CN109420174A - The application of GPR18 and its regulator in prevention and treatment disease of immune system - Google Patents

The application of GPR18 and its regulator in prevention and treatment disease of immune system Download PDF

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CN109420174A
CN109420174A CN201710771705.7A CN201710771705A CN109420174A CN 109420174 A CN109420174 A CN 109420174A CN 201710771705 A CN201710771705 A CN 201710771705A CN 109420174 A CN109420174 A CN 109420174A
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gpr18
lymph node
dendritic cells
function
product
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CN109420174B (en
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石彦
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Bodihekang (Beijing) Biotechnology Co.,Ltd.
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Tsinghua University
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    • A61P37/00—Drugs for immunological or allergic disorders
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    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Abstract

The invention discloses a kind of application of GPR18 and its regulator in prevention and treatment disease of immune system.The present invention provides the regulator of GPR18 or GPR18 it is following it is any in application: preparation is for preventing and/or treating the product of immunologic derangement related disease, prepare the product for adjusting periphery function of immune system.The GPR18 regulator is the substance that can promote or inhibit GPR18 to express, or the substance that GPR18 activity can be made to improve or decline.It is demonstrated experimentally that the inhibitor O-1918 of Cannabined receptor GPR18 is able to suppress the Dendritic Cells (expression CD103, CD11b and retinal dehydrogenase) in enteron aisle source to lymphatic metastasis.The present invention enhances body's immunity and is of great significance for preventing and/or treating immunologic derangement related disease such as rheumatism, lupus erythematosus, enteritis, multiple sclerosis.

Description

The application of GPR18 and its regulator in prevention and treatment disease of immune system
Technical field
The invention belongs to field of biotechnology, it is related to a kind of GPR18 and its regulator in prevention and treatment disease of immune system Using.
Background technique
Microorganism enters in animal body from skin, oral cavity, the positions such as respiratory tract, they and host evolve together, mutual shadow It rings, inhibits and adjust the function of other side.The regulatory mechanism studied between these fungal components and host has important meaning to human health Justice.Wherein immunization persons are concerned with influence of the commensal gut bacterium to host metabolism and anti-infectious function the most.Wherein one A project be fungal component how modulate host immune function.The research emphasis of most of document is the immunoregulation of enteron aisle part. This may be tip of the iceberg, and perhaps fungal component does not stop at enteron aisle to the effect of immune system.Such as germfree animal have it is bright Aobvious periphery immune deficiency, is mainly shown as the hypoplasia of whole body secondary lymphoid organ (namely lymph node).Because of lymph Knot is the area of origin of immune response, and how fungal component regulates and controls these widely distributed immune organs also just at a weight at a distance Want project.However up to the present, these fungal components are still not clear with contacting for periphery developing immune system.
The development of lymph node is the process of a precision and complexity.In embryo, it is thin that the former base of lymph node appears in epithelium In born of the same parents' cluster.After the retinoic acid stimulation issued by neighbouring nerve endings, lymphoid tissue inducing cell (LTi) starts to start original The development of lymph structure.After mouse birth, LTi cell is no longer stopped, however peripheral lymph nodes persistently become larger, the cell contained Number also continues growing.The latter lymphocyte by two weeks, being percolated of being born forms clearly T and B cell area, almost and grows up Mouse lymph nodes are the same.In contrast, the development of germfree animal lymph node stops completely after birth.It is above-mentioned developmentally the problem of band The defect of immune response is carried out.Germfree mouse is immunoreacted not strong after by the infection of pathogenic entero becteria shigella flexneri.Salmonella Symptom of the bacillus infection in germfree mouse is also more serious.Main place as immune response, it is envisaged that lymph node structure On defect will lead to the disorder of immune response.Does is so intestinal colony the development for how starting lymph node after birth?
Summary of the invention
The object of the present invention is to provide a kind of application of GPR18 and its regulator in prevention and treatment disease of immune system.
Application provided by the present invention is specially following several:
Application of the regulator of first: GPR18 or GPR18 in following (A)-(D) is any:
(A) product for preventing and/or treating immunologic derangement related disease is prepared；
(B) product for adjusting periphery function of immune system is prepared；
(C) prevent and/or treat immunologic derangement related disease；
(D) periphery function of immune system is adjusted.
Wherein, the regulator of the GPR18 is the substance that can promote or inhibit GPR18 to express, or GPR18 can be made living Property improve or decline substance.
