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Title:  Method of treating graft versus host disease by administration of a Fas antagonist
United States Patent: 
7,128,905
Issued: 
October 31, 2006

Inventors: 
Nagata; Shigekazu (Osaka, JP), Yatomi; Takehiro (Tokyo, JP), Suda; Takashi (Osaka, JP)
Assignee: 
Mochida Pharmaceutical Co., Ltd. (Tokyo, JP)
Osaka Bioscience Institute (Osaka, JP)

Appl. No.: 
10/084,139
Filed: 
February 28, 2002


 

Pharm Bus Intell & Healthcare Studies


Abstract

The present invention is drawn to methods of preventing and treating diseases wherein the involvement of apoptosis has been indicated.

SUMMARY OF THE INVENTION

The inventors of the present invention have conducted an intensive study on function of the Fas/Fas ligand system and the role of apoptosis mediated by the Fas/Fas ligand system in various diseases, and found that conditions may be improved in various disease models by suppressing the actions of the Fas/Fas ligand system, and in particular, by suppressing the Fas/Fas ligand system-mediated apoptosis; and that, for example, that death of cardiomyocytes upon reperfusion after ischemia, onset of the GVHD associated with allogenic bone marrow transplantation, and organ damages caused by endotoxin are suppressed by an antagonist which inhibits the Fas-mediated apoptosis. The present invention has been completed on the bases of such finding.

In other words, the present invention provides a drug, and in particular a drug for preventing and/or treating a disease, namely, a prophylactic/therapeutic agent which contains a Fas antagonist as its effective component, and which is adapted for use in a disease wherein the Fas/Fas ligand system is involved, and in particular, a disease wherein the Fas-mediated apoptosis is involved. The agent of the present invention may be used for such diseases as (1) heart diseases, and preferably, ischemic heart diseases, and especially, myocardial infarction; heart failure; and ischemic reperfusion injury; (2) renal diseases, and preferably, renal failure, renal ischemia, ischemic reperfusion injury, and acute renal failure; (3) GVHD; (4) diseases based on ischemia or ischemic reperfusion injury, and in particular, diseases based on ischemic reperfusion injury in heart, kidney, or liver; and diseases based on ischemic reperfusion injury associated with surgery or transplantation and ischemic reperfusion injury associated with thrombolytic therapy or angioplasty; (5) damages of organs caused by bacterial endotoxin, and endotoxemia, sepsis, and damages associated therewith; and in particular, liver damage and liver failure; and the like.

Another aspect of the present invention is an organ preservative agent characterized by its inclusion of a Fas antagonist. The present invention also provides an apoptosis inhibitory agent which contains a Fas antagonist as its effective component. The Fas antagonist is preferably at least one member selected from an anti-Fas ligand antibody, an anti-Fas antibody and a Fas derivative, and more particularly, the anti-Fas ligand antibody is preferably a humanized anti-Fas ligand antibody.

In other words, the present invention provides novel utilities of the Fas antagonist.

It should be noted that, in the present invention, a Fas antagonist is a substance which has a suppressive or inhibitory action, and more particularly, a substance which suppresses or inhibits the biological actions of the Fas/Fas ligand system, and in particular the Fas-mediated cell apoptosis.

BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention is described in further detail.

The prophylactic/therapeutic agent of the present invention may be used for various diseases wherein biological actions of the Fas/Fas ligand system, and in particular, the Fas mediated apoptosis are involved. In such diseases, the biological actions of the Fas/Fas ligand system, and in particular, the Fas mediated apoptosis relate to or contribute for the onset, remaining, or worsening of the symptoms or pathology of such diseases.

Exemplary such diseases are heart diseases, renal diseases, GVHD, ischemic reperfusion injury, and diseases caused by bacterial endotoxin. (1) Preferable exemplary heart diseases include ischemic heart diseases, and in particular, myocardial infarction; myocarditis caused by various factors; cardiomyopathy, and in particular, dilated cardiomyopathy; heart failure; and ischemic reperfusion injury and heart diseases caused by such ischemic reperfusion injury. The myocardial infarction include acute myocardial infarction and old myocardial infarction. The heart failure include the heart failure in ischemic heart diseases which often occur as a complication with the acute myocardial infarction or the old myocardial infarction.

