KR20210095372A - Pharmaceutical composition for treating or preventing immunological diseases comprising in vivo immune cell targeting h2s donor loaded liposome - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treating or preventing immunological diseases. More specifically, the pharmaceutical composition of the present invention includes a liposome carrying a hydrogen sulfide donor, and thus is possible to increase the amount of hydrogen sulfide in the spleen by targeting the spleen, which is the largest lymph node, or immune cells, and is possible to exhibit an immune disease therapeutic effect by promoting differentiation of non-contact T cells into regulatory T cells, or by promoting differentiation into M2 macrophages to regulate immunity. The liposome contains a phospholipid and a PEG-bound phospholipid in a mass ratio of 1 : 0.1 to 1, and a molecular weight of the PEG is 1 to 10 kDa.

Description

Pharmaceutical composition for the treatment or prevention of immune diseases comprising liposomes carrying immune cell-targeted hydrogen sulfide donors in the body {PHARMACEUTICAL COMPOSITION FOR TREATING OR PREVENTING IMMUNOLOGICAL DISEASES COMPRISING IN VIVO IMMUNE CELL TARGETING H2S DONOR LOADED LIPOSOME}

The present invention relates to a pharmaceutical composition for treating or preventing an immune disease comprising a liposome carrying a hydrogen sulfide donor.

Hydrogen sulfide is one of gasotrasmitter, and has several functions such as immune regulation, antioxidant action, and suppression of apoptosis. Hydrogen sulfide deficiency is one of the causes of autoimmune diseases. Autoimmune diseases are diseases caused by excessive immune responses due to problems in the regulation of immune homeostasis. It is known that immune homeostasis is regulated by regulatory T cells. Therefore, a substance inducing differentiation into regulatory T cells and activation of regulatory T cells may exhibit an effect of treating or preventing cancer or immune diseases such as autoimmune diseases, inflammatory diseases, or transplant rejection diseases. The differentiation of immature T cells into regulatory T cells can occur in lymph nodes. If a substance that can induce the differentiation of regulatory T cells by targeting the spleen, the largest lymph node, is developed, it could be used for the treatment of immune diseases.

Korean Patent No. 1835554

It is an object of the present invention to provide a composition for regulating immunity targeting immune cells in the spleen or in the body.

An object of the present invention is to provide a pharmaceutical composition for the treatment or prevention of immune diseases.

1. comprising a liposome carrying a hydrogen sulfide donor,

The liposome contains phospholipids and PEG-conjugated phospholipids in a mass ratio of 1:0.1 to 1,

The molecular weight of the PEG is 1 kDa to 10 kDa,

A composition for regulating spleen or immune cell-targeted immunity.

2. The method of 1 above, wherein the hydrogen sulfide donor is sodium hydrosulfide, sodium disulfide, sodium sulfide, diallyl sulfide, diallyl disulfide, diallyl trisulfide, dipropyl disulfide, allyl methylsulfide, 2,4-bis(4- Methoxyphenyl)-1,3,2,4-disulfidephosphataine-2,4-disulfide, morphol-4-nium 4 methoxyphenyl (morpholino)phosphinodithioate, phosphorothioate At least one selected from the group consisting of ate, 1,2-dithiol-2-thion, N-(acylthio)-benzamide, dithioperoxyanhydride and arylthioamide, the composition.

3. The above 1, wherein the phospholipid is 1,2-dimyristoyl-sn-glycero-3-phosphocholine (1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine, DMPC), 1,2 -dipexanoyl-sn-glycero-3-phosphocholine (1,2-dihexanoyl-sn-glycero-3-phosphocholine), 1,2-diheptanoyl-sn-glycero-3-phosphocholine ( 1,2-diheptanoyl-sn-glycero-3-phosphocholine), 1,2-dioctanoyl-sn-glycero-3-phosphocholine (1,2-dioctanoyl-sn-glycero-3-phosphocholine), 1 ,2-dinanoyl-sn-glycero-3-phosphocholine (1,2-dinonanoyl-sn-glycero-3-phosphocholine), 1,2-didecanoyl-sn-glycero-3-phosphocholine (1,2-didecanoyl-sn-glycero-3-phosphocholine), 1,2-diundecanoyl-sn-glycero-3-phosphocholine (1,2-diundecanoyl-sn-glycero-3-phosphocholine) , 1,2-dilauroyl-sn-glycero-3-phosphocholine (1,2-dilauroyl-snglycero-3-phosphocholine, DLPC), 1,2-ditridecanoyl-sn-glycero- 3-phosphocholine (1,2-ditridecanoyl-snglycero-3-phosphocholine), 1,2-dipentadecanoyl-sn-glycero-3-phosphocholine (1,2-dipentadecanoyl-sn-glycero3-phosphocholine) ), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPC), 1,2-diheptadecanoyl-sn-glycerol Rho-3-phosphocholine (1,2-diheptadecanoyl-sn-glycero-3-phosphocholine), 1,2-distearoyl-sn-glycero-3-phosphocholine (1,2-distearoyl-sn) -glycero-3-phosphocholine, DSPC), 1,2-distea Royl-sn-glycero-3-phosphoethanolamine (1,2-Distearoyl-sn-glycero-3-phosphorylethanolamine, DSPE), 1,2-dinona decanoyl-sn-glycero-3-phosphocholine (1,2-dinonadecanoyl-sn-glycero-3-phosphocholine), 1,2-diarachidoyl-snglycero-3-phosphocholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine), 1,2-dihenarachidoyl-sn-glycero-3-phosphocholine (1,2-dihenarachidoyl-sn-glycero-3-phosphocholine), 1,2-dibehenoyl-sn-glycero-3 -Phosphocholine (1,2-dibehenoyl-sn-glycero-3-phosphocholine), 1,2-ditricosanoyl-sn-glycero-3-phosphocholine (1,2-ditricosanoyl-sn-glycero- 3-phosphocholine), 1,2-dilignoceroyl-sn-glycero-3-phosphocholine (1,2-dilignoceroyl-sn-glycero-3-phosphocholine), hydrogenated phosphatidylcholine, 1,2-Dioleoyl-sn-glycero-3-phosphocholine (1,2-dioleoyl-sn-glycero-3-phosphocholine, DOPC), L-α-phosphatidylcholine (L-α-phosphatidylcholine, HSPC) , 1-myristoyl-2-steroyl-sn-glycero-3-phosphocholine (1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine, MSPC) and 1-myristoyl-2 -Palmitoyl-sn-glycero-3-phosphocholine (1-myristoyl-2-palmitoyl-sn-glycero-3-phosphocholine, MPPC) is at least one selected from the group consisting of, the composition.

