WO2019041598A1

WO2019041598A1 - Application of gpr55 and regulator thereof in prevention and treatment of immune system diseases

Info

Publication number: WO2019041598A1
Application number: PCT/CN2017/113542
Authority: WO
Inventors: 石彦
Original assignee: 清华大学
Priority date: 2017-08-31
Filing date: 2017-11-29
Publication date: 2019-03-07
Also published as: CN109420173A; CN109420173B

Abstract

Disclosed is an application of GPR55 and a regulator thereof in prevention and treatment of immune system diseases. The present invention provides an application of GPR55 or a substance capable of promoting the expression of GPR55 or capable of increasing the activity of GPR55 in any one of the following: preparation of products for preventing and/or treating immune disorder-related diseases, and preparation of a product for regulating the function of a peripheral immune system. Experiments show that the inhibitor O-1918 of the cannabinoid receptor GPR55 can inhibit intestinal-derived dendritic cells (expressing CD103, CD11b, and retinal dehydrogenase) from transferring to lymph nodes. The present invention has important significance for preventing and/or treating immune disorder-related diseases such as rheumatism, lupus erythematosus, enteritis and multiple sclerosis, and enhancing the immune function of the body.

Description

Application of GPR55 and its modulators in the prevention and treatment of diseases of the immune system

Technical field

The invention belongs to the field of biotechnology and relates to the application of a GPR55 and a modulator thereof for preventing and treating diseases of the immune system.

Background technique

Microorganisms enter the animal from the skin, mouth, respiratory tract, etc. They evolve with the host, affect each other, inhibit and regulate each other's functions. Studying the regulatory mechanisms between these commensal bacteria and hosts is important for human health. Among them, immunologists are most concerned about the effects of intestinal symbiotic bacteria on host metabolism and anti-infection. One of the topics is how symbiotic bacteria regulate host immune function. Most of the literature's research focuses on local immune regulation in the intestine. This may be just the tip of the iceberg, and the effect of commensal bacteria on the immune system may not stop at the intestines. For example, sterile animals have significant peripheral immunodeficiency, mainly manifested by hypoplasia of the systemic secondary lymphoid organs (ie, lymph nodes). Because lymph nodes are the origin of immune responses, how symbiotic bacteria regulate these widely distributed immune organs has become an important issue. However, the link between these commensal bacteria and the development of the peripheral immune system has not been clear so far.

The development of lymph nodes is a delicate and complex process. In the embryo, the primordium of the lymph nodes appears in the epithelial cell cluster. After being stimulated by retinoic acid from nearby nerve endings, lymphoid tissue-inducing cells (LTi) begin to initiate the development of primitive lymphoid structures. After the mouse is born, the LTi cells no longer stay, but the peripheral lymph nodes continue to grow and the number of cells contained continues to increase. One to two weeks after birth, the infiltrated lymphocytes form clear T and B cell regions, almost identical to adult mouse lymph nodes. In contrast, the development of lymph nodes in sterile animals completely ceased after birth. The above developmental problems bring about defects in the immune response. The sterile mice were not immune to the infection after being infected by the intestinal pathogen Shigella flexneri. The symptoms of Salmonella infection in sterile mice are also more severe. As the main site of the immune response, it is conceivable that defects in the structure of the lymph nodes may cause disorders in the immune response. So how does intestinal colony initiate lymph node development after birth?

Invention disclosure

It is an object of the present invention to provide an application of GPR55 and its modulators for the prevention and treatment of diseases of the immune system.

The applications provided by the present invention are specifically as follows:

First: the application of the modulator of GPR55 or GPR55 in any of the following (A)-(D):

(A) preparing a product for preventing and/or treating an immune disorder-related disease;

(B) preparing a product for regulating the function of the peripheral immune system;

(C) prevention and/or treatment of diseases associated with immune disorders;

(D) Regulate peripheral immune system function.

Among them, the modulator of GPR55 is a substance capable of promoting or inhibiting the expression of GPR55, or a substance capable of increasing or decreasing the activity of GPR55.