(2) Exemplary GVHD include GVHD after bone marrow transplantation such as incompatible bone marrow transplantation and bone marrow transplantation in congenital immune deficiency; GVHD after organ transplantation; posttransfusional GVHD such as GVHD after blood transfusion of a large amount to a patient of hypoimmunity; and the like. GVHD is associated with organ or tissue failure based on GVH reaction, and diarrhea, exhaustion such as weight loss and thinning, exanthem, and liver dysfunction are observed. GVHD is also associated with histological symptoms such as disorganization of bone marrow and lymphoid tissue and atrophy of intestinal villi.

(3) Exemplary renal diseases include renal ischemia, renal ischemic reperfusion injury, diseases caused thereby, and renal failure and diseases causing the renal failure, and preferably, acute renal failure. The renal failure include prerenal acute renal failure, postrenal acute renal failure, and renal acute renal failure. The diseases causing the renal acute renal failure include acute tubule necrosis due to renal circulation failure or renal ischemia, acute tubule necrosis due to renal toxicity, acute glomerulonephritis, acute interstitial nephritis, and acute cortical necrosis.

(4) Exemplary diseases based on ischemia and ischemic reperfusion injury include, among others, diseases based on ischemic reperfusion injury of heart, kidney, liver, brain, lung, spleen or pancreas, and preferably, heart, kidney, or liver; diseases based on ischemic reperfusion injury associated with surgery or transplantation and ischemic reperfusion injury associated with thrombolytic therapy or angioplasty.

The term "ischemic reperfusion injury" designates injury of the tissue or dysfunction of organ or tissue which occurs upon restoration of blood flow (reperfusion) after localized complete loss of the blood flow (ischemia) by such causes as infarction, surgery, transplantation, thrombolytic therapy, angioplasty, and the like. The term "diseases based on ischemic reperfusion injury" includes the diseases found in liver, heart, kidney, brain, lung, spleen, pancreas, or the like including liver failure, reperfusion arrhythmia, and renal failure as well as conditions and pathology associated with such diseases.

(5) Exemplary diseases caused by endotoxin include injury of organs by the endotoxin, and endotoxemia or sepsis and diseases caused by the endotoxemia or sepsis such as liver damage, acute liver failure, renal damage, and renal failure.

(6) Diseases based on organ injury other than the above-mentioned diseases are also included within the diseases subject to the prophylactic/therapeutic agent of the present invention. The term "diseases based on organ injury" includes not only the organ failures such as liver failure and renal failure but also the conditions such as jaundice, increase in blood GPT, GOT, LDH and the like, fatigue, malaise, hypophagia, consciousness disorder, excitation, coma, ascites, decrease in filtration volume by glomerulus, edema, proteinuria, oliguria, hyperkalemia, metabolic acidosis, increase in blood creatinine and blood urea nitrogen, and the like associated with such diseases. MODS associated with SIRS are also included.

Other diseases which are subject to the prophylactic/therapeutic agent of the present invention are viral hepatitis and nonviral alcoholic or drug hepatitis.

In the diseases as described above, the Fas antagonist suppresses the apoptosis of the cells which compose the organ or the tissue, for example, apoptosis of cardiomyocytes.

According to another aspect of the present invention, there is provided a preservative for an organ such as heart, kidney or liver characterized by its inclusion of a Fas antagonist as its effective component.

It should be noted that the present invention is adapted for use in human, but also in animals other than human.

