions based on the abnormalities seen on the ECG. The volume of damaged myocardium can be estimated based on the extent and duration of CR elevation. Ischemic heart disease includes ischemic stroke. The disease can be preceded by myocardial infarction, but the cause of the disease is severe calcification of the coronary arteries, affecting all its branches. The consequence is insufficient blood supply, which causes muscle cell loss. The loss of muscle cells associated with atherosclerosis is accompanied by interstitial collagen deposition and leads to a decrease in performance, which, together with the accompanying enlargement of the heart, causes an overload of the remaining muscle cells. The process continues, and the heart muscle continuously enlarges as compensation. In addition to the enlargement of the muscle cells (hypertrophy), hyperplasia (proliferation of cells) can also develop, as a result of which the heart becomes enormous in size (2-3 times the normal size). Finally, the heart is no longer able to compensate, and the.Heart failure causes arrhythmias and / or ischemic attacks. Heart failure develops slowly but steadily, with or without a previous myocardial infarction or angina. Ischemic heart disease is responsible for 40% of deaths from ischemic heart disease. During ischemic events and reperfusion in the heart, a variety of endogenous mediators (mediators), including several histamine-based secondary messengers, are produced in the body, which adversely affect myocardial function. Within a few minutes after the ischemic event, the strength of myocardial contraction decreases, and its return to normal values ​​largely depends on the duration of the ischemic period (Daemen et al. (1999). During an ischemic event, for example, the internal balance of the cell membrane is disturbed, free radicals from oxygen are generated, and nitric oxide (NO) synthesis and release occur. In addition, cytokines are also produced, especially TNFα and IL-1β [Belli (1990)].In the intact heart, these cytokines contribute to myocardial chemokine-induced dysregulation by upregulating gene expression of inducible NO synthase (iNOS) [Daemen et al. (1999)], cyclooxygenase-2 (CGX-2), and phospholipase A2X, as well as vascular adhesion molecules and several chemokines. This results in an immediate decrease in the force of myocardial contraction mediated by small molecule signaling, followed by cytokine-mediated neutrophil infiltration, which further damages the myocardium. Studies of animal hearts without blood or blood products have shown that TNFα [Herskowitz et al. (1995)] and IL-Ιβ are produced during ischemic events. Cardiac muscle cells also reduce their force of contraction due to the release of endogenous cytokines [Meldrum et al. (1998)1. Most of the experimental data on myocardial dysfunction mediated by TNPs and 11-1β have been derived from animal models. However, human myocardial tissue from patients undergoing extensive coronary artery bypass grafting has also been studied under controlled ex vivo conditions (Gurevích et al. (1990), Cleveland et al. (1997)1. In these experimental models, human atrial trabeculae (tissue from the inner lining of the heart) were suspended in a vessel with a physiological oxygen supply and then exposed to a simulated ischemic event. During this time, the force of contraction rapidly decreases; when tissue oxygenation is restored, the force of contraction increases, but notIt was found that the initial values ​​(0-70% decrease) and the release of keratin kinase (Keratin kinase) were detected as evidence of myocardial damage (Gureviteh et al. (199(1), Cleveland et al. (199?)]. When the biological effect of TNE is specifically neutralized during the ischemia / reperfusion (I / R) period, the strength of contraction is restored to a greater extent, indicating that endogenous TNF activity contributes to the dysregulation of myocardial contractility induced by the ischemic event (Cain et al. (1999)). Daemen et al. (1999) studied tissue damage induced by ischemia and subsequent reperfusion in a mouse model of renal ischemia. They showed that IL-18 mKNS downregulation occurred together with caspase-1 activity on the first day after ischemia. Upregulation of IFN-γ and IL-12 mKNS occurred on the sixth day after ischemia. Together, but not separately, there is neutralization of IFN-γ-induced IL-12 and IL-18 cytokines and a decrease in the upregulation of IFN-γ class 1 and 2 MMCs to the same extent as IFN-γ neutralization. IL-18 inhibitors and their disease context are described in the literature. For example, in International Publication No. WO98 / 24804, inhibitors of interleukin-1β converting enzyme (IGE) have been described. The document also shows that IGE may play a role in programmed cell death, or apoptosis, and that therapeutic applications of inhibiting apoptosis may include the treatment of myocardial infarction. International Publication No. WO01 / 589SS describes anti-XL-1S antibodies. These antibodies are mentioned among a number of different theoretically possible therapeutic applications for heart failure, myocardial infarction and myocardial infarction, WO1 / 85201 relates to the use of inhibitors 11-18 in the treatment of atherosclerosis. Séta et al. [Heart, 84, ÓŐ8-ÕŐ9 (2bó9)] describe the role of IL-18 in acute myocardial infarction, and recommend IL-18 as a mask for myocardial damage in patients with acute myocardial infarction. * * X In the document published by WO01 / 037Í9, osteoprotegerin, a member of the tumor necrosis factor receptor superfamily, and its role in the regulation of bone metabolism are described. This document discusses combination therapy with several compounds, including H.,-18 tobibitoroxi and TOF inhibitors. This document does not address heart disease. However, it has not been described so far that EL-18 plays a role in the development of sigmoid colon cancer, As^mfeyjssgglbgliitósía The invention is based on the finding that inhibitors of caspase 11 significantly increase cardiac contractility in a suprafusion human atrial ischemia / reperfusion model. Inhibition of caspase-1 (1CE) also attenuates the strength of contraction following ischemia and reperfusion. In a mouse model of myocardial infarction, IL-1 inhibitors improved survival and significantly increased ventricular function. These studies have shown that IL-1α inhibitors can be used to treat and prevent myocardial infarction. The invention relates to the use of 11,-18 inhibitors for the preparation of medicaments for the treatment and / or prevention of celiac disease. The invention further relates to the use of an expression vector containing a sequence encoding a BL-18 inhibitor for the treatment and / or prevention of a disease. Thus, the BL-18 inhibitor can be delivered to the diseased tissue or cell using gene therapy. Aytóg <?kröytójtótósa Figure 1: Effect of IL-18SP on ischemia-induced abnormal myocardial contraction (A) Kinetic response to ischemia injury. After equilibrium was reached, control trabecular meshwork was perfused into the myocardium while maintaining normal oxygenation. The trabecular meshwork was subjected to ischemia / reperfusion in the presence and absence of IL-18SP (5 μg / mL). The vertical axis represents the force of contraction expressed as a percentage of the initial force (time 0). The data are from a single patient's trabecular meshwork and are representative of the method in terms of the average changes over 90 min. (8) Contraction strength after ischemia, after neutralization of IL-1b with 1 or 5 pg / ml IL-18SP. Data are expressed as percentage change in force relative to control, after complete reperfusion (90 min). Numbers in parentheses indicate EL-18BP concentration in pg / ml. N=0. * p<0.01 compared to f / R (ischemia / reperfusion). Figure 2: shows the content of myocardial IL-18 protein. Trabefalate was homogenized after 90 minutes of perfusion under normal oxygenation (control) and 45 minutes after 30 minutes of ischemia (I / R). Trabefalate was compared to the same subject. IL-18 levels are shown on the vertical axis, pg / ml. NMAp<ö,ÖÍ. Figure 3: Steady-state expression of IL-18 and IL-18B mRNA in control and ischemic atrial tissue. IL-18 and IL-18B mRNA levels were determined by RT-ECR. Data from one or more subjects were evaluated. A shows the ethidium bromide sgs copper curve in which the ECR products were detected, and B shows the change in the quantitative values ​​of the EC product relative to the control (GAEDH). «44 M » 4 Figure 4; shows the effect of ICE inhibition on the force exerted after ischemia. The data are expressed as a percentage of the mean force after ischemia compared to control. The numbers in parentheses indicate the concentration of ICE in pg / ml. N~?