Second: GPR18 or GPR18 can be promoted to express or GPR18 activity can be made to improve substance at following (E)-(H) Application in any:
(E) preparation is for driving product of the Dendritic Cells in enteron aisle source to lymphatic metastasis；
(F) product for promoting lymph node to develop and/or lymph node is promoted to function is prepared；
(G) drive the Dendritic Cells in enteron aisle source to lymphatic metastasis；
(H) promote lymph node development and/or lymph node is promoted to function.
Third: the substance for being able to suppress GPR18 expression or GPR18 activity capable of being made to reduce is any at following (E ')-(H ') In application:
(E ') is prepared for inhibiting product of the Dendritic Cells in enteron aisle source to lymphatic metastasis；
Product of (the F ') preparation for inhibiting lymph node to develop and/or lymph node is inhibited to function；
(G ') inhibits the Dendritic Cells in enteron aisle source to lymphatic metastasis；
(H ') inhibits the development of lymph node and/or lymph node is inhibited to function.
Be able to suppress GPR18 expression or can make GPR18 activity reduce substance by inhibit lymph node function come It reduces immune activation and inhibits autoimmune reaction.
The present invention, which is also claimed, has the function of that the product at least one of shown in (a)-(d), active constituent are as follows GPR18 or the substance that GPR18 can be promoted to express or GPR18 activity can be made to improve；(a) prevent and/or treat immunologic derangement Related disease；(b) periphery function of immune system is adjusted；(c) drive the Dendritic Cells in enteron aisle source to lymphatic metastasis；(d) Promote lymph node development and/or lymph node is promoted to function.
The present invention, which is also claimed, has the function of the product at least one of shown in (a ')-(d ') as follows, active constituent For the substance for being able to suppress GPR18 expression or GPR18 activity capable of being made to reduce；(a ') prevention and/or treatment immunologic derangement are related Disease；(b ') adjusts periphery function of immune system；(c ') inhibits the Dendritic Cells in enteron aisle source to lymphatic metastasis；(d ') suppression Lymph node development processed and/or inhibition lymph node function.
In the present invention, above all immunologic derangement related diseases concretely rheumatism, lupus erythematosus, enteritis, Multiple sclerosis, the autoimmune diseases such as ankylosing spondylitis and excessive immune inflammatory reaction.
In the present invention, above the Dendritic Cells in all enteron aisle sources be specially expression CD103, CD11b with And the Dendritic Cells in the enteron aisle source of retinal dehydrogenase.
In one embodiment of the invention, above all drivings/inhibition enteron aisle source Dendritic Cells to leaching Fawning on transfer is specially the Dendritic Cells in driving/inhibition enteron aisle source to outside lymphonodi mesenterici and/or non-enteric system All lymphatic metastasis.
In the present invention, all substances for being able to suppress GPR18 expression or GPR18 activity capable of being made to reduce are equal above It can be GPR18 inhibitor, it is specific such as O-1918.
It is demonstrated experimentally that the inhibitor O-1918 of Cannabined receptor GPR18 is able to suppress the Dendritic Cells (table in enteron aisle source Up to CD103, CD11b and retinal dehydrogenase) to lymphatic metastasis.Therefore, in practical applications, it is expected to that oral cavity can be passed through Intake and injection GPR18 carminative and antagonist (can be chemically synthesized or using enteron aisle originated from fungus endogenous object Matter), to adjust the intensity of organism immune response, type and the quantity and function of each immune cell sub-sets, to reach treatment And/or epidemic prevention disorder related disease, such as rheumatism, lupus erythematosus, enteritis, multiple sclerosis, and enhance immune function and (such as exempt from Epidemic disease treatment and vaccine inoculation) purpose.
Detailed description of the invention
Fig. 1 is the lymphocyte isolated from the lymph node of adult normal mouse, after label, just by tail vein injection Often (SPF) or sterile (GF) mouse.
Fig. 2 is that adult germfree mouse lymph node lacks RALDH positive DC cell.
Fig. 3 is that enteric microorganism is by retinal dehydrogenase RALDH+Dendritic Cells adjusts lymph node development.
Fig. 4 is CD103+CD11b+RALDH+The analysis in DC like cell source.
Fig. 5 is that Candida tropicalis drives enteron aisle CD103+CD11b+RALDH+Dendritic Cells is to lymphatic metastasis.Figure In, the RALDH at ordinate+CD103+Indicate CD103+CD11b+RALDH+Dendritic Cells.
Fig. 6 is that the lipid extracts of Candida tropicalis can drive BMDC to lymphatic metastasis.