4. The above 1, wherein the PEG-conjugated phospholipid is PEG-conjugated DMPC, PEG-conjugated 1,2-dipexanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2 -diheptanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dioctanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dinanoyl- sn-glycero-3-phosphocholine, PEG-conjugated 1,2-didecanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-diundecanoyl-sn-glycerol Rho-3-phosphocholine, PEG-conjugated DLPC, PEG-conjugated 1,2-ditridecanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dipentadecanoyl -sn-glycero-3-phosphocholine, PEG-conjugated DPPC, PEG-conjugated 1,2-diheptadecanoyl-sn-glycero-3-phosphocholine, PEG-conjugated DSPC, PEG Conjugated DSPE, PEG-conjugated 1,2-dinona decanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-diaracidoyl-sn-glycero-3-phospho Choline, PEG-conjugated 1,2-dihenarachidoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dibehenoyl-sn-glycero-3-phosphocholine, 1,2-Ditricosanoyl-sn-glycero-3-phosphocholine to which PEG is bound, 1,2-dilignoseroyl-sn-glycero-3-phosphocholine to which PEG is bound, PEG Is at least one selected from the group consisting of hydrogenated phosphatidylcholine conjugated, PEG-conjugated DOPC, PEG-conjugated HSPC, PEG-conjugated MSPC, and PEG-conjugated MPPC.

5. The composition of 1 above, wherein the liposome further comprises at least one selected from the group consisting of cholesterol, campesterol, sitosterol and stigmasterol.

6. The composition of the above 1, wherein the hydrogen sulfide donor is located on at least one of the surface, interior and phospholipid bilayer of the liposome.

7. comprising a liposome carrying a hydrogen sulfide donor,

The liposome contains phospholipids and PEG-conjugated phospholipids in a mass ratio of 1:0.1 to 1,

The molecular weight of the PEG is 1 kDa to 10 kDa,

A pharmaceutical composition for the treatment or prevention of immune diseases.

8. The method of 7 above, wherein the hydrogen sulfide donor is sodium hydrosulfide, sodium disulfide, sodium sulfide, diallyl sulfide, diallyl disulfide, diallyl trisulfide, dipropyl disulfide, allyl methylsulfide, 2,4-bis(4- Methoxyphenyl)-1,3,2,4-disulfidephosphataine-2,4-disulfide, morphol-4-nium 4 methoxyphenyl (morpholino)phosphinodithioate, phosphorothioate At least one selected from the group consisting of ate, 1,2-dithiol-2-thion, N-(acylthio)-benzamide, dithioperoxyanhydride and arylthioamide, a pharmaceutical composition.

9. The above 7, wherein the phospholipid is DMPC, 1,2-dipexanoyl-sn-glycero-3-phosphocholine, 1,2-diheptanoyl-sn-glycero-3-phosphocholine, 1,2-Dioctanoyl-sn-glycero-3-phosphocholine, 1,2-dinanoyl-sn-glycero-3-phosphocholine, 1,2-didecanoyl-sn-glycero- 3-phosphocholine, 1,2-diundecanoyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2- Ditridecanoyl-sn-glycero-3-phosphocholine, 1,2-dipentadecanoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3 -Phosphocholine, 1,2-diheptadecanoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dis Thearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dinona decanoyl-sn-glycero-3-phosphocholine, 1,2-diaracidoyl-snglycero-3 -Phosphocholine, 1,2-dihenarachidoyl-sn-glycero-3-phosphocholine, 1,2-dibehenoyl-sn-glycero-3-phosphocholine, 1,2-dite Ricosanoyl-sn-glycero-3-phosphocholine, 1,2-dilignoceroyl-sn-glycero-3-phosphocholine, hydrogenated phosphatidylcholine, 1,2-dioleoyl-sn -glycero-3-phosphocholine, L-α-phosphatidylcholine, 1-myristoyl-2-steroyl-sn-glycero-3-phosphocholine and 1-myristoyl-2-palmitoyl- At least one selected from the group consisting of sn-glycero-3-phosphocholine, a pharmaceutical composition.