« *p<0.01 relative to 1 / R, Figure 5: Tissue keratin kinase (CK) activity following ϊ / R. CK was expressed in units of activity per milligram of wet tissue weight. Experimental conditions are shown below the horizontal axis, up. Ctrl and í / R, N-~6; 1L-I8.BP (.$ X,g / ml)5N™·.?; ÍCEi (10 and 20 pg / ml), N~5 in each case; *p<0.05, compared to 1 / R, Figure S: Mean change in force exerted by a trabecula incubated with 10 pg / ml for 15 min after reaching equilibrium, expressed as a percentage, before the addition of TNFa (1 ng / ml). TNFa and 1L-18BP-1 were added to both baths, Figure 7: Temporal response of atrial trabecula to 1L-18 under normal oxygenation. Mature 1L-18 (100 ng / ml) was added to the atrial trabeculae during the 90 min duration of the experiment. The vertical axis represents the mean change in the force exerted relative to the initial value. The initial value was determined after equilibrium was reached (not shown)), n^Ő. *p<Ö.Ö5, **p<0.ÖÖl, relative to the control at the same time point, for the remainder of the ghost period. Figure 8: The effect of TNFα (1.0 μg / ml) and TM'Pa (1.0 μg / ml) on the maintenance of cardiac muscle tissue CK activity is shown in Fig. 8. The CK activity was expressed relative to 1 mg of wet tissue (n~o). A.Mtemysvréste;e:yssn;ertóse The present invention is based on the recognition that IL-18 inhibitors have a beneficial effect in heart disease, particularly ischemic heart disease. As illustrated in the following examples, various IL-18 inhibitors have been shown to have a significant beneficial effect on myocardial ischemia-induced force. In addition, we also tested it in a myocardial infarction model using Íí,»í8 inisibitest I» and demonstrated more favorable survival data and significantly better ventricular function. The invention therefore relates to the use of 1L-18 luteobiol for the preparation of medicaments for the treatment and / or prevention of myocardial disease, During myocardial infarction, we experience all structural and functional abnormalities of the ventricular myocardium. The term prevention, as used herein, refers not only to the complete prevention of a certain effect, but also to any partial and substantial prevention, alleviation, reduction, mitigation and mitigation of the effect, before the onset of the disease or in its early stages. The term "treatment" as used herein means a beneficial effect on the progression of a disease, including the alleviation, reduction, mitigation or amelioration of the disease with respect to any pathological phenomena after the onset of the disease. The term "71.-18 inhibitor" for the purposes of the present invention refers to any molecule that reduces the production and / or effect of 1b-18 in such a way that the production and / or effect of 1b-18 is weakened or reduced, partially, significantly or completely inhibited or chlorinated. Inhibitors of IL-18 activity may include IL-18 antibodies, such as polyclonal and monoclonal antibodies. φ *· * Φ ** X ΧΦ * κ 4Φ Φ « ·> X Φ * < 4 V χ ψ * * ♦ ΦΦΦ φ «Φ* «»* »β φ φ 4 Φ Φ κΧ4φφ« According to the invention, the IL-18 inhibitor is selected from the following group: caspase-1 inhibitors (IL-18), antibodies against IL-18, antibodies against any of the IL-18 receptor subunits and IL-18 binding proteins, isoforms, mutants, fused proteins, functional derivatives thereof, which inhibit the biological activity of IL-18. The term "IL-18 binding proteins" is used interchangeably with the terms IL-18 binding protein and IL-18-BF. These include the IL-18 binding proteins described in WO 99 / 09063 (Novickes et al. (1999)), including the spatially different variants of IL-18 binding proteins and / or the IL-18 binding protein isofermies identified by Kint et al. (2000) which bind to IL-18. In particular, the human g and e isoforms of IL-18BP are preferably used in the present invention. The proteins useful in the present invention may be glycosylated or non-glycosylated proteins, may be derived from natural sources, such as urine, or may be, preferably, recombinant. Recombinant expression can be in a prokaryotic expression system, such as E. coli, or a eukaryotic, preferably mammalian, expression system. The term "mutant" is used herein in relation to IL-18BP and viral IL-18BF analogs, wherein one or more amino acid residues of a natural IL-18BF or viral IL-18BP are substituted or deleted with different amino acid residues, or one or more antisense residues are added to the natural sequence of IL-18BF or a viral IL-18BP, which does not significantly alter the activity of the resulting product compared to wild-type IL-18BP or viral IL-18BF. These mutants are prepared by known synthesis and / or site-directed mutagenesis techniques or by any other known technique suitable for this purpose. Mutants of the present invention are, for example, proteins encoded by nucleic acids, e.g., DNA or RNA, which encode Π,- I8BP-1, or which encode viral Π.-I8BΙM under stringent conditions according to the present invention. The term stringent conditions refers to hybridization and subsequent washing, and is maintained under what those skilled in the art generally call "stringent" conditions (see Ausubel et al., supra, Protocols in Molecular Biology, Interscience, NY,, 6.3 and 6.4 (193?, 1992) and Sambrook et al., supra,). Examples of stringent conditions include, but are not limited to, washing of the hybrid under investigation at temperatures below the Tm temperature, such as between 12 and 20 °C, for example, 2xSSC and 0.5% SDS for 5 min, 2xSSC and 0.1% SDS for 15 min, minutes: Ö,íxSSC and 0.5% SDS at 37 *C for 3Ö-ÖÖ minutes, then ÖJxSSC and 0.576 SDS at 68°C for 30-60 minutes. For the skilled person, this means that the stringency conditions to be used depend on the length of the DNA sequence, the oligonucleotide probes (e.g. 10-40 bases) and the mixed oligonucleotide probes. When performing mixed probes, it is preferable to use tetramethylammonium chloride (TMAC) instead of SSC (see Ausubel et al., cited in the public literature). Each such mutant has a sialic acid sequence, preferably an IL-18BP sequence, that is sufficiently similar to the duplicate of the IL-18BP sequence or sufficiently similar to the duplicate of the viral H.-18BF sequence, and thus has an effect comparable to that of H.