Second: GPR55 or a substance capable of promoting GPR55 expression or capable of increasing GPR55 activity in any of the following (E)-(H):

(E) preparing a product for driving the transfer of intestinal-derived dendritic cells to lymph nodes;

(F) preparing a product for promoting lymph node development and/or promoting lymph node function;

(G) driving intestinal-derived dendritic cells to lymph nodes;

(H) Promote lymph node development and/or promote lymph node function.

Third: Application of a substance capable of inhibiting GPR55 expression or capable of reducing GPR55 activity in any of the following (E') - (H'):

(E') preparing a product for inhibiting the transfer of intestinal-derived dendritic cells to lymph nodes;

(F') preparing a product for inhibiting lymph node development and/or inhibiting lymph node function;

(G') inhibiting the transfer of intestinal-derived dendritic cells to lymph nodes;

(H') inhibits lymph node development and/or inhibits lymph node function.

A substance capable of inhibiting GPR55 expression or capable of reducing GPR55 activity reduces immune activation and suppresses autoimmune response by inhibiting lymph node function.

The invention also claims the following methods:

First, a method for preventing and/or treating an immune disorder-related disease by using a modulator of GPR55 or GPR55 for preventing and/or treating an immune disorder-related disease; the GPR55 modulator is a substance capable of promoting or inhibiting GPR55 expression , or a substance capable of increasing or decreasing the activity of GPR55.

Second, a method for modulating the function of the peripheral immune system is to modulate peripheral immune system function using a modulator of GPR55 or GPR55; the GPR55 modulator is a substance capable of promoting or inhibiting the expression of GPR55, or is capable of increasing GPR55 activity or Falling matter.

Third, a method for driving intestinal-derived dendritic cells to lymph nodes is to use GPR55 or a substance capable of promoting GPR55 expression or capable of increasing GPR55 activity to drive intestinal-derived dendritic cells to lymph nodes.

Fourth, a method for promoting lymph node development and/or promoting lymph node function is to promote lymph node development and/or promote lymph node function by using GPR55 or a substance capable of promoting GPR55 expression or capable of increasing GPR55 activity.

Fifth, a method for inhibiting the transfer of intestinal-derived dendritic cells to lymph nodes is to inhibit the transfer of intestinal-derived dendritic cells to lymph nodes using a substance capable of inhibiting GPR55 expression or reducing GPR55 activity.

Sixth, a method for inhibiting lymph node development and/or inhibiting lymph node function is to inhibit lymph node development and/or inhibit lymph node function by using a substance capable of inhibiting GPR55 expression or reducing GPR55 activity.

The present invention also claims a product having at least one of the following functions (a) to (d), the active ingredient of which is GPR55 or a substance capable of promoting GPR55 expression or capable of increasing GPR55 activity; (a) prevention and/or prevention Treatment of immune-related disorders; (b) regulation of peripheral immune system function; (c) driving of intestinal-derived dendritic cells to lymph nodes; (d) promotion of lymph node development and/or promotion of lymph node function.

The present invention also claims a product having at least one of the following functions (a') to (d'), The active ingredient is a substance capable of inhibiting GPR55 expression or capable of reducing GPR55 activity; (a') preventing and/or treating immune disorder-related diseases; (b') regulating peripheral immune system function; (c') inhibiting intestinal origin Dendritic cells metastasize to lymph nodes; (d') inhibit lymph node development and/or inhibit lymph node function.

In the present invention, all of the intestinal-derived dendritic cells described above are specifically intestinal-derived dendritic cells expressing CD103, CD11b, and retinal dehydrogenase.

In the present invention, all of the aforementioned immune disorder-related diseases may be autoimmune diseases or hyperimmune inflammatory reactions, such as rheumatism, lupus erythematosus, enteritis, multiple sclerosis, ankylosing spondylitis and the like.

In the present invention, all of the aforementioned driving of intestinal-derived dendritic cells to lymph nodes specifically drives the transfer of the intestinal-derived dendritic cells to mesenteric lymph nodes and/or non-intestinal peripheral lymph nodes.

In the present invention, all of the above-described inhibition of intestinal-derived dendritic cells to lymph node metastasis specifically inhibits the transfer of the intestinal-derived dendritic cells to mesenteric lymph nodes and/or non-intestinal peripheral lymph nodes.