10. The above 7, wherein the PEG-conjugated phospholipid is PEG-conjugated DMPC, PEG-conjugated 1,2-dipexanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2 -diheptanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dioctanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dinanoyl- sn-glycero-3-phosphocholine, PEG-conjugated 1,2-didecanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-diundecanoyl-sn-glycerol Rho-3-phosphocholine, PEG-conjugated DLPC, PEG-conjugated 1,2-ditridecanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dipentadecanoyl -sn-glycero-3-phosphocholine, PEG-conjugated DPPC, PEG-conjugated 1,2-diheptadecanoyl-sn-glycero-3-phosphocholine, PEG-conjugated DSPC, PEG Conjugated DSPE, PEG-conjugated 1,2-dinona decanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-diaracidoyl-snglycero-3-phosphocholine , 1,2-dihenarachidoyl-sn-glycero-3-phosphocholine bound to PEG, 1,2-dibehenoyl-sn-glycero-3-phosphocholine to PEG, PEG 1,2-Ditricosanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dilignoseroyl-sn-glycero-3-phosphocholine, PEG Conjugated hydrogenated phosphatidylcholine, PEG-conjugated DOPC, PEG-conjugated HSPC), PEG-conjugated MSPC and PEG-conjugated MPPC) is at least one selected from the group consisting of, a pharmaceutical composition.

11. The pharmaceutical composition of 7 above, wherein the liposome further comprises at least one selected from the group consisting of cholesterol, campesterol, sitosterol and stigmasterol.

12. The pharmaceutical composition according to the above 7, wherein the hydrogen sulfide donor is located on at least one of the surface, interior and phospholipid bilayer of the liposome.

13. The pharmaceutical composition according to the above 7, wherein the immune disease is at least one selected from the group consisting of autoimmune disease, inflammatory disease, and transplant rejection disease.

14. The method of 13 above, wherein the autoimmune disease is rheumatoid arthritis, insulin dependent diabetes mellitus, juvenile diabetes, systemic lupus erythematosus, atopic dermatitis, Crohn's disease, psoriasis, multiple sclerosis, hyperthyroidism, anemia, Behcet's disease, autoimmune encephalomyelitis , At least one selected from the group consisting of myocardial infarction and asthma, a pharmaceutical composition.

The liposome of the present invention has excellent stability in the body and exhibits excellent targeting efficiency against the spleen or immune cells, which are the largest lymph nodes.

In addition, the composition of the present invention promotes differentiation of non-contact T cells into regulatory T cells by producing hydrogen sulfide in the spleen or immune cells, or promotes differentiation into M2 macrophages, thereby exhibiting an immunomodulatory effect, and therapeutic effect on immune diseases can represent

1 shows splenic-targeted hydrogen sulfide donor-carrying liposomes and their ⁶⁴ Cu radiolabeled forms according to some examples.
2 shows the distribution in the body of spleen-targeted hydrogen sulfide donor-supported liposomes confirmed through positron emission tomography (PET).
3 shows the half-life in blood of each of Examples 2 to 4 liposomes.
4 is a quantitative analysis result showing spleen targeting after intravenous administration of Examples 2 to 4 liposomes.
5 is a quantitative analysis result showing spleen targeting when 36 hours have elapsed after intravenous administration of the liposomes of Examples 2 to 4;
6 shows the qualitative and quantitative results confirming that the production _{of H 2} S is increased in the cells treated with the liposomes of Example 1 through fluorescence staining.
7 shows the differentiation effect of Raw 264.7 cells into M2 macrophages when treated with the liposomes of Examples of the present invention.

Hereinafter, the present invention will be described in detail.

The present invention provides a composition for regulating spleen or immune cell-targeted immunity comprising a liposome carrying a hydrogen sulfide donor.

The term 'hydrogen sulfide donor-supported liposome' refers to a liposome loaded with a hydrogen sulfide donor.

The hydrogen sulfide donor may be an organic or inorganic compound capable of generating hydrogen sulfide, such as H ₂ S gas, sulfide salts, Garlic-derived sulfur compounds, Lawesson reagents and derivatives thereof, phosphorothioates (Phosphorodithioates), 1,2-dithiole-2-thiones (1,2-Dithiole-3-thiones; DTTs), N-(acylthio)-benzamides (N-(acylthio)-benzamides), Dithioperoxyanhydrides, Arylthioamides, gem-Dithiol compounds, Ketoprofenate-caged compounds and thioamino acids ( Thioamino acids).

The sulfide salt may be sodium hydrosulfide (NaHS), sodium disulfide (Na ₂ S ₂ ), sodium sulfide (Na ₂ S), or the like.

Gallic-derived sulfur compounds include diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS), dipropyl disulfide (DPDS) or allyl methylsulfide ( ally methyl sulfide; AMS) and the like.

Lawesson's reagent is 2,4-bis(4-methoxyphenyl)-1,3,2,4-disulfidephosphataine-2,4-disulfide(2,4-Bis(4-methoxyphenyl)-1,3, 2,4-dithiadiphosphetane-2,4-disulfide, a derivative thereof is morpholin-4-ium 4 methoxyphenyl (morpholino) phosphinodithioate; GYY4137).

The hydrogen sulfide donor may be located on at least one of the surface, interior and phospholipid bilayer of the liposome.

Liposomes may have a bilayer membrane structure including phospholipids, for example, a micellar structure.

The liposome of the present invention may include a phospholipid combined with a phospholipid and polyethylene glycol (PEG).

The phospholipid may be phosphatidylcholine, phosphatidylglycerol, phosphatidylserine or phosphatidylethanolamine.