The Fas antagonist used in the present invention may be correctly referred to as an antagonist for the Fas/Fas ligand system, and the Fas antagonist is not limited to any particular type so long as it prevents or blocks the signal generation or transduction by the Fas at some stage, and it suppresses or inhibits the function or the biological action of the Fas/Fas ligand system, and in particular, the Fas-mediated apoptosis, and particularly, the Fas-mediated apoptosis by the Fas ligand. The Fas antagonist may act through various mechanisms, and exemplary Fas antagonists are those inhibiting the action or the function of the Fas ligand or the Fas; those interacting with the extracellular domain of the Fas ligand or the extracellular domain of the Fas; those inhibiting the interaction between the Fas ligand and the Fas; those affecting the interaction between the intracellular domain of the Fas and an intracellular factor which interacts therewith; those suppressing the activity of the intracytoplasmic factor (such as ICE-like protease) which is involved in the signal transduction of the Fas-mediated apoptosis; and the like. The Fas antagonists include both high molecular weight proteinaceous substance and low molecular weight compound. More illustratively, exemplary Fas antagonists used in the present invention include a Fas derivative, an anti-Fas ligand antibody, an anti-Fas antibody, an antisense oligonucleotide for the mRNA or the gene of the Fas or the Fas ligand, a substance which interacts with the intracellular domain of the Fas, an ICE inhibitor, and the like which are provided with the activity to inhibit the action of the Fas/FasL system, and in particular, the Fas-mediated apoptosis. Preferably, the Fas antagonist used in the present invention may be a Fas derivative, an anti-Fas antibody, or an anti-Fas ligand antibody which exhibits inhibitory action for the Fas-mediated apoptosis. In addition, the Fas and the Fas ligand are preferably of human origin; the anti-Fas antibody and the anti-Fas ligand antibody are preferably a human anti-Fas antibody and a human anti-Fas ligand antibody, respectively; and the anti-Fas ligand antibody is preferably a humanized anti-Fas ligand antibody. The humanized anti-Fas ligand antibody is preferably the one wherein the constant region and the framework region are of human origin, and the complementarity determining region are of non-human origin. The Fas antagonist used in the present invention is preferably the one which inhibits the apoptosis if the Fas-expressing cell in an appropriate assay described in International Patent Application Publication No. WO 95/13293 or the like.

It should be noted that the publications cited in the specification of the present invention are incorporated herein by reference.

The antibody used in the present invention may be either a polyclonal antibody or a monoclonal antibody, and the molecular species used in the present invention is not particularly limited. The antibody used in the present invention may be either an antibody molecule of normal form or a fragment thereof which is capable of binding to the antigen to inhibit the Fas antigen-mediated apoptosis, for example, Fab, F(ab').sub.2, Fv, or single chain Fv (scFv) which is the Fv of heavy chain linked to the Fv of light chain by an adequate linker to form a single chain. In addition, the antibody used in the present invention may be an immunoglobulin of any class, subclass or isotype. As described above, the antibody used in the present invention is not limited to any particular type as long as is capable of binding to the Fas ligand or the Fas antigen to inhibit the biological actions of the Fas/Fas ligand system, and in particular, the Fas antigen-mediated apoptosis.

The anti-Fas ligand antibody used in the present invention may be an antibody of any type (either monoclonal or polyclonal) and any origin produced by any appropriate process. The anti-Fas ligand antibody, however, is preferably a monoclonal antibody derived from a mammal. The monoclonal antibody used in the present invention may be produced in any animal species so long as it is a mammal which may be human or non-human. The monoclonal antibody from a mammal other than human may be the one from rabbit or other rodents. The non-limiting preferable examples of such rodents are mouse, rat and hamster, and use of such animals facilitates a convenient production of the monoclonal anti body. Furthermore, the monoclonal antibody may be the one which is capable of recognizing the antigen in a conventional immunoprocess such as radioimmunoassay (RIA), enzyme immunoassay (EIA, ELISA), immunofluorescent analysis, or the like, and whose activity of suppressing the apoptosis of the Fas antigen-expressing cell is measurable by an appropriate assay procedure described in International Patent Application Publication No. WO 95/13293, and the like.

Among these, an example of the most preferable anti-Fas ligand antibody is mouse F919-9-18 antibody produced by hybridoma F919-9-18 which was originally deposited on Jun. 22, 1995 in National Institute of Bioscience and Human Technology, Agency of Industrial Science and Technology (1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki-ken, Japan) (Accession No. P-15002) and transferred from the original deposition to the international deposition on May 9, 1996 (Accession No. FERM BP-5535). The sequences of the variable regions of the antibody are shown in FIG. 1 (cDNA is described in SEQ. ID No. 1) and FIG. 2 (cDNA is described in SEQ. ID No. 3).

The anti-Fas ligand antibody and the anti-Fas antibody used in the present invention may be prepared, for example, by the process described in International Patent Application Publication No. WO 95/13293, International Patent Application No. PCT/JP96/01820, and International Patent Application Publication No. WO 95/10540.

When a monoclonal antibody is used in the present invention, such monoclonal antibody may be prepared by the process known in the art, for example, by using Fas antigen, Fas ligand, or a partial peptide thereof for the immunization antigen, immunizing an animal with such antigen in accordance with a conventional process, fusing the resulting immunized cell with a known parent cell by a conventional cell fusion process, and screening for the monoclonal antibody-producing cell by a conventional screening process.