-18BP. One effect of IL-18B is that it is able to bind IL-18. If the mutant has sufficient binding activity for IL-18BP, it can be used to purify IL-18, for example by affinity chromatography, and therefore its effect is sufficiently similar to that of IL-18BF. Whether the effect of a given mutant is sufficiently similar to that of IL-18BF can be determined by conventional ghost design, for example by testing the mutant in a simple sandwich competition experimental design. <) χ φφχκ φ φφ » «χ * * * * φ φ φ ><· We examine Φ Φ χ ♦*'φ φφ and determine the extent to which the isotope binds to the photon ILHŐ; we can use, for example, a radioiotnum assay or ELISA assay. In a preferred embodiment, the sequence of a mutant is at least 40% identical or homologous to the IL-18BP homologous sequence encoded by the 1.L~1SBP or &gy & virus, as disclosed in International Patent Application WO Ü9 / Ö9ÖŐ3. More preferably, the sequence identity is at least 0%, at least 0%, at least 70%, at least 80%, most preferably at least 0%, Mutants of the IL-18BP polypeptide or mutants of the viral IL-18BPs that can be used in accordance with the present invention, and the nucleic acids encoding them, contain a substantially corresponding sequence region and can be substituted for peptides and polypeptides that are routinely used by those skilled in the art, but their use does not require the performance of unduly burdensome experiments based on the disclosure and guidance provided herein. Preferred in the present invention are those substitutions known as conservative substitutions. The IL-18BP polypeptides, proteins and viral IL-18BPs with conservative amino acid substitutions (substituted with synonymous amino acids) have similar physicochemical properties such that the substitution with an amino acid within the group preserves the biological function of the molecule (Grandiam 0974}]. It is clear that it is also possible to insert amino acids into or delete from the above sequences, if this does not cause a change in function; especially if only a few, for example less than 30, preferably less than 10 amino acids are inserted or deleted, and amino acids crucial for function, such as esteinase residues, are not deleted or replaced. The proteins and mutants obtained by such deletions and / or insertions are within the scope of the present invention. Preferred synonymous amino acids are given in Table 1. Particularly preferred synonymous amino acids are given in Table 2; the most preferred synonymous amino acids are given in Table 3. Table 1 Preferred synonymous amino acids Amino acid and amino acids Ser Ser, Thr, Gly, Asn Arg Arg, Glu, Lys, Glu, Small Leu Be, Phe, Tyr, Met, Val, Leu Pro Gly, Alá, Thr, Pro l'hf Pro, Ser, Alá, Gly, His, Gin, Thr Áia Gly, Thr, Pro, Alá Val Met, Tyr, Phe, 11«, Len, Val Gly Alá, Thr, Pro, Ser, Gly Be Met, Tyr, Phe, Val, Len, Be Phe Ttp, Met, Tyr, Be, Vál, l.eu, Phe Tyr Trp, Met, Phe, 11«, Val, Len, Tyr Cys Ser, Thr, Cys His Glu, Lys, Gin, Thr, Arg, His Gin Glu, Lys, Asm, ííís, Thr, Arg, Gin Table 2. Particularly preferred synonymous amino acids Amino acids Synonymous amino acids Ser Ser Arg Hb, Lys, A.rg Len Len, fíe, Phe, Met Pm Alá, Pro Thr Thr Aia Pro, Ah? Vb Val, Met, ife Gly Oly lle He, Meg phe, Vei Í,e« Phe Meg Tyr, ife. Leu, Phe 'i>· Phe, Tyr Cys Cys, Ser His His, Gin, Arg Gb Gitt, Gin, His ÁSS. Asp, Asm Lys lys, Arg Asp Asp, Áss Gh: Gb, Gh· Met Meg Phe, He, Val, .Leu Tsp Trp Table 3. Most preferred synonymous amino acids Amino acids Synonymous asaínos Ser Ser Arg Arg Lee Len, He, Mel Ere Pro Thr Thr X »· * «*»« * Φ * ·χ XX# V # Any known method for preparing amino acid substitution mutants of IL-188F polypeptides and viral IL-18BF mutants can be used in accordance with the invention, such as those disclosed in U.S. Patents 4,959,314, 4,588,585, and 4,757,462 (Mark et al.), 5,116,945 (Kelte et al.), 4,965,195 (Namen et al.), 4,879,111 (Chong et al.), and 5,017,691 (Lee et al.). Lysine-substituted proteins are disclosed in U.S. Patent No. 4,904,584 (Shaw et al.). By fused protein'1teeuhniuorotes we mean polypeptides which comprise IL-18BF, or IL-18SIM, fragments or mutants thereof, fused with another protein, where the other protein is for example present in the body fluid for a longer period of time. IL-18BF or the virus IL-18BP may be fused with another protein, polypeptide or the like, which may be, for example, an immunoglobulin or a fragment of a umntringlcbal. By functional derivatives, we mean derivatives, mutants and fused proteins of IL-18BP and viral IL-18BP, which can be formed by the functional groups on the side chain of the residues or at the N- or C-terminal end by methods known in the art, and which are within the scope of the invention, provided that the function of the protein, which is essentially identical to the action of IL-18BP or viral IL-18BP, is not lost, and the pharmaceutical composition containing such derivatives does not have toxic properties. Such derivatives include, for example, derivatives containing a polyethylene glycol side chain, which mask the antigen binding sites and increase the resistance of the IL-188F and IL-18BF viruses in body fluids. Further derivatives include, for example, aliphatic esters formed on the carboxyl group, amides formed by reactions of the carboxyl group with ammonia or primary or secondary amides, free arms of amino acids with acyl groups. (for example, with altenoyl groups or carfcocyclic amide groups) *4 * X 4 4 * Λ 44 π N-acetyl derivatives formed by the reaction of the ester groups (for example, the hydrolyzed groups of the ester and phenyl residues), According to a further advantageous embodiment of the invention, the IL-1α inhibitor is a s,11-1 g or tus, which is directed against the 11,.-:18R subunits. Ax :11..-18R are antibodies, the production of which is carried out on 11.-1 bfert and β, so that the present invention can be applied to the body. The antibodies of the invention may be polyclonal or motile, human, humanized or even fully human antibodies. The antibodies of the invention and their derivatives are characterized by their affinity for the Ih-lk-hms and the four In carriers bound to them and by their low titer. The antibodies of the invention are characterized by their ability to produce an adequate or significant improvement or alleviation of any symptoms or reactions associated with a pathological condition or a pathological condition. They can be administered to a patient for a period of time necessary to achieve or maintain a satisfactory level of efficacy and are of low toxicity. Antibodies are easily produced in animals, such as mice, rats, and mice, by incubating with 1L-tfe-eal or 11,-lkfe-vsi or β. The mice used for the production of hybridomas have well-formed 8-cell ImoÁsrtk, which are adapted to produce monoclonal antibodies to non-human primates, Chimeric antibodies are immunoglobulin molecules that are characterized by the fact that two or more of them are derived from different types of proteins. The variable part of the chimeric antibody is derived from a human mammalian cell, for example, a mouse cell, and the immunogenic part is derived from an animal immunoglobulin molecule. Preferably, both parts and the combination are also present in the human body, which can be achieved by conventional methods [Eiliod et al., 1994). Homologous antibodies are immunoglobulin molecules that can be produced by genetic engineering and in which the constant part derived from the mouse part is replaced by its equivalent, so that the antigen-binding site of the mouse antibody is unchanged. The resulting mouse antibody preferably has a lower degree of immunogenicity than human antibodies [Eiliod et al., 1993]. In a further preferred embodiment, the 11, 19 and nz It-ISR antibodies are humanized antibodies. Preferred examples of humanized anti-ISR antibodies are the antibodies disclosed in the patent application Ser. No. 37 / 037 / 037. In another preferred embodiment, the antibody is entirely human. Methods for producing human antibodies are described in detail, for example, in WOÖÖ / WIÓ, n WO 99 / 53049, OSö 162 9© and AU Sdsölöö. One method for producing fully human antibodies involves the production of mouse humoral (hum) antibodies, i.e., strains of mice capable of producing human lg (smmegre). This method involves the introduction of a series of lg (lg) sites into mice in which endogenous lg genes have been expressed. The lg sites are complex, with a wide range of physical structures and expression patterns. Many antibodies can be produced by first selecting, in particular, the V, D, and I genes found on lg sites. These sites contain intermediate regulatory elements that regulate antibody expression, allele exclusion, class selection, and differentiation. By introducing unverified etulseri lg inassxgéoek into the mouse, it was shown that the mouse recombinant machinery is ésstefehetó (comp13 ♦ *x * X íí * S * >'X tibilis) with human genes, Hn-mAbs with specific hibndoma secretions with the cloned isotypes can be produced by hybridization with the satjomouse antigen, Methods for producing completely homogeneous snbtesteh and cases are known from the prior art (for example Meudoz and Murtóámi (1997): Baggomasm and .tennkafersal (1991): Tomüoks and wtaM (in the context of the invention and the patent application