Phospholipids Phospholipids are 1,2-dimyristoyl-sn-glycero-3-phosphocholine (1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine, DMPC), 1,2-dipexanoyl-sn -glycero-3-phosphocholine (1,2-dihexanoyl-sn-glycero-3-phosphocholine), 1,2-diheptanoyl-sn-glycero-3-phosphocholine (1,2-diheptanoyl- sn-glycero-3-phosphocholine), 1,2-dioctanoyl-sn-glycero-3-phosphocholine (1,2-dioctanoyl-sn-glycero-3-phosphocholine), 1,2-dinanoyl- sn-glycero-3-phosphocholine (1,2-dinonanoyl-sn-glycero-3-phosphocholine), 1,2-didecanoyl-sn-glycero-3-phosphocholine (1,2-didecanoyl) -sn-glycero-3-phosphocholine), 1,2-diundecanoyl-sn-glycero-3-phosphocholine (1,2-diundecanoyl-sn-glycero-3-phosphocholine), 1,2-di Lauroyl-sn-glycero-3-phosphocholine (1,2-dilauroyl-snglycero-3-phosphocholine, DLPC), 1,2-ditridecanoyl-sn-glycero-3-phosphocholine ( 1,2-ditridecanoyl-snglycero-3-phosphocholine), 1,2-dipentadecanoyl-sn-glycero-3-phosphocholine (1,2-dipentadecanoyl-sn-glycero3-phosphocholine), 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPC), 1,2-diheptadecanoyl-sn-glycero-3-phosphocholine Choline (1,2-diheptadecanoyl-sn-glycero-3-phosphocholine), 1,2-distearoyl-sn-glycero-3-phosphocholine (1,2-distearoyl-sn-glycero-3-phosphocholine) , DSPC), 1,2-distearoyl-sn-glycero- 3-phosphoethanolamine (1,2-Distearoyl-sn-glycero-3-phosphorylethanolamine, DSPE), 1,2-dinona decanoyl-sn-glycero-3-phosphocholine (1,2-dinonadecanoyl- sn-glycero-3-phosphocholine), 1,2-diarachidoyl-snglycero-3-phosphocholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine), 1,2-dihenaraki Doyl-sn-glycero-3-phosphocholine (1,2-dihenarachidoyl-sn-glycero-3-phosphocholine), 1,2-dibehenoyl-sn-glycero-3-phosphocholine (1, 2-dibehenoyl-sn-glycero-3-phosphocholine), 1,2-ditricosanoyl-sn-glycero-3-phosphocholine (1,2-ditricosanoyl-sn-glycero-3-phosphocholine), 1, 2-dilignoceroyl-sn-glycero-3-phosphocholine (1,2-dilignoceroyl-sn-glycero-3-phosphocholine), hydrogenated phosphatidylcholine, 1,2-dioleoyl -sn-glycero-3-phosphocholine (1,2-dioleoyl-sn-glycero-3-phosphocholine, DOPC), L-α-phosphatidylcholine (L-α-phosphatidylcholine, HSPC), 1-myristoyl- 2-steroyl-sn-glycero-3-phosphocholine (1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine, MSPC) and 1-myristoyl-2-palmitoyl-sn-glycerol It may be at least one selected from the group consisting of rho-3-phosphocholine (1-myristoyl-2-palmitoyl-sn-glycero-3-phosphocholine, MPPC).

PEG-conjugated phospholipids include PEG-conjugated DMPC, PEG-conjugated 1,2-dipexanoyl-sn-glycero-3-phosphocholine, and PEG-conjugated 1,2-diheptanoyl-sn-glycerol. Rho-3-phosphocholine, PEG-conjugated 1,2-dioctanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dinanoyl-sn-glycero-3-phospho Forcholine, PEG-conjugated 1,2-didecanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-diundecanoyl-sn-glycero-3-phosphocholine, DLPC with PEG, 1,2-ditridecanoyl-sn-glycero-3-phosphocholine with PEG, 1,2-dipentadecanoyl-sn-glycero-3- with PEG Phosphocholine, PEG-conjugated DPPC, PEG-conjugated 1,2-diheptadecanoyl-sn-glycero-3-phosphocholine, PEG-conjugated DSPC, PEG-conjugated DSPE, PEG-conjugated 1,2-dinona decanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-diaracidoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1, 2-dihenarachidoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dibehenoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2- Ditricosanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dilignoseroyl-sn-glycero-3-phosphocholine, PEG-conjugated hydrogenated phosphatidylcholine, It may be at least one selected from the group consisting of PEG-conjugated DOPC, PEG-conjugated HSPC, PEG-conjugated MSPC, and PEG-conjugated MPPC.

PEG may have a molecular weight of 1 kDa to 10 kDa, 1 kDa to 9 kDa, 2 kDa to 8 kDa, 3 kDa to 7 kDa, or 4 kDa to 6 kDa.

The liposomes of the present invention may be prepared by mixing PEG-conjugated phospholipids with PEG-conjugated phospholipids. For example, the liposomes of the present invention may be prepared by mixing DSPC and PEG-conjugated DSPE.

The type or content of phospholipids or PEG-conjugated phospholipids used for preparing liposomes can be adjusted in consideration of various properties such as the size of the liposome to be prepared.

Liposomes may include phospholipids and PEG-conjugated phospholipids in a mass ratio of 1:0.01 to 2.

Liposomes contain phospholipids and PEG-bound phospholipids from 1:0.01 to 2, 1:0.05 to 1.5, 1:0.1 to 1, 1:0.1 to 0.9, 1:0.1 to 0.8, 1:0.1 to 0.7, 1:0.1 to It may be included in a mass ratio of 0.6, 1:0.1 to 0.5, 1:0.1 to 0.4, 1:0.1 to 0.3, or 1:0.1 to 0.2.

When PEG-bound phospholipids are included in too high a ratio compared to non-PEG-bound phospholipids, the efficiency of targeting the spleen or immune cells is lowered, and when PEG-bound phospholipids are included in too small ratios, the stability in the body is lowered. Therefore, in order to prepare a hydrogen sulfide donor-supported liposome capable of increasing the targeting efficiency of the spleen or immune cells while maintaining stability in the body, phospholipids and PEG-conjugated phospholipids should be mixed in an appropriate amount.