More illustratively, when the immunization antigen is human Fas ligand or its fragment, the nucleotide sequence of the human Fas ligand disclosed in Takahashi, T. (International Immunology, vol. 6, pages 1567 1574, 1994) is used, and this nucleotide sequence is inserted in a known expression vector system to transform an adequate host cell, the desired Fas ligand protein is obtained by purification from the transformed cell or the culture supernatant of the transformed cell, and the thus obtained purified Fas ligand protein is used for the immunization antigen.

The mammal which is immunized with the immunization antigen is not limited to any particular type, and the mammal may be selected by considering the compatibility with the parent cell used in the cell fusion. Exemplary animals are mouse, rat, hamster, and rabbit.

The immunization of the animal with the immunization antigen may be carried out by a known procedure. After the immunization and confirmation of the increase of the serum level of the desired antibody, the immunocytes are isolated from the animal, and subjected to cell fusion. The preferable immunocytes are splenocytes.

The parent cell to be fused with the immunocyte is not limited to any particular type. However, use of known mammal myeloma cell lines, and in particular, a mouse myeloma cell line such as P3-X63-Ag8-U1 (P3-U1) is preferred. The cell fusion of the above-described immunocyte and the myeloma cell may be carried out basically in accordance with a known process such as the procedure of Milstein et al. (Milstein et al., Methods Enzymol. 73: 3 46, 1981).

The hybridoma is then screened for the one producing the target antibody used in the present invention and subsequently cloned.

The monoclonal antibody is obtained from the thus prepared hybridoma producing the monoclonal antibody used in the present invention by such procedures as cultivating the hybridoma according to the conventional method and obtaining the monoclonal antibody from the supernatant; or transplanting the hybridoma to a mammal compatible with the hybridoma for propagation, and obtaining the monoclonal antibody from the ascite of the mammal. The former procedure is adapted for producing the monoclonal antibody of high purity, and the latter procedure is adapted for producing the monoclonal antibody in a large amount.

The monoclonal antibody produced by such process for use in the present invention may be further purified by a known purification means such as salt precipitation, gel filtration, affinity chromatography, and the like.

The monoclonal antibody used in the present invention is not limited to the one produced by using a hybridoma, and may be the one produced by an antibody-producing cell immortalized by EBV and the like or the one produced by a genetic engineering procedure.

In addition, the anti-Fas ligand antibody or the anti-Fas antibody used in the present invention is preferably a chimeric antibody or a humanized antibody which is an antibody intentionally altered for the purpose of reducing heteroantigenicity to human.

The use of non-human monoclonal antibody such as mouse antibody is associated with defects when it is repeatedly used in treating a human. The first defect is that the mouse monoclonal antibody has a relatively short circulation halflife and when used for human, the mouse monoclonal antibody will not develop other important functional properties of the immunoglobulin.

The second defect is that the non-human monoclonal antibody includes a substantial length of amino acid which is immunogenic when injected into a human patient. More illustratively, it has been demonstrated by a number of studies that, after injection of a foreign antibody, an extremely strong immunoreaction against the antibody may be induced in the patient to essentially nullify the therapeutic effectivity of the antibody after the first treatment. Furthermore, if various mouse monoclonal antibodies or other monoclonal antibodies with the antigenicity against human are developed in future and one or more such non-human antibodies are used for once or for several times, the subsequent administration of such non-human antibody after such initial administration may be nullified due to the crossreactivity even if the subsequent therapy had no relation to the initial therapy . In some a case, the non-human antibody administered after the initial administration may even act as a hazardous substance.

An exemplary such chimeric antibody is a chimeric antibody comprising the variable region from the monoclonal antibody of a mammal other than human such as mouse, and the constant region from the human antibody. Such chimeric antibody may be produced by a known chimeric antibody production process, and in particular, by a genetic engineering process.