WO 93(24893, A preferred selected 11-18 inhibitor of the invention is a 11-18BF or its isoform, mutant, fused protein, functional derivative. These isoforms, fused proteins and functional derivatives retain the ability of 11-18BE to bind to the biological activity of 11-18BE, and preferably have at least one effect equivalent to that of 11-18. In this regard, these promoters are generally more effective than the unmodified Ik-13.139. The ib-I8BF sequences and their cleaved variants can be prepared according to the procedure described in WO 99(0903), or according to the procedure of Biovtek and Masteal (1999) or Kíax and Nsnnkatár (1999). The functional derivatives of Ik-lbBF are conjugated with polymers and the protein has more favorable properties, for example! better stability, longer half-life, more favorable biological activity, better absorption by the human eye and we can avoid the need for a large amount of sümmizing casting. In this case, the lldö-BE can be coupled to a polyethylene glycol (EEG), The coupling to E&ö-bez is carried out by known methods, for example! the method described in patent application WO 92(1 3095. The heat transfer is a beneficial effect. It was taken by the 1L-1.8 mblbltomk, especially the B..-1.8BE PEGdsez is connected. A further embodiment of the invention is the 1L-18 inhibitor condensed with a protein. Such a condenser contains all or part of the 11,-18 peptide, which is either fused with a salt or a salt. It will be apparent to the skilled person that the resulting fused protein of the invention will exhibit the activity of the 11,-18,139, particularly its ability to bind 11,-18. The condensation may be direct or may involve a short link across the protein, such as 1-3 amino acids, or may involve a longer peptide residue, such as 13-20 amino acids. The top link is a peptide. The sequence of anuíly is EFM (Gls-Ebe-Met). For example, a 13-amino acid bush was found, whose sequence is öfe-EhaOly-Áte-Gly-kamVzi-Lteoöly-Gly-GhnEhe-Mes, where the first latkor sz is inserted between the Π.-Ι8Β9 sequence and the inmmsgiobnlm sequence.The resulting condensed protein has more favorable properties, such as remaining in the body fluid for a longer time (longer half-life), having a greater specific effect, a higher level of expression, or being easier to synthesize than the condensed protein. A preferred core molecule is IL-18BP fused to the constant portion of the Ig molecule. Preferably, it is fused to the chain of the Ig molecule, such as human IgG1 CB2 and CHS. A generation of specific fused proteins comprising IL-18BP and a portion of a ltototngbolom is described, for example, in WO 99((190§3, for example. And other isoforms of Ig molecules can also be used to produce generations of the phase proteins of the invention, such as the IgG; and IgG^ isoferms, or other Ig: classes, such as IgM and IgA, for example. The fused proteins can be monomeric or monomeric proteins, and can be inserted or hotmmndmners. In a further embodiment of the invention, the HL-18 inhibitor is administered in combination with a TNF antagonist. The INF antagonist can exert its effect in a variety of ways. One way is by binding to the TNF molecule, or sequestering it, with high affinity and specificity to partially or substantially neutralize the TNF epitope or epitopes responsible for binding to the TNF receptor (hereinafter referred to as a "sequestering antibody"). The sequestering antagonist can be, for example, an antibody against TNF. TNF can also be an antagonist that inhibits the TNF signaling pathway, which is activated by the cell surface receptor upon binding of TNF (hereinafter also referred to as signaling antagonists). Both groups of antagonists can be used in the treatment or prevention of heart disease, alone or together, or in combination with an IL-11 inhibitor. TNF antagonists are readily identified and readily evaluated in vitro for their affinity for natural TNF and for sensitive cell lines, such as human B cells, in which TNF induces cell proliferation and immunoglobulin secretion. The assays included TNF preparations in addition to various dilutions of the antagonist to be tested, where the dilution was, for example, 0.1-200-fold molar ratio relative to the amount of TNF used; in addition, samples containing TNF alone or antagonist alone were also tested (Tuecí and Mutaatásviai, 1992). The TNF antagonist of the invention is preferably a sequestering antagonist. Among the sequestering antagonists, polypeptides that bind TNF with high affinity and have low immunogenicity are preferred. TNF receptor molecules and TNF neutralizing antibodies are particularly preferred. For example, soluble TNF-RI and TNF-RII can be used according to the present invention. Truncated versions of these receptors, which contain the cell-secreted domains of the receptors and their functional parts, are particularly preferred antagonists according to the invention. Truncated soluble TNF receptors of type I and type II are described, for example, in European Patent Publication No. EP 914431. TNF receptors are soluble in truncated form, and have been detected in urine and serum as 30 kDa and 40 kDa TNF inhibitor binding proteins, which have been named T8P1s and TSPHs, respectively (Engefmann et al., 1995). The use of the lt-18 inhibitor concomitantly with, following or independently of the TNF antagonist is also advantageous in the context of the present invention. In a further preferred embodiment, the TNF antagonist useful in the present invention is human TNF-RI (T8P1), which is soluble. Natural and recombinant soluble INF receptor molecules and methods for their preparation are described in European Patent Publications EP 308 378, EP 398 327 and EP 433 900. Functionally similar derivatives, fragments and biologically active portions of the receptor molecules may also be used in the present invention. Biologically active equivalents or derivatives of the receptor molecules refer to a corresponding portion of the polypeptide, or to the sequence encoding the receptor molecule, of suitable size and capable of binding TNF with such affinity that the interaction with the TNF receptor bound to the motofelan is inhibited or blocked. The II.18 inhibitor may be administered simultaneously with, after, or separately from the TNF inhibitor. According to the invention, the medicament may also contain known agents useful in the treatment of heart diseases, such as aurates, e.g. nitroglucerne, vizhtol, ACF febbititoks, digitalis beta-blockers, calcium blockers, together with the IL-18 inhibitor. The active agents may be used simultaneously, sequentially or separately. ΦΦ X * *#φφ φ * « φφ *# * XXX χ X Φ % *»♦ »* »»« ♦» ♦«« ♦♦» »♦ According to a further preferred embodiment of the invention, the lt-18 inhibitor is administered in an amount of about 0.001-100 mg / kg, 1-10 mg / kg or 2-5 mg / kg. The isbibifor of the invention is preferably administered systemically, more preferably subcutaneously or intramuscularly. The invention further relates to the use of an expression vector containing an IL-18 inhibitor coding sequence for the preparation of a medicament for the treatment and / or prevention of myocardial disease, wherein the IL-18 inhibitor is selected from the following: antibodies against IL-18, antibodies against any of the IL-18 receptor subunits and IL-18 binding proteins, or their seforms, mutants, fused proteins, which inhibit the biological effect of IL-18. Thus, the IL-18 inhibitor can be delivered to the appropriate location by gene therapy. For the treatment and / or prevention of heart disease, the gene therapy vector containing the lt-18 inhibitor sequence is directly injected into the diseased tissue, thereby avoiding the problems associated with systemic administration of gene therapy vectors, such as dilution of the vector, penetration and access to target cells or tissues, and side effects. The invention includes the use of a vector for inducing and / or promoting the endogenous production of an IL-18 inhibitor in a cell in which the expression of the IL-18 inhibitor is normally inhibited or which expresses