In the present invention, all of the substances described above which are capable of inhibiting the expression of GPR55 or capable of reducing the activity of GPR55 may be GPR55 inhibitors, specifically, such as O-1918.

DRAWINGS

Figure 1 shows lymphocytes isolated from lymph nodes of adult normal mice. After labeling, normal (SPF) or sterile (GF) mice are injected through the tail vein.

Figure 2 shows the absence of RALDH positive DC cells in adult sterile mouse lymph nodes.

Figure 3 shows that intestinal microbes regulate lymph node development through retinal dehydrogenase RALDH ⁺ dendritic cells.

Figure 4 is an analysis of the source of CD103 ⁺ CD11b ⁺ RALDH ⁺ DC-like cells.

Figure 5 shows the transfer of intestinal CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cells to lymph nodes by Candida tropicalis. In the figure, RALDH ⁺ CD103 ⁺ at the ordinate indicates CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cells.

Figure 6 shows that the lipid extract of Candida tropicalis can drive intestinal BMDC to lymph node metastasis.

Fig. 7 is a liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis result of the ninth stage obtained by liquid chromatography of lipid extract of Candida tropicalis.

Figure 8 shows that some of the molecular structures in the ninth paragraph (top, middle) are very close to endogenous cannabinoids (bottom, AEA).

Figure 9 shows that AEA and fungal fat extracts are more potent in driving CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cell migration compared to other endogenous cannabinoids.

Figure 10 shows that O-1918, an inhibitor of GPR55 and GPR55, inhibits the migration of CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cells.

The best way to implement the invention

The following examples are provided to facilitate a better understanding of the invention but are not intended to limit the invention. The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the following examples, unless otherwise specified, were purchased from conventional biochemical reagent stores. For the quantitative tests in the following examples, three replicate experiments were set, and the results were averaged.

Inhibitor of GPR55 O-1918: Tocris product, article number 2288.

Example 1. O-1918, an inhibitor of the cannabinoid receptor GPR55, inhibits the metastasis of intestinal DC cells to lymph nodes

1. The return of lymphocytes to lymph nodes is defective in sterile mice.

Lymphocytes isolated from lymph nodes of adult normal C57BL/6 mice were labeled with CFSE and injected into normal (SPF) or sterile (GF) C57BL/6 mice via the tail vein (dose was 2 x per mouse) 10 ⁶ cells) After 24 hours, various lymph nodes were isolated, subjected to fluorescence imaging after sectioning, or after cell suspension was obtained and analyzed by flow cytometry.

The result is shown in Figure 1. Left: Infusion of lymphocytes into the inguinal lymph nodes (iLN), mesenteric lymph nodes (mLN) and spleen (spl), and analysis of lymphocyte subtypes to iLN reflux (bottom left). Right: GF, SPF, and expression of MAdCAM-1 and PNAd on high endothelial venules (HEV) in iLN in GF mice (converted) after SPF. This experiment shows that the return of lymphocytes to lymph nodes is defective in sterile mice due to the absence of expression of PNED.

Second, adult sterile mouse lymph node loss RALDH positive DC cells

The lymph nodes of normal (SPF) and sterile (GF) C57BL/6 mice were compared for staining, and the presence or absence of RALDH-positive DC cells was observed.

The result is shown in Figure 2. Top: Dendritic cells of a class of retinal dehydrogenase (RALDH) are absent from the lymph nodes of adult sterile mice compared to normal mice. After being housed in a cage with SPF mice, RALDH-positive cells appeared in the peripheral lymph nodes of the sterile mice. Bottom: Comprehensive data analysis.

Third, intestinal microbes regulate lymph node development through RALDH ⁺ dendritic cells

RALDH ⁺ dendritic cells and RALDH ^- dendritic cells were isolated from SPF-class C57BL/6 mouse lymph nodes, and sterile (GF) C57BL/6 mice (injected at a dose of 2 × 10 ⁵ cells) were injected through the tail vein. Seven days later, lymph nodes were taken for sectioning and flow cytometry analysis.