More preferably, the anti-Fas ligand antibody used in the present invention is a reshaped human antibody wherein complementarity determining region (CDR) of the human antibody is replaced with the complementarity determining region derived from the antibody of a mammal other than human such as mouse. More illustratively, the constant region and the framework region are preferably of human origin, and the complementarity determining region is preferably of non-human origin. A preferable example of the reshaped human antibody (humanized antibody) is humanized antibody having the CDR derived from the mouse F919-9-18 antibody, which is disclosed in International Patent Application Publication No. WO 97/02290 (Application No. PCT/JP96/01820). Examples of the variable regions is shown in FIG. 3 (cDNA is described in SEQ. ID No. 5) and FIG. 4 (cDNA is described in SEQ. ID No. 7).

It should be noted that, if necessary, an amino acid in the framework (FR) region in the variable region of the antibody may be substituted with another amino acid so that the complementarity determining region of the humanized antibody would form an adequate antigen-binding site.

The humanized antibody used in the present invention may be prepared in accordance with Leachman et al. (Nature 332: 323 (1988) and European Patent Publication No. EP-A-0239400); Queen et al. (Proc. Natl. Acad. Sci. USA 86: 10029 (1989), International Patent Application Publication Nos. WO 90/07861 and WO 92/11018); Co et al. (Proc. Natl. Acad. Sci. USA 88: 2869 (1991)); Co and Queen (Nature 351: 501 (1991)); Co et al. (J. Immunol. 148: 1149 (1992)), and the like.

The Fas derivative used in the present invention is not limited to any particular type as long as it is capable of binding at least with the Fas ligand, or capable of inhibiting the Fas ligand-mediated apoptosis. The Fas derivative may also be the one which comprises an amino acid sequence of a known Fas that has been arbitrarily mutated by substitution, deletion, addition or/and insertion, and which inhibits the biological actions of the Fas/Fas ligand system, and in particular, the Fas-mediated apoptosis, with the binding activity to the Fas ligand retained. The Fas derivative may also be a mutant of Fas, Fas in a truncated form, a chimeric protein, a fusion protein, and a chemically modified Fas. The Fas from which the Fas derivative is derived may be the one derived from any animal species, although use of the Fas of human origin is preferred in consideration of the antigenicity.

Exemplary Fas derivatives are the extracellular domain of a known Fas; a Fas antigen from which the transmembrane domain has been deleted; a chimeric protein of the extracellular domain of a Fas and another protein such as hFas-Fc which is a chimeric protein of the extracellular domain of human Fas and Fc fragment of human immunoglobulin. The Fas derivative may be the one prepared by any production process by utilizing known Fas sequences and known gene engineering techniques. For example, the process for producing the human Fas-Fc is described in the Examples of International Patent Application Publication No. WO 95/13293. Another preferable Fas derivative is the Fas having a deletion in its N terminal. A Fas derivative coded in plasmids (pM1304 and pM1317) included in the E. coli which were originally deposited on Mar. 14, 1996 in National Institute of Bioscience and Human Technology, Agency of Industrial Science and Technology (1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki-ken, Japan) (Accession Nos. P-15514 and P-15515) and transferred from the original deposition to the international deposition on Mar. 6, 1997 (Accession No. FERM BP-5854 and Accession No. FERM BP-5855) (The accession Nos. in Taiwan were CCRC 940171 and CCRC 940170, respectively.) is a derivative including the extracellular domain of the known human Fas from which N terminal sequence of from 1st to 29th amino acid has been deleted, and this highly active derivative is a preferable example of the effective component for the prophylactic/therapeutic agent of the present invention (partial nucleotide sequences in the vector (pM1304) including the nucleotide sequence of the cDNA coding for shFas(nd29)-Fc are described in FIGS. 5 to 9 and SEQ ID No. 9; and; partial nucleotide sequences in the vector (pM1317) including the nucleotide sequence of the cDNA coding for shFas(nd29)-hinge are described in FIGS. 10 to 12 and SEQ ID No. 11). The Fas derivatives used in the present invention as described above may be confirmed for their binding activity with the Fas ligand or inhibitory activity for the Fas-mediated apoptosis by an appropriate assay procedure.

The antisense oligonucleotide for the gene or the mRNA of the Fas or the Fas ligand used in the present invention is not limited to particular sequence as long as it inhibits the expression of the Fas or the Fas ligand, and maybe, for example, the antisense oligonucleotide of the Fas ligand disclosed in International Patent Application Publication No. WO 95/13293 (This publication is herein incorporated by reference).