the inhibitor in sufficient amounts, wherein the IL-18 inhibitor is selected from the following: IL-18 binding proteins or isoforms thereof that inhibit the biological activity of IL-18. The vector may contain a regulatory sequence that is functional in the cell in which the IL-18 inhibitor is desired to be expressed. The regulatory sequence may be introduced into the right-hand side of the genome by homologous recombination, thereby operably linking the regulatory sequence to the gene whose expression is desired to be induced or increased. This technology is commonly referred to as endogenous geroactivators and is described in WO§ 1 / 0995 S. It will be apparent to those skilled in the art that the expression of IL-18 can also be directly blocked by using an IL-18 inhibitor using the same technique. Alternatively, a negative regulatory element, such as an expression inhibitor, can be introduced into the IL-18 gene to downregulate or inhibit the expression of IL-18. It will be apparent to those skilled in the art that downregulating or inhibiting IL-18 expression in this manner is as effective in preventing and / or treating disease as using an IL-18 inhibitor. The IL-18 inhibitor useful in the present invention is preferably administered in a pharmaceutical composition, optionally together with a therapeutically effective amount of a TNF inhibitor. IL-18I3P and its above-described isoforms, mutants, fused proteins, phosphodiesterase derivatives, active fractions - and circularized permutated derivatives - are preferred active ingredients in pharmaceutical preparations. The term "pharmaceutically acceptable" includes any carrier that neither interferes with the biological activity of the active ingredient nor produces a toxic effect on the organism to which the drug is administered. For parenteral administration, the active protein or proteins may be dissolved in a suitable solvent, using physiological saline, dextrose, serum albumin or Ringer's solution as the vehicle. The active ingredient of the pharmaceutical composition according to the invention can be administered to the body of the individual to be treated in various ways. The treatment can be carried out transdermally, transdermally (for example in the form of a delayed release preparation), subcutaneously, intravenously, subcutaneously, orally. Any other route of administration is also possible, such as injection into epithelial or endothelial tissues or gene transfer, where DNA encoding the agent is introduced into the patient's body (e.g., by means of a vector) to induce expression and expression of the desired protein. The proteins of the invention may be administered together with other conventional components of pharmaceutical compositions, such as pharmaceutical excipients, excipients, diluents, and carrier proteins. For parenteral (e.g. intravenous, subcutaneous or intramuscular) administration purposes, the active protein or proteins are formulated as a solution, suspension, emulsion or powder in a pharmaceutically acceptable carrier (e.g. water, saline or dextrose solution) and with additives which ensure the isotonicity (e.g. sodium chloride) or chemical stability of the solution (e.g. suspensions and powders). The active protein or proteins can be used in the usual manner. The biological activity of the protein or molecule of the invention can also be increased by conjugation methods, which prolong the half-life of the molecule in human organisms. For this purpose, the molecule can be conjugated to, for example, polyethylene glycol, as described in WO §2 / 13085. The therapeutically effective amount of the active substance (peptides) that can be used depends on several factors, such as the type of antagonist, the affinity of the antagonist for the receptor, the residual cytotoxic effect of the antagonist, the method of treatment, and the clinical condition of the patient (including whether a nontoxic level of endogenous IL-18 activity is required). A "therapeutically effective amount" is defined as the amount of the inhibitor that, when administered to a patient, inhibits the biological activity of IL-1β. The effective dose, whether single or multiple doses, for a given individual will depend on a number of factors. These include the pharmacological properties of the IL-1β inhibitor, the route of administration, the patient's condition and characteristics (sex, age, weight, general health, size), the severity of the disease, other treatments, the frequency of treatment, and the desired effect. One skilled in the art will be able to determine and adjust the appropriate dosage regimen and to perform in vitro and in vitro methods by which the inhibition of IL-1β in a given individual can be determined. According to the invention, the 11-18 inhibitors are administered in doses of 0.1-10 mg / kg body weight, 0.1-5 mg / kg body weight, 1-3 mg / kg body weight or 2 mg / kg body weight. The preferred method of administration according to the invention is single administration. In addition, the present invention is preferably administered topically. In order to deliver the 11-IS Inhibitor directly to the site of interest, topical administration is preferred. According to a further preferred embodiment, the 18-mg dose is administered to the patient as a single dose or as a single dose the next day. The daily dose is usually given to the patient in several divided doses to achieve the desired result. The second or subsequent doses following the first dose may be the same as the initial or previous dose or may be greater or less. The second or subsequent doses may be given before or during the onset of the disease. According to the invention, the .11.-1 Inhibitor may be administered either as a single agent or as part of a combination therapy prior to, concurrently with, or following a therapeutic, adjuvant, or other medical treatment. The .11.-10 Inhibitor is administered in a therapeutically effective dose, particularly a ** »* *s ***$ * « $ »*❖ *2 « «$í> *« * « A« TNF inhibitor and / or other cardioprotective agent. If the active ingredient is administered together with other pharmaceutically active substances, these may be administered in one pharmaceutical composition or in separate compositions. The invention also provides a method for preparing a pharmaceutical composition comprising combining an 11..-1$ inhibitor and / or a THE antagonist with a pharmaceutically acceptable carrier. The invention also provides a method for treating heart disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a II..-18 inhibitor, optionally in combination with a THF antagonist. Examples Example I Inhibition of II,-18 reduces myocardial ischemic dysfunction: in vitro Materials and methods Reagents; The IL-18BPa isoform was expressed at the N-terminus of a hamster ovary cell (Hls)6 fragment and purified until homogeneous. The ability of FL-1 .SBPa-CHisjé to neutralize IL-18 is known (Kim et al., 2000). The ICE inhibitor (ICEi) 2kc-Try-Val-zkla-A^-toorineethylketoate (YVAD) was obtained from Alexis Biochemicals (San Bíego) and was dissolved at a concentration of 10 mg / ml in DMSO-phe. ICEi-·?: was diluted in Tyrode's solution before use. ICEi reduces endotoxin-induced secretion of IL-1β by 92% in human peripheral blood monoclonal cells, as detected by ELISA kit (Cistron Biotechnologies, Pine Brokk, NT). Isolated ventricular septal defect During extensive coronary artery bypass grafting, patients require implantation of a catheter-equipped oxygen pump into the right atrium. A small segment of the right atrial appendage is routinely excised and removed. The foam was obtained from this removed tissue. Tissue from human atrial tissue was placed in oxygenated Tyrode buffered solution for 4 x 10 min. Every 12 h, fresh modified Tyrode solution was prepared with deionized distilled water containing 5.0 mmol / L D-glucose, 2.0 mmol / L potassium chloride, 118.0 mmol / L acetonitrile, 4.0 mmol / L potassium chloride, 1.2 mmol / L MgSO4x7H2O, 25.0 mmol / L sodium bicarbonate; and 1.2 mmol / liter sodium dihydrogen phosphate. The substrate Tyrode solution also contained 7 mmol / liter