The result is shown in Figure 3. Upper: RALDH ⁺ dendritic cells or RALDH ^- dendritic cells isolated from the lymph nodes of SPF mice, which were injected into sterile mice through the tail vein, caused changes in lymph node volume and imaging of mature T and B regions. Bottom: The size of the lymph nodes, as well as the statistical results of the area of the B and T areas. This experiment demonstrates that intestinal microbes regulate lymph node development through RALDH ⁺ dendritic cells.

Analysis of CD103 ⁺ CD11b ⁺ RALDH ⁺ DC-like cell sources

The effects of intestinal commensal bacteria on the development of immune organs may not be straightforward. There is a class of unconventional dendritic cells in the lamina propria, which are capable of expressing CD103, CD11b and retinal dehydrogenase (RALDH). They can come into contact with lymphocytes, and this process has a great impact on the fate of these lymphocytes. On the surface, lymph node development seems to have little to do with the above process. The preliminary work of our laboratory found that while the lymphocytes of newborn mice induce cell disappearance, if the intestinal colonies appear in time, a CD103 ⁺ CD11b ⁺ DC-like cell will appear in the lymph nodes. When these cells isolated from normal mice are injected into sterile mice through the tail vein, they promote the development of the latter lymph nodes and a large number of lymphocytes enter the lymph nodes. These dendritic cells highly express retinal dehydrogenase and can express a substance called peripheral lymphotransmitter on the vascular epithelium at the entrance of the lymph node, which can also be regarded as a marker for address localization. T and B cells form lymph nodes by recognizing peripheral lymphotropins into lymph nodes. This process is particularly evident when the mouse is born. However, in adult rats, there are still a small number of such dendritic cells in the lymph nodes, which maintain the long-term homeostasis of the lymph nodes. In vitamin A-deficient mice, dendritic cells such as lymph nodes disappear, causing structural damage. We have demonstrated by labeling that these dendritic cells are derived from the gut and are of the same type as the unconventional dendritic cells (expressing CD103, CD11b and retinal dehydrogenase) in the intestinal lamina propria. .

The specific method is as follows: neonatal C57BL/6 mice were intragastrically administered with FITC Dextran (FITC-dextran2000KD (Sigma) 0.3 mg/g body weight), and 6 hours later, the CD11b and CD103 single positive in the peripheral lymph nodes were detected by flow cytometry, and the double negative ( The ratio of DN) to double positive (DP) dendritic cells.

The results are shown in Fig. 4. It can be seen from the figure that the CD11b and CD103 double positive dendritic cells have the strongest FITC signal, and they are found to be derived from the intestinal tract.

5. Candida tropicalis drives intestinal CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cells to lymph node metastasis

Adult SPF grade C57BL/6 mice were mixed with antibiotics in drinking water (antibacterial and antifungal only, 1 g/L of ampicillin, 1 g/L of neomycin, 1 g/L of metronidazole and 0.5 g/L) Vancomycin, the concentration indicates the final concentration in drinking water, Sigma) or the antifungal drug fluconazole (final concentration in drinking water is 0.5g/L, Sigma), and lymph nodes are taken after three weeks. The percentage of CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cells in mouse mesenteric lymph nodes (mLN) and Peyer's patches (PP) was analyzed by flow cytometry.

Adult normal C57BL/6 mice were intragastrically administrated with three major intestinal fungi, Candida tropicalis, Saccharomyces cerevisiae, and Trichosporon (per mouse per mouse). After 24 hours of inoculum 10 ⁸ CFU), lymph nodes were taken for flow cytometry to analyze the percentage of CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cells in mouse inguinal lymph nodes (iLN) and mesenteric lymph nodes (mLN). In the same manner, the experiment was performed on newborn C57BL/6 mice and sterile C57BL/6 mice.