The prophylactic/therapeutic agent of the present invention may be in the form of a pharmaceutical composition or kit such as an injection or an oral medicine wherein the Fas antagonist is combined with at least one pharmaceutical carrier or medium such as sterilized water, physiological saline, a vegetable oil, a mineral oil, a higher alcohol, a higher fatty acid, or a nontoxic organic solvent; and optional additives such as an excipient, a colorant, an emulsifier, a suspending agent, a surfactant, a solubilizer, a nonadsorptive, a stabilizer, a preservative, a humectant, an antioxidative, a buffer, an isotonizing agent, or a pain relieving agent. Preferably, the AIDS-preventing and treating drug of the present invention is parenterally administered either systemically or locally, and rapidly or gradually, for example, by intravenous, intramuscular, intraperitoneal, or subcutaneous injection. The prophylactic/therapeutic agent of the present invention should be administered at an adequate dose determined by taking the conditions and age of the patient as well as the administration route into the consideration. For example, an adequate divided dose may be selected in the range of approximately 0.1 to 100 mg/kg in the case of systemic administration. The prophylactic/therapeutic agent of the present invention, however, is not limited to the administration route and the dose as described above. The prophylactic/therapeutic agent of the present invention may also contain a combination of two or more Fas antagonists, and may be used in combination with another drug.

The prophylactic/therapeutic agent of the present invention may be formulated into a pharmaceutical preparation in a normal process. For example, an injection may be prepared by dissolving the purified Fas antagonist in a medium such as physiological saline or a buffer and optionally supplementing the solution with an additive such as an anti-adsorptive. The preparation may also be in the form of a lyophilizate which is to be reconstituted before the use, and may contain any of the excipients that are generally used for facilitating the lyophilization.

The Fas antagonist used in the prophylactic/therapeutic agent of the present invention suppresses injury of the organ or tissue of the host and exhibits the effect of increasing the survival time and the survival rate in the heart ischemic reperfusion model as described in the Examples or in the GVHD model and in particular, in the GVHD model as described in the Examples. The Fas antagonist also exhibits the suppressive effect for the increase of serum creatinine in the renal disease model, and the suppressive effect for the increase of GOT, GPT and the like which are indices of liver damage as well as the effect of increasing the survival rate in endotoxin-induced liver damage model. Accordingly, the prophylactic/therapeutic agent of the present invention administered to a patient suffering from such diseases will exhibit the effect of suppressing the injury and cell death, and in particular, the apoptosis of the cells of the particular organ or the tissue, and hence, the effect of preventing or treating the disease, the effect of alleviating the conditions and pathology associated with the disease, and the effect of suppressing the progress or worsening of the conditions.

In addition, the agent of the present invention has the effect of facilitating the preservation of various organs as demonstrated by in vitro cytotoxicity inhibitory effect as well as the suppression of the tissue damage in heart and renal ischemic reperfusion models.

It should be also noted that the animals used in the Examples using the anti-Fas ligand antibody are rodents (mouse and rat), and therefore, the prophylactic and therapeutic effects are mainly demonstrated by using anti-mouse Fas ligand antibody. The effects similar to those of the Examples are expected for the anti-human Fas ligand antibody and the humanized anti-human Fas ligand antibody when they are administered to human.

The Fas antagonist has prophylactic and therapeutic effects to heart diseases, GVHD, renal diseases, the diseases based on ischemic reperfusion injury, the diseases based on organ damage; effects as an organ preservative; as well as effects of inhibiting cell apoptosis. Therefore, the Fas antagonist used in the present invention and the drug containing such Fas antagonist are quite useful as a prophylactic and therapeutic agent for diseases wherein the Fas-mediated apoptosis is involved. For example, the agent of the present invention is capable of preventing and treating heart diseases, in particular, ischemic heart diseases such as myocardial infarction; myocarditis caused by various factors; cardiomyopathy, and in particular, dilated cardiomyopathy; heart failure; and ischemic reperfusion injury and heart diseases caused by such ischemic reperfusion injury.