Fig. 7 is separating obtained 9th section of the liquid chromatography-tandem of lipid extracts liquid chromatogram of Candida tropicalis Mass spectrum (LC-MS/MS) analyzes result.
It is very close (under, AEA) with endocannabinoids that Fig. 8 is certain molecular structures in the 9th section (on, in).
Fig. 9 is that can drive CD103 strongly compared to other endocannabinoids, AEA and fungus fat extract+ CD11b+RALDH+Dendritic Cells Migration.
Figure 10 is that the inhibitor O-1918 of GPR55 and GPR18 can inhibit CD103+CD11b+RALDH+Dendritic Cells Migration.
Specific embodiment
Experimental method used in following embodiments is conventional method unless otherwise specified.
The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.
The inhibitor O-1918:Tocris Products of GPR18, article No. 2288.
Embodiment 1, Cannabined receptor GPR18 inhibitor O-1918 can inhibit enteron aisle DC cell to lymphatic metastasis
One, the reflux of lymphocyte to lymph node is defective in germfree mouse
The lymphocyte isolated from the lymph node for growing up normal C57BL/6 mouse, it is quiet by tail after being marked with CFSE Arteries and veins injects normally (SPF) or sterile (GF) C57BL/6 mouse, and (dosage is each mouse 2 × 106Cell) separated after 24 hours it is each Class lymph node, fluorescence imaging after being sliced, or analyzed after obtaining cell suspending liquid by flow cytometer.
As a result as shown in Figure 1.Left: the lymphocyte of injection is to inguinal lymph nodes (iLN), lymphonodi mesenterici (mLN) The analysis (lower-left) that reflux and lymphocyte subtype with spleen (spl) flow back to iLN.It is right: GF, SPF, and mated with SPF Afterwards in GF mouse (converted) in iLN on High endothelial venulae (HEV) MAdCAM-1 and PNAd expression.This experiment table The reflux of bright lymphocyte to lymph node is defective in germfree mouse, the reason is that the not expression of PNAd.
Two, adult germfree mouse lymph node lacks RALDH positive DC cell
It takes 5 weeks normal (SPF) and the lymph node of sterile (GF) C57BL/6 mouse to carry out staining versus, observes in the two The presence or absence of RALDH positive DC cell.
As a result as shown in Figure 2.It is upper: it is yellow that a kind of view is lacked compared with normal mouse, in the lymph node of the germfree mouse of adult The Dendritic Cells of aldehyde dehydrogenase (RALDH).After mating raising with SPF mouse, occur again in germfree mouse peripheral lymph nodes The cell of the RALDH positive.Under: comprehensive data analysis.
Three, enteric microorganism is to pass through RALDH+Dendritic Cells adjusts lymph node development
RALDH is separated from SPF grades of C57BL/6 mouse lymph nodes+Dendritic Cells and RALDH-Dendritic Cells passes through Tail vein injects sterile (GF) C57BL/6 mouse, and (implantation dosage is 2 × 105Cell), taken after seven days lymph node carry out slice and Flow cytometry analysis.
As a result as shown in Figure 3.It is upper: the RALDH isolated in SPF mouse lymph nodes+Dendritic Cells or RALDH-Dendron shape Cell causes the variation of lymph node volume and mature T occurs after injecting germfree mouse by tail vein, the imaging in the area B.Under: leaching Fawn on the statistical result in size and the area B and the area T area.This is experiments have shown that enteric microorganism is to pass through RALDH+It is this kind of Dendritic Cells adjusts lymph node development.
Four, CD103+CD11b+RALDH+The analysis in DC like cell source
Commensal gut bacterium may not be direct to the effect of Development of Immune Organs.Have in enteron aisle lamina propria a kind of unconventional Dendritic Cells, they can express CD103, CD11b and retinal dehydrogenase (RALDH).Their energy and lymphocyte Contact is generated, and this process produces very big influence to the destiny of these lymphocytes.On the surface, lymph node is developed Any connection do not appeared to the above process.The previous work in our laboratories is found, thin in the induction of newborn mice lymphoid tissue While born of the same parents disappear, it will appear a kind of CD103 if intestinal colony occurs in time, in lymph node+CD11b+The cell of DC sample.With After these cells separated in normal mouse enter germfree mouse by tail vein injection, the hair of the latter's lymph node can be promoted It educates and enters lymph node with big amount lymphocyte.These Dendritic Cells height express retinal dehydrogenase, and can make lymph node A kind of substance for being periphery lymph mediator element is expressed on the vascular endothelia of inlet, can also regard the mark of an address location as Will.T and B cell are exactly to pass through identification periphery lymph mediator element to enter lymph node, form lymph node development.This process is small Mouse is particularly evident when being born.However in adult rats, lymph node still has a small amount of this kind of Dendritic Cells, these cells maintain Lymph node long-term stable state.In the mouse of vitamin A deficiency, this kind of Dendritic Cells of lymph node disappears, and causes structure Destruction.We prove that this kind of Cells Derived from Dendritic is intrinsic in enteron aisle and our above said enteron aisles by the method for label Unconventional Dendritic Cells (expression CD103, CD11b and retinal dehydrogenase) is same type in layer.