The result is shown in Figure 5. Upper left: Adult SPF mice were mixed with antibiotics or the antifungal fluconazole in drinking water, CD103 ⁺ CD11b ⁺ RALDH ⁺ dendrites in mesenteric lymph nodes (mLN) and Peyer's patches (PP) after 3 weeks. The percentage of cells. Upper right: Adult normal mice were inguinal lymph nodes (iLN) and mesenteric lymph nodes (mLN) after 24 hours of intragastric administration with cultured Candida tropicalis, Saccharomyces cerevisiae and Trichosporon. Percentage of CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cells. Bottom left: Similar to the upper right, the result of newborn mice. Bottom right: Similar to the results of upper right and lower left, adult sterile mice. It can be seen that Candida (C. tropicalis) in intestinal microbes drives the transfer of CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cells to lymph nodes.

6. The lipid extract of Candida tropicalis can drive intestinal CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cells to lymph node metastasis

The ribonucleic acids, proteins and lipids of various fungi and bacteria (the fungi have Candida tropicalis, Saccharomyces cerevisiae and Trichosporon, and the bacteria are Escherichia coli) are obtained by a separate extraction method. After these isolates were injected into mice, only Candida tropicalis lipids could drive the transfer of dendritic cells to lymph nodes. details as follows:

The fungi and bacterial lipids were extracted by chloroform-methanol extraction, wherein the fungi were Candida tropicalis, Saccharomyces cerevisiae and Trichosporon, and the bacteria were E coli. The fungus or bacteria were sonicated in chloroform-methanol (2:1 by volume), centrifuged, and the methanol was washed with water, and the chloroform was blown off under a low temperature nitrogen gas to obtain a lipid extract.

The lipid extracts of the fungi and bacteria obtained above were separately subjected to liquid chromatography analysis, as follows: chromatography column: diameter 1.5 cm, length 30 cm; filler silica gel (200-300 mesh, particle size 45-75 μm, pore size 40-70A) , specific surface area of 400-600 m ² /g, pore volume of 0.60-0.85 ml / g), atmospheric pressure filling. The lipid extracted from 5 g (wet weight) fungus or bacteria was loaded with 100% chloroform (30 ml), and then the volume ratio of chloroform:methanol was 10:0, 8:2, 6:4, 5:5, 3:7. , 0:10 elution, the first 5 gradients each eluted 30ml, each flat divided into two paragraphs before and after, the last gradient (ie the sixth gradient) eluted 45ml, divided into three paragraphs. This forms 1 to 13 paragraphs. At room temperature, free fall, all samples were blown dry with nitrogen.

After the lipid extract is separated by liquid phase, a segmented component is obtained. Each segment obtained by liquid phase analysis is dissolved in the same volume of DMSO as the unsegmented total lipid, and Transwell experiment is carried out (lipid is added to the lower chamber, lipid The ratio of the culture medium to the 1:1000 assay for the activity of each segment to attract the migration of mouse bone marrow-derived dendritic cells (BMDC) (the skilled person knows that the chemotaxis of BMDC is similar to that of CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cells, The reason for using BMDC instead of CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cells is that it is difficult to obtain sufficient cell numbers for large-scale analysis. Furthermore, the latter has poor activity in culture and is not suitable for long-term use. experiment).

The results are shown in Figure 6. A: Liquid chromatography spectrum of various fungal lipids; B: Several passages in tropical yeast can induce the migration of dendritic cells in vitro, with the ninth segment being the strongest. It can be seen that the relevant activity in the lipids in the fungus can be concentrated and purified by the liquid phase.

7. Structural determination of endogenous cannabinoid AEA analogues from Candida tropicalis

Liquid phase separation of the C tropicalis lipid extract in the ninth stage, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, Thermal X-caliber software for automatic analysis of the data of the Waters QTOF mass spectrometer (Full Scan mode) The molecular composition of the lipid is obtained.

The results are shown in Figures 7 and 8.

In Fig. 7, the upper part: liquid phase separation of liquid extract of C tropicalis lipid extract in the ninth stage; liquid chromatography results of N-arachidonic acid aminoethanol (AEA) standard. Bottom: AEA mass spectrometry results; AEA homologs extracted from LC-MS/MS results in the ninth paragraph of liquid phase separation of C tropicalis lipid extracts.

In Figure 8, upper, middle: some of the molecular structures in the ninth paragraph (shown as Formula I and Formula II, respectively). Bottom: Endogenous cannabinoids (AEA as shown in Formula III)) Molecular structure.