The agent of the present invention is capable of preventing and treating GVHD and the conditions and pathology associated with the GVHD. The GVHDs include GVHD after bone marrow transplantation such as incompatible bone marrow transplantation and bone marrow transplantation in congenital immune deficiency; GVHD after organ transplantation; posttransfusional GVHD such as GVHD after blood transfusion of a large amount to a patient of hypoimmunity; and the like. The GVHD is associated with organ or tissue failure based on the GVH reaction, and diarrhea, exhaustion such as weight loss and thinning, exanthem, and liver dysfunction are observed. The GVHD is histologically characterized by such symptoms as disorganization of bone marrow and lymphoid tissue and atrophy of intestinal villi. The agent of the present invention can also be used for prevention and treatment of such conditions and pathology associated with the GVHD.

The agent of the present invention may also be used for direct prevention or treatment of the damages and dysfunctions of various organs in ischemic reperfusion injury found in liver, heart, kidney, lung, spleen, small intestine, large intestine, stomach, pancreas, brain, muscle, skin, and the like, as well as the diseases based on ischemic reperfusion injury such as liver failure, reperfusion arrhythmia, renal failure, necrotizing enterocolitis and the like. In addition, when reperfusion after the ischemia is required in the course of a surgery or transplantation, the agent of the present invention is expected to exhibit a prophylactic or therapeutic effect for the damage of the organ or tissue to improve the posttransplantation acceptance rate and maintain the function of the organ or the tissue. The agent of the present invention is also expected to exhibit an effect of inhibiting the tissue damage and formation or expansion of necrotic infarcted lesion as well as the effect of improving the organ or tissue dysfunction. The agent of the present invention may also be used as an agent for preventing or treating the disease caused by ischemic reperfusion injury after thrombolytic therapy or angioplasty. The agent of the present invention may also be used for the purpose of direct prevention and treatment of the damage and dysfunction of liver or kidney in the diseases based on various organ failures such as liver failure and renal failure, as well as prevention, treatment and alleviation of jaundice, increase in blood GPT, GOT, LDH and the like, fatigue, malaise, hypophagia, consciousness disorder, excitation, coma, ascites, decrease in filtration volume by glomerulus, edema, proteinuria, oliguria, hyperkalemia, metabolic acidosis, increase in blood creatinine and blood urea nitrogen, and the like associated with such diseases. The agent of the present invention can also be used as an organ preservative for transplantation which is used by addition to the preservative fluid used in the transplantation of the tissue or organ or by addition to the perfusate of the organ. Furthermore, the agent of the present invention can be used as an agent for preventing or treating the diseases wherein Fas is involved such as the diseases based on ischemic reperfusion injury as described above. The agent of the present invention can also be used as an agent for preventing or treating MODS associated with SIRS.

The Fas antagonist used in the present invention suppresses not only the damage of acute stage but also the damage of chronic stage in the case of the organ damage caused by endotoxin, in particular, liver damage, endotoxemia or sepsis. Therefore, the Fas antagonist used in the present invention is expected to prevent, treat or alleviate the diseases based on such damages and the pathology associated with such diseases, and therefore, the Fas antagonist has properties quite preferable as a drug.

With regard to the liver, the Fas antagonist used in the present invention is expected exhibit prophylactic, therapeutic, or alleviating effects for liver failure, tissue damage and liver dysfunction in ischemic reperfusion injury caused by decrease or blockage of blood flow (blood supply) in surgery such as transplantation or in shock or circulation failure. With regard to the heart, the Fas antagonist used in the present invention is expected to exhibit prophylactic, therapeutic, or alleviating effects for irreversible cell death and lethal arrhythmia caused by overload of intracellular calcium ion as a result of reperfusion after recanalization, percutaneous transluminal coronary recanalization (PTCR) or percutaneous transluminal coronary angioplasty (PTCA) for myocardial infarction. With regard to the kidney, the Fas antagonist used in the present invention is expected to exhibit prophylactic, therapeutic, or alleviating effects for renal ischemia after surgery or kidney transplantation, renal ischemic reperfusion injury, diseases based on such ischemia or ischemic reperfusion injury, renal failure, the diseases causing such renal failure, and damages of cells inherent to renal glomeruli (endothelial cells, epithelial cells, mesangial cells), mesangial matrix, extracellular matrix of basal membrane or epithelial cells of tubule.
 


Claim 1 of 3 Claims

1. A prophylactic or therapeutic method of treating graft versus host disease (GVHD) which comprises administering an effective amount of a Fas antagonist that interacts with the extracellular domain of the Fas ligand, to a patient in need thereof; wherein the Fas antagonist is an anti-Fas ligand antibody.
 

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