The liposomes of the present invention contain phospholipids and PEG-conjugated phospholipids in an appropriate ratio, thereby exhibiting excellent targeting efficiency against spleen or immune cells and at the same time exhibiting a stable effect in the body. Therefore, the liposome carrying the hydrogen sulfide donor of the present invention can produce hydrogen sulfide with excellent efficiency in the spleen or immune cells, which are the largest lymph nodes present in the body, and can regulate immune homeostasis.

The liposome carrying the hydrogen sulfide donor of the present invention can be used as a platform for treating immune diseases.

The liposome of the present invention may further include a sterol-based compound.

The sterol-based compound may be located between the phospholipids.

Sterol compounds include cholesterol, 3b-[N-(N',N'-dimethylaminoethane)-carbamyl}cholesterol (3b-[N-(N',N'-dimethylaminoethane)-cabamyl]cholesterol, DCChol), stigmasterol, campesterol, sitosterol, ergosterol, lanosterol, dinosterol, gogosterol, avenasterol, saringo Sterol (saringosterol), fucosterol (fucosterol), cholesteryl hemisuccinate (cholesteryl hemisuccinate), cholesteryl benzoate (cholesteryl benzoate), cholesteryl oleate (cholesteryl oleate), cholesteryl oleyl carbonate (cholesteryl oleyl carbonate), cholesteryl isostearate, cholesteryl linoleate, cholesteryl acetate, cholesteryl palmitate, cholesteryl stearate It may be at least one selected from the group consisting of cholesteryl stearate, cholesteryl chloride, cholesteryl nonanoate, and cholesteryl arachidonate.

By further including the above-described sterol-based compound, the structure of the liposome can be further stabilized.

The liposome may further include other types of compounds, polypeptides, or proteins in addition to the above-described phospholipids, PEG-conjugated phospholipids, PEG, and sterol-based compounds.

The liposome of the present invention may be prepared through self-assembly.

The present invention hydrogen sulfide donor-supported liposomes target the spleen or immune cells to generate or deliver hydrogen sulfide, thereby promoting differentiation from naive T cells to regulatory T cells in vitro and/or in vivo or for regulatory T cells. It may exhibit the effect of increasing the stability of cells.

The liposome carrying the hydrogen sulfide donor of the present invention can promote differentiation into M2 macrophages by generating or delivering hydrogen sulfide by targeting the spleen or immune cells. M2 macrophages are activated macrophages and may have anti-inflammatory action. In addition, M2 macrophages attenuate the cytotoxicity of T cells, can activate regulatory T cells, and induce immune tolerance.

The liposome carrying the hydrogen sulfide donor of the present invention may exhibit an immunomodulatory effect, such as an immunostimulating effect and/or an immune oversuppressing effect.

The composition for immune modulation of the present invention may be used as a pharmaceutical composition or a health functional food for the purpose of regulating immune activity and preventing, improving or treating immune diseases, wherein the amount and form of use may be appropriately adjusted according to the purpose. .

The present invention provides a pharmaceutical composition for treating or preventing an immune disease comprising a liposome carrying a hydrogen sulfide donor.

The hydrogen sulfide donor-supported liposome has been described above, and thus a detailed description thereof will be omitted.

As described above, the liposome of the present invention produces or delivers hydrogen sulfide to the spleen or immune cells to increase the amount of hydrogen sulfide in the spleen or immune cells, thereby differentiating naive T cells into regulatory T cells and stabilizing regulatory T cells, or M2 By inducing the differentiation of macrophages, it can exhibit the effect of treating immune diseases.

The immune disease may be at least one selected from the group consisting of an autoimmune disease, an inflammatory disease, and a transplant rejection disease.

Autoimmune diseases include rheumatoid arthritis, insulin-dependent diabetes, juvenile diabetes, systemic lupus erythematosus, atopic dermatitis, Crohn's disease, psoriasis, multiple sclerosis, hyperthyroidism, anemia, Behcet's disease, autoimmune encephalomyelitis, myocardial infarction and asthma. It may be at least one selected from.

The term 'treatment' refers to any action that improves or beneficially changes the symptoms of an individual suspected of or having an immune disease.

The term 'prevention' refers to any action that suppresses or delays an immune disease.

The pharmaceutical composition of the present invention may be in the form of a capsule, tablet, granule, injection, ointment, powder or beverage.

The pharmaceutical composition of the present invention may be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, and aqueous suspensions, external preparations, suppositories, and injections.

The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may be binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, flavoring agents, etc., for oral administration, and in the case of injections, buffering agents, preservatives, analgesic agents, Solubilizers, isotonic agents, stabilizers, etc. can be mixed and used. For topical administration, bases, excipients, lubricants, preservatives, etc. can be used.

The dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier, for example, when administered orally, tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. It may be prepared in the form of an injection, and in the case of an injection, it may be prepared in the form of unit dosage ampoules or multiple dosage forms. In addition, the dosage form of the pharmaceutical composition of the present invention may be prepared as a solution, suspension, tablet, capsule, sustained release formulation, and the like.

Carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, filler, anticoagulant, lubricant, wetting agent, flavoring, emulsifying or preservative, and the like.

The route of administration of the pharmaceutical composition of the present invention is, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or work is included.

The pharmaceutical composition of the present invention may be administered orally or parenterally, and when administered parenterally, external or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection may be selected.

The dosage of the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient, the degree of disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art. For example, the pharmaceutical composition of the present invention may be administered in an amount of 0.0001 to 1000 mg/kg or 0.001 to 500 mg/kg per day. Administration of the pharmaceutical composition of the present invention may be administered once a day, may be administered several times divided. The above dosage does not limit the scope of the present invention in any way.