The specific method is as follows: newborn C57BL/6 mouse FITC Dextran stomach-filling (FITC-dextran 2000KD (Sigma) 0.3 milligram of every gram of weight), CD11b and CD103 Dan Yang in peripheral lymph nodes is detected by flow cytometry after 6 hours Property, the ratio of double-negative (DN) and double positive (DP) Dendritic Cells.
As a result as shown in figure 4, the FITC signal of the bis- Protein-Positive Dendritic Cells of CD11b and CD103 is most strong as seen from the figure, it is seen that They derive from enteron aisle.
Five, Candida tropicalis drives enteron aisle CD103+CD11b+RALDH+Dendritic Cells is to lymphatic metastasis
SPF grades of C57BL/6 mouse of adult are mixed into mixing antibiotic in drinking water, and (only antibacterium is not antimycotic, 1g/L's Ampicillin, the neomycin of 1g/L, the metronidazole of 1g/L and the vancomycin of 0.5g/L, concentration indicate the end in drinking water Concentration, Sigma) or antifungal Fluconazole (fluconazole) (final concentration of 0.5g/L, Sigma in drinking water), three Zhou Yihou takes lymph node to carry out in flow cytometry analysis mouse lymphonodi mesenterici (mLN) and peyer's patch (PP) CD103+CD11b+RALDH+The percentage of Dendritic Cells.
Normal C57BL/6 mouse grow up respectively with three kinds of enteron aisle main fungals --- the Candida tropicalis of culture (Candida tropicalis), saccharomyces cerevisiae (Saccharomyces cerevisiae) and trichosporon bacteria (Trichosporon) stomach-filling (every kind of bacterium of each mouse 108CFU) after 24 hours, lymph node is taken to carry out flow cytometry analysis small CD103 in mouse inguinal lymph nodes (iLN) and lymphonodi mesenterici (mLN)+CD11b+RALDH+The percentage of Dendritic Cells. Same method has carried out the experiment to newborn C57BL/6 mouse and sterile C57BL/6 mouse.
As a result as shown in Figure 5.Upper left: adult SPF mouse is mixed into mixing antibiotic or antifungal fluorine health in drinking water Azoles (fluconazole), lymphonodi mesenterici (mLN) and peyer's patch (PP) interior CD103 after three weeks+CD11b+ RALDH+The percentage of Dendritic Cells.Upper right: adult normal mouse is in the Candida tropicalis (Candida with culture Tropicalis), saccharomyces cerevisiae (Saccharomyces cerevisiae) and trichosporon bacteria (Trichosporon) stomach-filling 24 CD103 in inguinal lymph nodes (iLN) and lymphonodi mesenterici (mLN) after hour+CD11b+RALDH+The percentage of Dendritic Cells Than.Lower-left: similar upper right, the result of newborn mice.Bottom right: similar upper right and lower-left, the result for germfree mouse of growing up.It can be seen that intestines Candida albicans (Candida tropicalis, C tropicalis) in road microorganism drives CD103+CD11b+RALDH+Dendron shape Transfer of the cell to lymph node.
Six, the lipid extracts of Candida tropicalis can drive enteron aisle CD103+CD11b+RALDH+Dendritic Cells To lymphatic metastasis
By each fungi of separating and extracting method acquirement and bacterium, (fungi has Candida tropicalis, saccharomyces cerevisiae and hair spore Daughter bacteria, bacterium are Escherichia coli) ribonucleic acid, protein and lipid.After these isolate re-injection mouse, only tropical false silk Saccharomycete lipid can drive transfer of the Dendritic Cells to lymph node.It is specific as follows:
Chloroform-methanol extraction method extracts the lipid of fungi and bacterium, and wherein fungi has Candida tropicalis (Candida Tropicalis), saccharomyces cerevisiae (Saccharomyces cerevisiae) and trichosporon bacteria (Trichosporon), bacterium are Escherichia coli (E coli).The ultrasonication in chloroform-methanol (volume ratio 2:1) of fungi or bacterium, is washed with water first after centrifugation Alcohol, low temperature nitrogen obtain lipid extracts after drying up chloroform.