of choline chloride to adjust osmolarity. Unless otherwise stated, chemicals and reagents used were Sigma products.2-4 pieces (4-7 mm long, <1.0 mm in diameter) were immersed in the force transducer and 30 ml of warmed (37 °C) modified Tyrods buffer; the non-oxygenated section was replaced with a 92.5% O / 7.5% CO2 mixture. This gas mixture was filled to a higher partial oxygen pressure of 350 Hg:ntnx-ttsl (1 Hgmnv-LLI Pa), the partial pressure of carbon dioxide was 3Ő-40 Hgtnm, and the pH value was 7.35-7.45; All parameters were routinely monitored with an automated blood gas analyzer. The temperature of the chamber was maintained at 37°C throughout the experiment. During the stimulated ischemia stage, the gas mixture was changed to a 92.5% N / 7.5% CO mixture. This mixture corresponded to a partial oxygen pressure of less than 50 Rgmm. The buffer solution was changed every 29 minutes, except for the 30-minute period of the stimulated ischemia. Experimental data; The trabecula was equilibrated for 90 min, and the initial tensile force was increased to 1,000 st?,g-it and the developed force was allowed to develop. A trabecula in which mm is 25Ő ?ng-cal develops a greater force. f; saries from the experiment. During the 90-minute equilibration period, the area was stimulated with platinum electrodes (Radnóti Glass, Mosrovia, California). The electrodes were placed on one side of the scrotum, stimulated with a Grass SD9 stimulator (W&rwíek, Rí), with 6-second pulses at a voltage 20% above threshold, at a frequency of 1 Hz during the normotensive period, and at a frequency of 3 Hz during the ischemic period. Contractions were monitored with a force transducer (Grass FRÖ3), and the data were recorded with a computer-controlled multiplier and digitizer (Mactab Quad órígge, MaeLab / 8e, AD Instruments, Milford, MA) and continuously recorded with a Macintosh computer. After equilibrium was established, we studied a patient's trabeculum in three different experimental setups: in the control experiment, suprafusion was used for 90 minutes providing normal oxygen supply: in the I / R experiment, 30 minutes of stimulated ischemia followed by 45 minutes of reperfusion were used; in the third experiment, anticytokine was used. In the latter case, antileukin was added to the suprafusion bath before the onset of ischemia and was also used during the 45-minute reperfusion phase. Preserves trabecular CK aquifolium The CK activity of the final (91) minute) reperfused tissue was determined by the method of K&plan et al. (1993). The assay was performed using a CK kit (Sigma) and an automated spectrophotometer. The results were expressed in CK activity units / mg· (based on the wet weight of the tissue). RNA isolation and reverse transcription-linked PCR Fresh trabeculae were homogenized in Tri-reagent (Molecular Research Center, Cincinnati) and total RNA was isolated by chloroform extraction and isopropanol precipitation. RNA was dissolved in diethylpyrophosphate-treated water, treated with DNA, and mtyd methylation was determined using a GeneQuant 1 (Amersham Pharmacia Siotech) instrument. cDNA procedures are described by Reznikov et al. (2000). The following sequence was used for each PCR: 15 min pre-excitation at 95 °C, 1 min cycles at 94 °C for 49 s, 55 °C for 45 s, and 72 °C for 1 min, the final extension phase was a 10 min extension at 72 °C. The optimal number of cycles was 35. Primers for glyceraldehyde-3-phosphate dehydrogenase (GADPH) and human IL-18 (Reznikov et al., 2000) and primers for human IL-18BPa (Kim et al., 2000) are known.PCR products were separated on a 1.5% agarose gel containing 0.5xTBE (50 mM irisin / 45 mM boric acid / 0.5 mM EDTA, pH 8.3) and 0.5 mg / ml ethidium bromide, visualized under UV illumination and photographed. Densitometry was performed on the negative (ÍMAGEQUANT software, Molecular Dynamics) and the relative absorbance of IL-18 and IL-Í8BPPCR products was corrected for the absorbance obtained for GAPDH. 11..-1.8 definition Fresh trabeculae were homogenized as described for CK measurements. IL-18 was determined by liquid phase electrochemiluminescence (ECL, Yes, Gauthersburg, MD). Mouse anti-human IL-18 mAb (R&D Systems) was labeled with a nuclear isotope (IgE). Affinity-matched purified goat anti-human IL-18 antibody (R&D) was labeled with biotite (yes). The biotinylated labeled antibody was diluted to a final concentration of 1 pg / ml in PBS (pH 7.4) containing 0.25% BSA, 0.5% Tween-20, and 0.0135 azide (ECL buffer). 25 µl of biotinylated antibody per test tube was preincubated at room temperature on 25 µl of paramagnetic beads coated with sereptavidin (Dynal, Grcat Neck, NY) at a concentration of 1 pg / ml for 30 min with vigorous shaking. The samples to be tested (25 µl) were transferred to test tubes and 25 µl of ruthenium-labeled antibody (final concentration 1 pg / ml, diluted in ECL buffer) was added. The tubes were incubated for 24 h. The reaction was performed in a tube19 * X * * * * φ ·> V* φ * * ♦ φ ΐ <.« * « * * 'then add 2Ö0 μΐ PBS and adjust the degree of chemical dispersion with the Örígea Analyzer (Yes). The limit of detection is 11,-1.8 pg / ml,. Confocal microscopy images of the tissue obtained by inserting the cannula of the oleaginous suction tube; tissue) were placed in a 1 cm plastic holder (Meldrum et al., 1998), embedded, frozen in tissue-fixing medium (Triangle Biomedical Sciences, Durham, N'C) on isopropanol-cooled dry ice. Frozen sections (5 μm) were sectioned with a Leica CM 1850 (Leica, Deerfield, IL). The sections were fixed in 4% paraphosaldehyde for 10 min, air-dried, and incubated in PBS supplemented with 10% normal goat serum for 20 min. The sections were mounted in a 10% dilution of rabbit authi-horonate. Sections were incubated with 1 pg / ml non-immune salivary IgG (Peprotecb, Feocky Hill, NJ) as a control, followed by incubation with 1 pg / ml non-immune salivary IgG. The antibodies were diluted in FBS containing 1% BSA. The sections were kept overnight at 4 °C and then washed three times with PBS containing 0.5% BSA.The sections were then incubated with a secondary goat anti-rabbit antibody conjugated to Alexa 488 (Molecular Probes) for 60 min in the dark at room temperature. The nuclei were stained with 1 pg / ml bisbenzimidazole blue (Simon). After staining, the sections were washed and examined with a Leica DM SXA confocal laser scanner and analyzed with Slidebook software (Macintosh) (Intellectual Innovations, Denver). Statistical analysis The mean ± standard deviation (SD) values ​​were calculated from the data. The mean change in expression measured after 90 minutes compared to the control was determined for each patient tissue. The statistical significance of the difference between the groups was determined by one-way ANOVA, with Bonferroni-Du»» post hoc analysis. Statistical analysis was performed with Sit-view 4.51 software (Abacus Concepts, Calabasas, CA). Results Effect of neutralization of endogenous Π.,-18 with Π..-18BP on force exerted after ischemic condition Figure 1A illustrates the kinetic response of the trabeculum to 1 / R injury. The figure shows the last 15 minutes of equilibrium, normalized to 10% of the initial value. The control trabeculae were stabilized under normal oxygenation during the experiment. As can be seen, the force exerted decreases to 10% of the control trabeculae. In the ischemia-exposed trabeculae, the force of contraction rapidly decreased; during reperfusion, the force of contraction reached approximately 25% of the control force. In contrast, the force of contraction of the trabeculae exposed to ischemic stress in the presence of 1L-1SBP reached 55% of the control force. To estimate the 1 / R response in cardiac tissue from different patients, the control The force exerted on the trabeculae after 90 minutes was considered 100% for each patient sample, and the percentage change in the force exerted was calculated for each experimental group. As shown in Figure 11, the force exerted by 1 / R on untreated trabeculae after ischemia decreased on average to 35% of control, but in the presence of 1 pg / ml IL-18B.P this force decreased to only 06.2% of control, and in the presence of 5 pg / ml XL-18BP it decreased to only 0.0% of control. These results indicate that 1 / R causes the release of biologically active IL-18 after the endogenous precursor 11.