The pharmaceutical composition of the present invention may be provided by mixing with conventionally known therapeutic substances for immune diseases. That is, the pharmaceutical composition of the present invention may be administered in combination with a known substance having an effect of treating or preventing an immune disease.

The term 'administration' refers to the introduction of a predetermined substance into an individual by an appropriate method, and the term 'subject' refers to all animals, including humans, mice, mice, and livestock that have or can develop a disease.

In addition, the present invention provides a health functional food for preventing or improving immune disease comprising a liposome carrying a hydrogen sulfide donor.

Since the hydrogen sulfide donor-supported liposome and immune disease have been described above, a detailed description thereof will be omitted.

The health functional food of the present invention may be formulated into one selected from the group consisting of tablets, pills, powders, granules, powders, capsules and liquid formulations, further comprising one or more of carriers, diluents, excipients and additives.

Carriers, excipients, diluents and additives include lactose, dextrose, sucrose, sorbitol, mannitol, erythritol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium phosphate, calcium silicate, microcrystalline cellulose, poly selected from the group consisting of vinylpyrrolidone, cellulose, polyvinylpyrrolidone, methylcellulose, water, sugar syrup, methylcellulose, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate and mineral oil. ingredients may be used.

The health functional food of the present invention contains natural carbohydrates, various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like, and these components may be used independently or in combination.

Hereinafter, examples will be given to describe the present invention in detail.

Example

1. Preparation of hydrogen sulfide donor-supported liposomes

Distearoyl-sn-glycero-3-phosphorylcholine (DSPC), polyethylene glycol-5k (PEG-5k) conjugated DSPE (mPEG-DSPE, MW: 5k), cholesterol, and hydrogen sulfide donor GYY4137 were mixed in various amounts and magnetically A liposome carrying a spleen-targeted hydrogen sulfide donor was prepared through assembly. Table 1 shows the contents of the components included in the four types of liposomes (Examples 1 to 4) prepared with different contents.

Ingredients Example 1 Example 2 Example 3 Example 4 mPEG-DSPE, MW: 5k 0mg 1mg 3mg 6mg DSPC 6mg 6mg 6mg 6mg cholesterol 1mg 1mg 1mg 1mg GYY4137 0.5mg/ml 0.5mg/ml 0.5mg/ml 0.5mg/ml

2. Confirmation of stability and spleen-targeting effect of hydrogen sulfide donor-supported liposomes

The spleen targeting effect according to the liposome composition ratio was confirmed by PET image using radiolabel. As a radioisotope for radiolabeling, ⁶⁴ Cu was used. PET images were obtained at 0 hours, 2 hours, 12 hours and 36 hours after intravenous injection of the liposomes of Examples 1 to 4 into mice, respectively.

As a result, Example 1 was found in the urine quickly after intravenous injection, and it was confirmed that Example 1 was not stable in the body. In addition, it was confirmed that Examples 2 to 4 were stable in the body compared to Example 1, and it was confirmed that the spleen intake effect was excellent. In particular, it was confirmed that the liposome of Example 2 showed the most excellent spleen uptake effect (see FIG. 2 ).

In order to evaluate how high the liposome injected into the human body is ingested into the spleen, the mean Standardized Uptake Value (mean SUV) after intravenous administration of Examples 2 to 4 liposomes was confirmed. The efficiency of uptake in the spleen of Example 2 was significantly higher (see FIGS. 4A and 4B ).

In addition, the ratio of spleen intake to muscle after intravenous administration of the liposomes of Examples 2 to 4 was confirmed. As a result, the muscle-to-spleen intake ratio of Example 2 was the highest, and showed a significant value compared to Examples 3 and 4 (see FIG. 4C ).

In addition, in order to confirm that the liposome is present in the spleen even after a sufficient time has elapsed after the liposome injection, the average standard intake coefficient and the muscle-to-spleen intake ratio after 36 hours after the liposome injection were confirmed. As a result, the muscle-to-spleen intake ratio of Example 2 was the highest, and showed a significant value compared to Examples 3 and 4 (see FIGS. 5A and 5B).

3. Hydrogen Sulfide Generation Effect of Liposomes

As described above, after treating Example 2, which has stability in the body and has excellent spleen targeting effect, to Raw 264.7 macrophages, _{an increase in H 2} S production was confirmed in the cells.

_{Specifically, Example 2 HISP-1 (green) capable of selectively staining H 2} S in a cell group treated with liposomes, a cell group treated with GYY4137 alone and an untreated cell group (control group) (green), capable of staining the nucleus of the cell Staining was performed with Hoechst 3342 (blue) and combinations thereof. As a result, it was confirmed that the group treated with Example 2 liposomes _{significantly increased H 2} S production in cells compared to the case of GYY4137 alone treatment (see FIG. 6 ).

4. Effect of Liposomes on Differentiation of M2 Macrophages

In order to confirm that the liposome of the present invention exhibits the M2 macrophage differentiation effect, the degree of cell differentiation was confirmed after treatment with Example 2 in Raw 264.7 macrophages. Specifically, 100,000 Raw 264.7 macrophages of the same amount were aliquoted in a culture dish for a confocal microscope, and then either untreated or treated with GYY 4137, Example 2 and liposomes, respectively. The concentrations of GYY 4137 and GYY 4137 supported in Example 2 were the same at 0.025 mg/ml.

As shown in FIG. 7A, when macrophages were treated with Example 2, it was confirmed that the macrophage uptake effect occurred rapidly. Through this, it was confirmed that the immune cell targeting efficiency of the liposome of the present invention is excellent.

7B is an image obtained using a confocal microscope 24 hours after each material was treated in a culture dish in which macrophages were dispensed.