The lipid extracts of fungi obtained as above and bacterium are subjected to liquid-phase chromatographic analysis respectively, specific as follows: chromatographic column: Diameter 1.5cm, length 30cm；Filler be silica gel (200-300 mesh, 45-75 μm of granularity, aperture 40-70A, specific surface area 400- 600m2/ g, pore volume 0.60-0.85ml/g), normal pressure filling.100% chlorine of lipid extracted from 5g (weight in wet base) fungi or bacterium Imitative (30ml) loading, then uses chloroform: methanol volume ratio is 10:0,8:2,6:4,5:5,3:7,0:10 elution, and preceding 5 gradients are every A elution 30ml, is each divided equally into former and later two paragraphs, the last one gradient (i.e. the 6th gradient) elutes 45ml, is divided equally into three A paragraph.So as to form 1 to 13 paragraphs.Room temperature, freely falling body, all samples are all with being dried with nitrogen.
Lipid extracts obtain segmentation ingredient after liquid phase separation, and obtain each section of liquid phase analysis is total with unsegmented Lipid is dissolved in the DMSO of same volume, and progress Transwell experiment be (lipid addition bottom chamber, lipid and culture solution Ratio 1:1000 measures the activity that each section attracts bone marrow derived Dendritic Cells (BMDC) to migrate, and (those skilled in the art are bright The chemotactic and CD103 of BMDC+CD11b+RALDH+Dendritic Cells is similar, and experiment replaces CD103 using BMDC herein+CD11b+ RALDH+The reason of Dendritic Cells is: the latter, which is difficult to obtain enough cell numbers, largely to be analyzed, furthermore, the latter is training Activity in nutrient solution is bad, should not be used in long-term experiment).
As a result as shown in fig. 6, A: the liquid chromatography spectrum of all kinds of fungi lipids；B: several paragraphs can lure in tropical saccharomycete The migration of Dendritic Cells in vitro is led, wherein the 9th section most strong.It can be seen that related activity can pass through liquid in lipid in fungi It is mutually concentrated and is purified.
Seven, from the structure determination of the endocannabinoids AEA analog of Candida tropicalis
By the 9th section of C tropicalis lipid extracts liquid phase separation, liquid chromatography-tandem mass spectrometry (LC-MS/ is carried out MS it) analyzes, Thermal X-caliber software is automatically analyzed (Full Scan to the mass spectrometric data of Waters QTOF Mode), the molecule for obtaining lipid is constituted.
As a result as shown in Figure 7 and Figure 8.
It is upper: the 9th section of liquid-phase chromatographic analysis of C tropicalis lipid extracts liquid phase separation in Fig. 7；N- arachidonic Sour ethylaminoethanol (AEA) standard items liquid chromatography results.Under: AEA mass spectral results；C tropicalis lipid extracts liquid phase point The AEA homologue extracted in LC-MS/MS result in from the 9th section.
In Fig. 8, on, in: certain molecular structures in the 9th section (respectively as shown in Formulas I and Formula II).Under: endocannabinoids (AEA is as shown in formula III)) molecular structure.
The result shows that: the 9th section of C tropicalis lipid extracts liquid phase separation is homologous containing endocannabinoids AEA Object.According to LC-MS/MS as a result, AEA homologue therein is closest to arachidonic acid n-propylamine (N-propyl Arachidonoyl amine) or arachidonic acid isopropylamine (N-isopropyl arachidonoyl amine).
Eight, enteron aisle CD103 can be driven from the endocannabinoids AEA analog of Candida tropicalis+CD11b+ RALDH+Dendritic Cells is to lymphatic metastasis
Different endocannabinoids and C tropicalis lipid extracts are SPF grades big by 4 weeks by being injected intraperitoneally C57BL/6 mouse.The DMSO liquid storage of C tropicalis lipid and cannboid is dissolved in PBS buffer solution for injecting.Same dosage DMSO as blank control.The processing time one hour.Migration DC in flow cytomery lymphonodi mesenterici (mLN) (i.e. CD103+CD11b+RALDH+Dendritic Cells) ratio.250 μ g lipid of every mouse of C tropicalis lipid dosage is corresponding Be dissolved in the part DMSO.
As a result as shown in Figure 9, it is seen that: compared to other endocannabinoids, AEA and C tropicalis lipid extracts CD103 can be driven strongly+CD11b+RALDH+Dendritic Cells Migration.