-18 is released by ICE. We determined the level of TL-1.8 in freshly extracted atrial tissue. As shown in Figure 2, basal IL-18 was present in the trabeculae that were obtained before the oxygenated bodies were inserted into the right atrium. After a 90-minute equilibration period, a 30-minute ischemic period, and a 45-minute reoxygenation period, the trabeculae were homogenized and the IL-8 levels were determined. The IL-18 content of the tissue increased by 4.5-fold after LR in the examined tissue (Figure 2). β The mRNA levels of IL-8 and IL-18BP were also determined in these tissues, and in freshly harvested atrial myocardium before ischemia, the expression of IL-8 and IL-18BP was observed (Fig. 3, A and B). Similar to the increase in IL-18 protein, IL-18 induced a further (4.7-fold) increase in the steady-state mRNA level. IL-18SR gene expression was also detectable in freshly harvested atrial tissue, but increased only slightly (13-fold) after the 1K period. Determining the location of 11,-18 in human cardiac muscle Given that ECL assays showed that 11,48 protein and 11,48 RNA were present in freshly harvested myocardial homogenates, histochemical staining was used to determine the location of 11,-18. Atrial tissue was harvested immediately before insertion of the oxygenation pump cannulas and immediately snap frozen (not shown). IL-18 was detected in resident myocardial macrophages and vascular endothelial cells. IL-18 is present in macrophages and endothelial cells prior to surgical ischemia and prior to contact with any foreign surface. The presence of IL-18 in resident macrophages and senile epithelial cells is consistent with previous studies of preformed constitutive IL-18 precursors in human peripheral blood mononuclear cells freshly isolated from healthy one-year-olds (Porén et al., 1999).From this we can conclude that the preformed Π..48 proconvulsor is prominent in the myocardium of patients who are scheduled for coronary artery bypass surgery due to ischemic heart disease. Effect of 1CE inhibition on force exerted after ischemia Since 1L48BP effectively attenuates myocardial ischemia-induced dysfunction, we hypothesized that inhibition of the conversion of the preformed ii.,-18 precursor IE48~e would also attenuate myocardial ischemia-induced dysfunction. Therefore, we added the specific ICE inhibitor YVÁD to the suprafusion bath before ischemia induction. Inhibition of ICE continued with the addition of YVÁD during the ischemic phase and during the reperfusion period. YVÁD-mediated IGE inhibition attenuated myocardial ischemia-induced dysfunction, as the contractile force increased to 35% of the control after 1 / R at a concentration of 10 pg / ml and 75.8% at 20 pg / ml! in the horse (Figure 4). These results demonstrate that biologically active IL-18 in human myocardium is generated from the preformed IL-18 precursor. The results also suggest that myocardial ischemia activates latent ICE. Maintaining cell viability The determination of CN putative intrastellate cells was used to estimate cell viability after ER. According to the study, the higher the CK value, the greater the number of viable cells. All anticytokine interventions acted in the direction of preserving cell viability. As shown in Figure 5, 1L4SSP and 1C.E inhibition (111 and 20 μg / ml) increased the post-ER cellular CK level from 1.399 to 5.921, 5.075, 6.624 and 4.602 CK activity units per milligram (based on wet tissue), respectively. These observations indicate that ER-induced activation of .11.48 helps to preserve muscle cell viability in the above ex vivo model. The neutralization of TMFse-induced cardiac hypertrophy As shown in Figure 6, the developed force (DE) of the trophectasias decreased to 18H 90 minutes after exposure to exogenous TNFα. We examined the effect of neutralization of endogenous .11-18 on the contraction of human myocardium exposed to exogenous TNFα by incubating the tissue with 11,-18BP for 10 minutes before adding TNFα; we found that the developed force (DF) decreased to a lesser extent, as shown in Figure 6. After 90 minutes, the developed force (DF) in the control group decreased by 18%, while in the TNFα-exposed group it decreased by 58% compared to the control. However, the effect of TNFα was not significant. The force exerted by trabeculae incubated with IL-18BF was reduced by only 0.05% compared to control. These data indicate that the direct effect of TNFα on myocardial contractility is at least partially mediated by the biologically active endogenous 11-18. Effect of exogenous IL-18 on exerted force In the next study, we determined the direct effect of exogenous IL-18 on myocardial contractility. IL-1b was added to the superphase tracheole 90 minutes after equilibrium was reached, and each bath was changed. As shown in Figure 7, IL-18 slowly but progressively reduced the force exerted over the course of the experiment. With continuous IL-1b treatment for 90 minutes, the force exerted decreased by 42%. These data indicate that exogenous IL-13, like TNF-α, has a myocardial relaxant effect. It is noteworthy that the myocardial relaxant effect of 11,-18 is not as great as that of TNFct. Maintaining cell viability Some of these cases often undergo programmed cell death (apoptosis). To estimate the viability of the trabeculae exposed to TNFα, we measured the intracellular creatine kinase (CK) content of the tissue. In this study, high CK levels indicate cellular viability. As shown in Figure 8, the measured CK activity in control trabeculae that received 90 minutes of normal oxygenation superfusion was 88±2 units per milligram of wet tissue. In contrast, lower CK levels were measured in trabeculae exposed to 30 / 45 minutes of L'ZR exposure and 90 minutes of TN'fö. exposure, 1774-1181 and 3246*21? units, respectively. In the presence of TNFtx in the presence of IL-18UP, CK levels of 5005*212 units / mg tissue were measured in the trabeculae treated with TNFtx. Interestingly, trabeculae treated with TNFtx preserved CK levels to a greater extent than trabeculae exposed to IL-18UP.This was an unexpected effect, as at the end of the experimental period the decrease in force exerted was similar in the I / R-exposed tissue as in the TNF-exposed tissue. Example 3 The protective effect of 1L-18BF against myocardial infarction In vehicle Proceedings Intramuscular electrotransfer of the 1L-18BF expression plasmid carrier in mice C57BV6 mice were injected every three weeks with an expression plasmid for IL-18BF cDNA, designated peDNS3~.iL 18BP, as described in WO 01 / 85201. Control mice were injected without plasmid. Mouse IL-18BF isoform d cDNA (accession number Q9ZÖM9) was isolated by the method of Kim et al. (2000) and subcloned into the BcoR1 / Nöít site of the peDNA mammalian cell expression vector, under the control of the ehomegalevirus promoter (litvitrogen). Control plasmid A was prepared similarly, but without the therapeutic cDNA. The control group consisted of 31 mice, and the experimental group, which received IL-18BF, consisted of 27 mice. IL-18BF-I and the control expression plasmid (100 pg) were injected into both lateral cranial bodies of the splenic cords of the mice as described by Mailat et al. (1999). Transcutaneous electrical impulses (8 square-wave SOOV / em electrical pulses, 20 ms duration, 2 Hz frequency) were delivered by a PS-15 electropulsator (Genetronics, France) using two stainless steel plate electrodes, 4.2–53 mm apart, on either side of the leg. Induction of infarction in the left ventricle 2.4 hours after treatment with 1L-1 8BP, mice were anesthetized with IP altein and ketamine, ventilated, and the chest was opened. The left main coronary artery was continuously ligated using 8-0 prolene suture to induce myocardial infarction, then the chest was closed, and the animals were allowed to recover from anesthesia. Preoperative mortality was less than 20%. Postoperative mortality was 48% in the control group and 26% in the experimental group, and almost invariably occurred on days 4-5 after ligation. After ligation, mice were anesthetized and the size of the left ventricle (LV) was measured by closed-chest cardiac ultrasound (ECG), using an ATI HDI 5000 cardiac ultrasound device. The shortening of the EV segment was calculated from the measured end-systolic and diastolic parameters. Ultrasound examination of the heart «fast. the heart was removed, fixed and sectioned. The infarct sections were stained with sinus red to determine the size of the infarct. Results Left ventricular diastolic diameter was measured 7 days after ligation in surviving mice according to the following procedure: 0.53X601 mm (a~2Ö) in mice treated with ÍL~18BP, compared to 0.59+0.01. mm in control mice («--16), p<0.