As a result of calculating the elongation factor to quantitatively analyze the effect of M2 macrophage differentiation in the above-mentioned four groups, the M2 macrophage differentiation effect was significantly higher in the group treated with Example 2 liposomes (see FIG. 7D ).

The elongation factor is a value obtained by dividing the longest axis (b) of the cell by the shortest axis (a), and is defined by Equation 1 below (see FIG. 7C ).

[Equation 1]

Elongation factor=b/a.

M2 macrophages can serve to attenuate the cytotoxicity of T cells or to activate regulatory T cells, and are known to be responsible for anti-inflammatory action. Liposomes can exhibit the effect of activating regulatory T cells, and ultimately can exhibit the effect of treating immune diseases such as anti-inflammatory treatment and autoimmune treatment effect.

Claims (14)

a liposome carrying a hydrogen sulfide donor,
The liposome contains phospholipids and PEG-conjugated phospholipids in a mass ratio of 1:0.1 to 1,
The molecular weight of the PEG is 1 kDa to 10 kDa,
A composition for regulating spleen or immune cell-targeted immunity.
The method according to claim 1, wherein the hydrogen sulfide donor is sodium hydrosulfide, sodium disulfide, sodium sulfide, diallyl sulfide, diallyl disulfide, diallyl trisulfide, dipropyl disulfide, allyl methylsulfide, 2,4-bis(4-methoxy Phenyl) -1,3,2,4-disulfide phosphataine-2,4-disulfide, morphol-4-nium 4 methoxyphenyl (morpholino) phosphinodithioate, phosphorothioate, 1,2-dithiol-2-thione, N- (acylthio)-benzamide, dithioperoxyanhydride and at least one selected from the group consisting of arylthioamide, the composition.
The method according to claim 1, wherein the phospholipid is 1,2-dimyristoyl-sn-glycero-3-phosphocholine (1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine, DMPC), 1,2-dipec Sanoyl-sn-glycero-3-phosphocholine (1,2-dihexanoyl-sn-glycero-3-phosphocholine), 1,2-diheptanoyl-sn-glycero-3-phosphocholine (1, 2-diheptanoyl-sn-glycero-3-phosphocholine), 1,2-dioctanoyl-sn-glycero-3-phosphocholine (1,2-dioctanoyl-sn-glycero-3-phosphocholine), 1,2 -dinanoyl-sn-glycero-3-phosphocholine (1,2-dinonanoyl-sn-glycero-3-phosphocholine), 1,2-didecanoyl-sn-glycero-3-phosphocholine (1 ,2-didecanoyl-sn-glycero-3-phosphocholine), 1,2-diundecanoyl-sn-glycero-3-phosphocholine (1,2-diundecanoyl-sn-glycero-3-phosphocholine), 1 ,2-dilauroyl-sn-glycero-3-phosphocholine (1,2-dilauroyl-snglycero-3-phosphocholine, DLPC), 1,2-ditridecanoyl-sn-glycero-3- 1,2-ditridecanoyl-snglycero-3-phosphocholine, 1,2-dipentadecanoyl-sn-glycero-3-phosphocholine (1,2-dipentadecanoyl-sn-glycero3-phosphocholine), 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPC), 1,2-diheptadecanoyl-sn-glycero- 3-phosphocholine (1,2-diheptadecanoyl-sn-glycero-3-phosphocholine), 1,2-distearoyl-sn-glycero-3-phosphocholine (1,2-distearoyl-sn-glycero) -3-phosphocholine, DSPC), 1,2-distearo 1-sn-glycero-3-phosphoethanolamine (1,2-Distearoyl-sn-glycero-3-phosphorylethanolamine, DSPE), 1,2-dinona decanoyl-sn-glycero-3-phosphocholine (1,2-dinonadecanoyl-sn-glycero-3-phosphocholine), 1,2-diarachidoyl-snglycero-3-phosphocholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine), 1,2-dihenarachidoyl-sn-glycero-3-phosphocholine (1,2-dihenarachidoyl-sn-glycero-3-phosphocholine), 1,2-dibehenoyl-sn-glycero-3 -Phosphocholine (1,2-dibehenoyl-sn-glycero-3-phosphocholine), 1,2-ditricosanoyl-sn-glycero-3-phosphocholine (1,2-ditricosanoyl-sn-glycero- 3-phosphocholine), 1,2-dilignoceroyl-sn-glycero-3-phosphocholine (1,2-dilignoceroyl-sn-glycero-3-phosphocholine), hydrogenated phosphatidylcholine, 1,2-Dioleoyl-sn-glycero-3-phosphocholine (1,2-dioleoyl-sn-glycero-3-phosphocholine, DOPC), L-α-phosphatidylcholine (L-α-phosphatidylcholine, HSPC) , 1-myristoyl-2-steroyl-sn-glycero-3-phosphocholine (1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine, MSPC) and 1-myristoyl-2 -Palmitoyl-sn-glycero-3-phosphocholine (1-myristoyl-2-palmitoyl-sn-glycero-3-phosphocholine, MPPC) is at least one selected from the group consisting of, the composition.
The method according to claim 1, wherein the PEG-conjugated phospholipid is PEG-conjugated DMPC, PEG-conjugated 1,2-dipexanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-di Heptanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dioctanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dinanoyl-sn- Glycero-3-phosphocholine, PEG-conjugated 1,2-didecanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-diundecanoyl-sn-glycero- 3-phosphocholine, PEG-conjugated DLPC, PEG-conjugated 1,2-ditridecanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dipentadecanoyl-sn -Glycero-3-phosphocholine, PEG-conjugated DPPC, PEG-conjugated 1,2-diheptadecanoyl-sn-glycero-3-phosphocholine, PEG-conjugated DSPC, PEG-conjugated DSPE, PEG-conjugated 1,2-dinona decanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-diaracidoyl-sn-glycero-3-phosphocholine, 1,2-dihenarachidoyl-sn-glycero-3-phosphocholine with PEG, 1,2-dibehenoyl-sn-glycero-3-phosphocholine with PEG, PEG Conjugated 1,2-ditricosanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dilignoseroyl-sn-glycero-3-phosphocholine, PEG-conjugated At least one selected from the group consisting of hydrogenated phosphatidylcholine, PEG-conjugated DOPC, PEG-conjugated HSPC, PEG-conjugated MSPC and PEG-conjugated MPPC.