The results showed that the ninth stage of liquid phase separation of C tropicalis lipid extract contained endogenous cannabinoid AEA homologue. According to LC-MS/MS results, the AEA homologue is closest to N-propyl arachidonoyl amine or N-isopropyl arachidonoyl amine.

8. Endogenous cannabinoid AEA analogues from Candida tropicalis can drive intestinal CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cells to lymph node metastasis

Different endogenous cannabinoids and C tropicalis lipid extracts were injected intraperitoneally into 4 week old SPF grade C57BL/6 mice. A DMSO stock of C tropicalis lipids and cannabinoids was dissolved in PBS buffer for injection. The same dose of DMSO was used as a blank control. Processing time is one hour. Flow cytometry was used to detect the proportion of migratory DCs (ie, CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cells) in mesenteric lymph nodes (mLN). The amount of C tropicalis lipid was dissolved in the DMSO fraction corresponding to 250 μg of lipid per mouse.

The results are shown in Figure 9. It can be seen that AEA and C tropicalis lipid extracts are more potent in driving CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cell migration than other endogenous cannabinoids.

Nine, GPR55 inhibitor O-1918 can inhibit intestinal CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cells to lymph node metastasis

C tropicalis lipid extract was mixed with cannabinoid receptor inhibitor in PBS buffer and intraperitoneally injected into four large SPF grade C57BL/6 mice. One hour later, mouse mesenteric lymph nodes (mLN) were stained, and the proportion of migratory dendritic cells migratory DC (ie, CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cells) was measured by flow cytometry. CD11c ⁺ MHCII ^int resident DC served as a control. The C tropicalis lipid dose was consistent with the above (ie 250 ug per mouse). Cannabinoid receptor inhibitors were finally dissolved in PBS: Otenanbant (CB1 inhibitor), AM630 (CB2 inhibitor), O-1918 (GPR55 and GPR18 inhibitor) were 2 μM; PSB-SB-487 (GPR55) The inhibitor) had a final concentration of 200 nM.

The results are shown in Figure 10. It can be seen that inhibition of GPR55 (such as the use of GPR55 inhibitor O-1918) can effectively reduce the promoting effect of C tropicalis lipids on the migration of CD103 ⁺ CD11b ⁺ RALDH ⁺ dendritic cells.

Industrial application

Experiments have shown that the inhibitor of the cannabinoid receptor GPR55, O-1918, inhibits the transfer of intestinal-derived dendritic cells (expressing CD103, CD11b, and retinal dehydrogenase) to lymph nodes. Therefore, in practical applications, it is expected that the strength and type of immune response can be regulated by oral intake and injection of GPR55 drivers and antagonists (chemically synthesized or using endogenous substances derived from intestinal fungi). And the number and function of each immune cell subtype to achieve the purpose of treating and / or preventing immune disorders related diseases such as rheumatism, lupus erythematosus, enteritis, multiple sclerosis, and enhancing immune function (such as immunotherapy and vaccination).

Claims

The application of a modulator of GPR55 or GPR55 in any of the following (A)-(D):

(A) preparing a product for preventing and/or treating an immune disorder-related disease;

(B) preparing a product for regulating the function of the peripheral immune system;

(C) prevention and/or treatment of diseases associated with immune disorders;

(D) regulating peripheral immune system function;

The GPR55 modulator is a substance capable of promoting or inhibiting the expression of GPR55, or a substance capable of increasing or decreasing the activity of GPR55.
A method for preventing and/or treating an immune disorder-related disease by using a modulator of GPR55 or GPR55 to prevent and/or treat an immune disorder-related disease;

The GPR55 modulator is a substance capable of promoting or inhibiting the expression of GPR55, or a substance capable of increasing or decreasing the activity of GPR55.
A method for regulating the function of the peripheral immune system by using a modulator of GPR55 or GPR55 to regulate peripheral immune system function;

The GPR55 modulator is a substance capable of promoting or inhibiting the expression of GPR55, or a substance capable of increasing or decreasing the activity of GPR55.
GPR55 or a substance capable of promoting GPR55 expression or capable of increasing GPR55 activity in any of the following (E)-(H):