Öl Left ventricular systolic diameter was measured 7 days after ligation in surviving rats according to the following procedure: 0.45*0.02 in IL-1SSP-treated mice compared to 0.05+0.02 in control mice, »<0.0 i Shortening of the left ventricular segment: 15+1% in mice treated with Í.E-18BP, compared to 11+-1¾ in control mice, ρΟ,ΟΕ Summary of the results: IL-18BP reduces the mortality of mice with myocardial infarction induced by total left ventricular coronary occlusion by 50%. Left ventricular function is significantly improved, as evidenced by reduced left ventricular systolic and diastolic diameters. 1. Bőid, R. CbxWfttdm §2,723-38 (1990) 2. Buggemann et al., £«r. J, ímmnno / . 2.1, 1323-1326 (1991) 3. Cain, BS, Meldrum, DR, Dinarello, C,A,, Meng, X., Banetjee, A. and Harken, AH J, j?es. 76, 117-125 (19911) 4. Cleveland, Í.C.1, Mekirum, DR, Caist, BS, Barserjee, A. and Hsrk.es, AH Cimderioa 96,29-32 (1997) 5. Daemen MA, vsad Veer C, Wolfs TG et al., Ischsndtereperfsstos-inífoced IFN-gamma up~ -reguktlon: involvement of IL-12 and 11.-18:7. Znomm» / . 162,5596-5510 (1999) 6. DrDonatao, LA,, Hayakawa, M,, RothwarC DM, Zandi, E, and Karin, M.: Mkw 2g|, 16514-46517 (1997) 7. Flliott, ML, Maim', RN, Feidsnana, M,, Loog-Fox, A,, Charles, R, Bljh H,, and Woody, JN, Now 344, 1125-1127 (1994) 8. Engehnanu, H., Ndviek, D., and Wallacb, D,., / . .dós / , üáeta. 265, 1531-1536 (1990) rf rfrf rf rf rfrfrf rfrfrfrf rf rf * * rfrf rfrf rf * rfrf rf rf vrf rfrf rf rf rfrfrf rfrf rf rf rfrfrf rfrf rf rfrfrf « rfrf 9, Fsmmk fe AX Fsntnk MW Hsfefe DX Liviagstoa és CA, Dimrsíio, Béfe 91,2Í18-2125 (1998) 19. Gtwtan, éfenen, 188 862-864 (1874) ) 1. Gursviích, L, Fmlkís, 1., Yttas, Y>, Psz, Υ.» Maisa, M.» Mofe M, and Yaktatah, V.? 7th km. GM. Cfefe B 242452 (1996) 12, llsfeüwfe A., ötöt, fe Ássad, AA and Wasseíirtgfa, fe dm. 7 Pata / , ,148 419-42.8 (1998) IX Medtotar, 9., .Liptai, H. Wagner, K„ FíeSer, and K, fefe, / mmtm. 6§ 35Ö218. 14, Kapta, LX, Hiúm, H,, Bsnfeen, A. and Whíttnan, GX, 7 -tag. fe. 34,31 1-5. 15, Kim SH, Hseasieis M„ tatakov t,, Famuzzi G„, Nevtók D., Robinsteia M„ Diaareile C,A. tosctarai nfeöwstas of sin natumlly oecadug tatom of fe 11.48 bitang protein to ínhibit B..-18, Aw. MnX taőd. fe, USA fel 190-1193 (200Ö) 16, Kínt S,H. and colleagues 7. .tomtta .166 148-454 (2601) 17, Knigbt DM, Tdsb H., Le L, Siegel S„ Sbeaiy fe Metassmgb M„ featat B., Moom MA, Vífcek L, Daáortsa F. and Maskatatai Cettsirueboa esd laktól eheraetedzaiíon of a mome-fcumaa «intene artti-TNE artírbody. MM. attwri. 30:16 1443-1453 (1993) 18, Msattas and colleagues Molecule (imfe: ,4 Xoéíovtóny Atom / , Cold Spdsg Hatbor Laboratory New York (1982) 19, Mekkam, D.fe Cleveland, IC, Jr„ Cta, H.fe 44¾ X. és Harto, AB, Aon, aw. fen. 6A 439-443 (1998) 26, Msosfe, MM, Gmen, LA,, Cmwtlsa, JRE, Jtó X-fe MayaardCmde, F,B„ Yaag, X-fe Osllo, ML, Lőnie, DM, Lee, B:W,, Fde&ses, K.,L.,;Luxra, L, Roy, CM-Nx, Abderraht, H.,. Krrshesbatmt, F-, Negaebí, M,« febp 13,61,, Ptrkoshírsa, A,, feles, LF,, MH, Davis, CG,» Zsebe, K,.M, és íakobevits, A, “Ettsedoaal trasspiaai of megettem kontart immurtte regfsaborsafmiial asdbody rsspesse In attack fefe? fetafe, .15 146456 (1992), 21, Nafcamurs, K,, Oksmsrs, fe Magata K, és T«m, fe .tófeé tom«, 37 399-595 (1989)22, fevtek, .fe Kist. SH, f ártotta, G.ftamrkov, fe Dmarélte, C„ és Rsbntsto, M, fentafe 16,127-136 (1999) 22, Neviek, D„, Kim, 9Ή, EaetóoL fe, teAv, !l·.,, Dmastao, C. es Rabmstaia, M.sZmmrmhy .1.6, 127-136 (1999) 23, Femet, F., Garca, KX, Hornért, 'LF., Dew, SX, és Sím®, ,i,.fe J, .fel. nothing. 271,3967-3979 (1996) 24, Pmm, AJ., Farttazt, J es Dtamtkr, CA».Ertre AW. father. Fact 6(24 96 2256-2261 (1999) 25, Raebuxn, CD., CM, Calkms, MA Ztntmenttaa, Y. Song, L. Α», A. Bamtjee, X Kong es A,H. lights, Xfefe IMS 319-325 (21X1) 26, Mnfefev, fel·,.. Kim, SB, Westeotí, 3.Y,, Eristaaa, I, Famaszi, ö., Nofek, D,, febtatótó, M, es Dtatato, CA., fen. Xfe Anta. Psychology 97 2174–2179 (2999) 27, Torigsw, K., BXfe §:„ Ofeng. T„ Kobnyfebi, 8,, Tatai» M., Knsnksto, T„, Matatott, T., Saaeu, <x, kojtsta, fe feji,. ml·,, (mfe t., ikefe m,, ikogsnk, h. és ktsrimoto, m 7. mm, (fen. .2.22 25737-25742 (1997)28, Tettatas és murtfetata» fen® AW. 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Claims

1» Use of an IL-18 inhibitor. For the preparation of a medicament suitable for the treatment and / or prevention of srivombantom, wherein the IL-18 inhibitor is selected from the following: caspase-1 inhibitor (ICB), IX-18 ellem anötestrit, any of the 11-18 receptor subunits eSms oniitótótó and fi.,-18 totótó proteins or their Itobstótó srtoltótótó, fastcivsab potóipjel or functional derivatives, which inhibit the biological effect of .11.-Iá, 2. The use according to claim 1, wherein the antibody against the IX-18 gene is 3. The use according to claim 1, wherein the 11-18 hribhor is an antibody against the H-1S receptor.

4. The use according to claim 1, wherein the IX-1.8 receptor β antagonist is a 11-18 receptor.

5. The use according to any one of the preceding claims, wherein the antibody is a humanized or recombinant antibody. The use according to claim 1, wherein the IL-18 inhibitor is a γ-TyrAX1-Alo-Asp-kıöo'Oötibdu (YVAÍ3). '?'. The use according to claim 1, wherein the IL-18 inhibitor is an IL-18 inhibitor protein or a fragment, mutant, fused protein or functional derivative thereof that inhibits the biological activity of IL-18. The use according to claim Ά, wherein the IL-18 inhibitor is a γ-glutamine-containing protein or a γ-glutamine-containing protein or a γ-glutamine-containing protein or functional derivative thereof that inhibits the biological activity of IL-18.

9. The use according to claim 1 or 2, wherein the fused protein comprises a tocodentate group (Ig). The use according to any one of claims 8 to 11, wherein the functional derivative comprises at least one group linked to one or more .ftmfc groups, which are located at one or more sites of the amino acid residues, 11. The use according to claim 9, wherein the group is a polyphenylene ester.

12. A composition according to any one of the preceding claims, wherein the medicament comprises a tumor necrosis factor (TNF) agonist. Use according to claim 9 to 11, wherein the 11-IS Inhibitor is administered simultaneously with, after or before the INF astagen.

14. The use according to claim 11 or 12, wherein the TNF agonist is TBB1 and / or T8P1L.

15. The use according to any one of the preceding claims, wherein the it-18 inhibitor is administered at a concentration of about 500-1000 mg / kg or 1-10 mg / kg or 2-5 ng / kg. Use of a vector containing a sequence of II-IS proteins for the production of a therapeutic agent for the treatment and / or prevention of srvrzombantslom, wherein the It-IS Inhibitor is selected from the following: antibodies against II-18, antibodies against any of the II-IS receptor subunits and IL-18-binding proteins or isoforms thereof, fused with a gene that inhibits the biological activity of II-18.

17. Use of a vector for expression of an IX-18 inhibitor that induces endogenous production of IX-18 in a cell as a drug for the treatment and / or prevention of cancer, wherein the IX-18 inhibitor is selected from the following; proteins such as IX-18 or isofluranes thereof that inhibit the biological activity of IX-18.