The composition of claim 1, wherein the liposome further comprises at least one selected from the group consisting of cholesterol, campesterol, sitosterol, and stigmasterol.
The composition of claim 1, wherein the hydrogen sulfide donor is located on at least one of a surface, an interior and a phospholipid bilayer of the liposome.
a liposome carrying a hydrogen sulfide donor,
The liposome contains phospholipids and PEG-conjugated phospholipids in a mass ratio of 1:0.1 to 1,
The molecular weight of the PEG is 1 kDa to 10 kDa,
A pharmaceutical composition for the treatment or prevention of immune diseases.
8. The method of claim 7, wherein the hydrogen sulfide donor is sodium hydrosulfide, sodium disulfide, sodium sulfide, diallyl sulfide, diallyl disulfide, diallyl trisulfide, dipropyl disulfide, allyl methylsulfide, 2,4-bis(4-methoxy Phenyl) -1,3,2,4-disulfide phosphataine-2,4-disulfide, morphol-4-nium 4 methoxyphenyl (morpholino) phosphinodithioate, phosphorothioate, 1,2-Dithiol-2-thione, N-(acylthio)-benzamide, dithioperoxyanhydride and at least one selected from the group consisting of arylthioamide, a pharmaceutical composition.
The method according to claim 7, wherein the phospholipid is DMPC, 1,2-dipexanoyl-sn-glycero-3-phosphocholine, 1,2-diheptanoyl-sn-glycero-3-phosphocholine, 1, 2-Dioctanoyl-sn-glycero-3-phosphocholine, 1,2-dinanoyl-sn-glycero-3-phosphocholine, 1,2-didecanoyl-sn-glycero-3- Phosphocholine, 1,2-diundecanoyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-ditri Decanoyl-sn-glycero-3-phosphocholine, 1,2-dipentadecanoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phospho Forcholine, 1,2-diheptadecanoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-distearo 1-sn-glycero-3-phosphoethanolamine, 1,2-dinona decanoyl-sn-glycero-3-phosphocholine, 1,2-diarachidoyl-snglycero-3-phospho Forcholine, 1,2-dihenarachidoyl-sn-glycero-3-phosphocholine, 1,2-dibehenoyl-sn-glycero-3-phosphocholine, 1,2-ditricosano 1-sn-glycero-3-phosphocholine, 1,2-dilignoseroyl-sn-glycero-3-phosphocholine, hydrogenated phosphatidylcholine, 1,2-dioleoyl-sn-glycerol Rho-3-phosphocholine, L-α-phosphatidylcholine, 1-myristoyl-2-steroyl-sn-glycero-3-phosphocholine and 1-myristoyl-2-palmitoyl-sn- At least one selected from the group consisting of glycero-3-phosphocholine, a pharmaceutical composition.
The method according to claim 7, wherein the PEG-conjugated phospholipid is PEG-conjugated DMPC, PEG-conjugated 1,2-dipexanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-di Heptanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dioctanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dinanoyl-sn- Glycero-3-phosphocholine, PEG-conjugated 1,2-didecanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-diundecanoyl-sn-glycero- 3-phosphocholine, PEG-conjugated DLPC, PEG-conjugated 1,2-ditridecanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dipentadecanoyl-sn -Glycero-3-phosphocholine, PEG-conjugated DPPC, PEG-conjugated 1,2-diheptadecanoyl-sn-glycero-3-phosphocholine, PEG-conjugated DSPC, PEG-conjugated DSPE, PEG-conjugated 1,2-dinona decanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-diaracidoyl-snglycero-3-phosphocholine, PEG 1,2-dihenarachidoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dibehenoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-ditricosanoyl-sn-glycero-3-phosphocholine, PEG-conjugated 1,2-dilignoseroyl-sn-glycero-3-phosphocholine, PEG-conjugated At least one selected from the group consisting of hydrogenated phosphatidylcholine, PEG-conjugated DOPC, PEG-conjugated HSPC), PEG-conjugated MSPC and PEG-conjugated MPPC), a pharmaceutical composition.
The pharmaceutical composition of claim 7, wherein the liposome further comprises at least one selected from the group consisting of cholesterol, campesterol, sitosterol and stigmasterol.
The pharmaceutical composition of claim 7, wherein the hydrogen sulfide donor is located on at least one of a surface, an interior and a phospholipid bilayer of the liposome.
The pharmaceutical composition of claim 7, wherein the immune disease is at least one selected from the group consisting of autoimmune diseases, inflammatory diseases, and transplant rejection diseases.
The method according to claim 13, wherein the autoimmune disease is rheumatoid arthritis, insulin dependent diabetes mellitus, juvenile diabetes mellitus, systemic lupus erythematosus, atopic dermatitis, Crohn's disease, psoriasis, multiple sclerosis, hyperthyroidism, anemia, Behcet's disease, autoimmune encephalomyelitis, myocardial At least one selected from the group consisting of infarction and asthma, a pharmaceutical composition.

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