(E) preparing a product for driving the transfer of intestinal-derived dendritic cells to lymph nodes;

(F) preparing a product for promoting lymph node development and/or promoting lymph node function;

(G) driving intestinal-derived dendritic cells to lymph nodes;

(H) Promote lymph node development and/or promote lymph node function.
A method for driving intestinal-derived dendritic cells to lymph nodes by using GPR55 or a substance capable of promoting GPR55 expression or capable of increasing GPR55 activity to drive intestinal-derived dendritic cells to lymph nodes.
A method for promoting lymph node development and/or promoting lymph node function is to promote lymph node development and/or promote lymph node function by using GPR55 or a substance capable of promoting GPR55 expression or capable of increasing GPR55 activity.
A substance capable of inhibiting GPR55 expression or capable of reducing GPR55 activity in any of the following (E') - (H'):

(E') preparing a product for inhibiting the transfer of intestinal-derived dendritic cells to lymph nodes;

(F') preparing a product for inhibiting lymph node development and/or inhibiting lymph node function;

(G') inhibiting the transfer of intestinal-derived dendritic cells to lymph nodes;

(H') inhibits lymph node development and/or inhibits lymph node function.
A method for inhibiting the transfer of intestinal-derived dendritic cells to lymph nodes by inhibiting GPR55 expression or reducing GPR55 activity to inhibit intestinal-derived dendritic cells to lymphoid cells Knot transfer.
A method for inhibiting lymph node development and/or inhibiting lymph node function is to inhibit lymph node development and/or inhibit lymph node function by using a substance capable of inhibiting GPR55 expression or reducing GPR55 activity.
The method according to claim 4 or 7, or the method according to claim 5 or 8, wherein the intestinal-derived dendritic cells express CD103, CD11b and retinal dehydrogenase.
The use or method according to any one of claims 7-9, characterized in that the substance capable of inhibiting GPR55 expression or capable of reducing GPR55 activity is a GPR55 inhibitor.
The use or method of claim 11 wherein the GPR55 inhibitor is O-1918.
a product having at least one of the following functions (a) to (d), wherein the active ingredient is GPR55 or a substance capable of promoting GPR55 expression or capable of increasing GPR55 activity;

(a) prevention and/or treatment of immune-related diseases; (b) regulation of peripheral immune system function; (c) driving of intestinal-derived dendritic cells to lymph nodes; (d) promotion of lymph node development and/or promotion of lymph node function Features.
A product having at least one of the following functions (a') to (d'), wherein the active ingredient is a substance capable of inhibiting GPR55 expression or capable of reducing GPR55 activity;

(a') prevent and/or treat immune disorder-related diseases; (b') regulate peripheral immune system function; (c') inhibit intestinal-derived dendritic cells to lymph node metastasis; (d') inhibit lymph node development and / Or inhibit lymph nodes to function.
The product according to claim 13 or 14, wherein the intestinal-derived dendritic cells express CD103, CD11b and retinal dehydrogenase.
The product according to claim 14 or 15, wherein the substance capable of inhibiting GPR55 expression or capable of reducing GPR55 activity is a GPR55 inhibitor.
The product of claim 16 wherein said GPR55 inhibitor is O-1918.
The use or method or product of any of claims 1-17, wherein the immune disorder-related disease is an autoimmune disease or an excessive immune inflammatory response.
The use or method or product of claim 18, wherein the immune disorder-related disease is rheumatism, lupus erythematosus, enteritis, multiple sclerosis or ankylosing spondylitis.
The invention of claim 4 or the method of claim 5 or the product of claim 13 wherein said driving intestinal-derived dendritic cells are transferred to lymph nodes to drive said intestinal source The dendritic cells metastasize to the mesenteric lymph nodes and/or non-intestinal peripheral lymph nodes.
The method according to claim 7 or the method according to claim 8 or the product according to claim 14, wherein the inhibiting the transfer of intestinal-derived dendritic cells to lymph nodes to inhibit the intestinal source The dendritic cells metastasize to the mesenteric lymph nodes and/or non-intestinal peripheral lymph nodes.