Nine, GPR18 inhibitor O-1918 can inhibit enteron aisle CD103+CD11b+RALDH+Dendritic Cells is carried down to lymph It moves
After C tropicalis lipid extracts and Cannabined receptor inhibitor mixed are dissolved in PBS buffer solution, pass through abdominal cavity It is administered to the big SPF grades of C57BL/6 mouse of surrounding.After one hour, mouse lymphonodi mesenterici (mLN) is taken to dye, flow cytometer Detect migration Dendritic Cells migratory DC (i.e. CD103+CD11b+RALDH+Dendritic Cells) ratio.CD11c+ MHCIIintResident DC is as control.C tropicalis lipid dose is (i.e. every mouse of 250ug) consistent with the above. Cannabined receptor inhibitor is finally dissolved in the concentration in PBS solution: (CB2 inhibits by Otenanbant (CB1 inhibitor), AM630 Agent), O-1918 (GPR55 and GPR18 inhibitor) be all 2 μM；PSB-SB-487 (GPR55 inhibitor) ultimate density is 200nM.
The results are shown in Figure 10, it is seen that: the inhibition (as used GPR18 inhibitor O-1918) of GPR18 can effectively be dropped Low C tropicalis lipid is to CD103+CD11b+RALDH+The facilitation of Dendritic Cells Migration.

Claims (10)

  1. Application of the regulator of 1.GPR18 or GPR18 in following (A)-(D) is any:
    (A) product for preventing and/or treating immunologic derangement related disease is prepared；
    (B) product for adjusting periphery function of immune system is prepared；
    (C) prevent and/or treat immunologic derangement related disease；
    (D) periphery function of immune system is adjusted；
    The GPR18 regulator be can promote or inhibit GPR18 express substance, can make GPR18 activity improve or under The substance of drop.
  2. 2.GPR18 can promote GPR18 to express or can make the substance of GPR18 activity raising in following (E)-(H) is any Application:
    (E) preparation is for driving product of the Dendritic Cells in enteron aisle source to lymphatic metastasis；
    (F) product for promoting lymph node to develop and/or lymph node is promoted to function is prepared；
    (G) drive the Dendritic Cells in enteron aisle source to lymphatic metastasis；
    (H) promote lymph node development and/or lymph node is promoted to function.
  3. 3. being able to suppress GPR18 expression or the substance that GPR18 activity can be made to reduce answering in following (E ')-(H ') is any With:
    (E ') is prepared for inhibiting product of the Dendritic Cells in enteron aisle source to lymphatic metastasis；
    Product of (the F ') preparation for inhibiting lymph node to develop and/or lymph node is inhibited to function；
    (G ') inhibits the Dendritic Cells in enteron aisle source to lymphatic metastasis；
    (H ') inhibits lymph node development and/or lymph node is inhibited to function.
  4. 4. application according to claim 2 or 3, it is characterised in that: the 1 expressed by dendritic cells in the enteron aisle source CD103, CD11b and retinal dehydrogenase.
  5. 5. application according to claim 3 or 4, it is characterised in that: described to be able to suppress GPR18 expression or make The substance that GPR18 activity reduces is GPR18 inhibitor.
  6. 6. application according to claim 5, it is characterised in that: the GPR18 inhibitor is O-1918.
  7. 7. having the function of the product as follows at least one of shown in (a)-(d), active constituent is GPR18 or can promote The substance that GPR18 is expressed or GPR18 activity can be made to improve；
    (a) prevent and/or treat immunologic derangement related disease；(b) periphery function of immune system is adjusted；(c) enteron aisle source is driven Dendritic Cells to lymphatic metastasis；(d) promote lymph node development and/or lymph node is promoted to function.
  8. 8. having the function of the product as follows at least one of shown in (a ')-(d '), active constituent is to be able to suppress GPR18 expression Or the substance that GPR18 activity can be made to reduce；
    (a ') prevention and/or treatment immunologic derangement related disease；(b ') adjusts periphery function of immune system；(c ') inhibits enteron aisle The Dendritic Cells in source is to lymphatic metastasis；(d ') inhibits lymph node development and/or lymph node is inhibited to function.
  9. 9. product according to claim 8, it is characterised in that: described to be able to suppress GPR18 expression or GPR18 be made living Property reduce substance be GPR18 inhibitor.
  10. 10. product according to claim 9, it is characterised in that: the GPR18 inhibitor is O-1918.
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