Type 2 immunity inhibitor

Abstract

To provide novel means for inhibiting type 2 immune response.SOLUTION: An inhibitor of type 2 immunity contains, as an active ingredient, N-acetyl-D-glucosamine or a substance containing N-acetyl-D-glucosamine as a component.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a suppressant of type 2 immunity and a composition for ameliorating diseases involving type 2 immunity. [Background technology]

[0002] Brush cells, a type of small intestinal epithelial cell, act as sensors that trigger the host's defense against parasites (type 2 immune response). For example, when brush cells receive succinic acid produced by parasites, they promote type 2 innate immune response and the number of brush cells themselves increases. The present inventors have also found that a seven-transmembrane G protein-coupled receptor called GPRC5C is specifically expressed in brush cells in the small intestine, but its function has not been elucidated. Recently, hyaluronic acid and its component N-acetyl-D-glucosamine (GlcNAc) have been reported as ligands for GPRC5C expressed in hematopoietic stem cells (Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Yu Wei Zhang et al., Nature Cell Biology 2022 Jul;24(7):1038-1048. Summary of the Invention [Problem to be solved by the invention]

[0004] While type 2 immune responses contribute to defense against parasitic infections, they also cause allergic diseases such as atopic dermatitis. If type 2 immune responses can be suppressed, it is expected that this will lead to the development of methods for preventing and treating allergic diseases. The present invention has been made under such circumstances, and aims to provide a novel means for suppressing type 2 immune responses. [Means for solving the problem]

[0005] As a result of extensive investigations aimed at solving the above problems, the present inventors discovered that N-acetyl-D-glucosamine suppresses type 2 immune responses, leading to the completion of the present invention. That is, the present invention provides the following (1) to (6).

[0006] (1) A suppressant of type 2 immunity, characterized by containing, as an active ingredient, N-acetyl-D-glucosamine or a substance having N-acetyl-D-glucosamine as a constituent component.

[0007] (2) A suppressant of type 2 immunity according to (1), characterized in that the substance having N-acetyl-D-glucosamine as a constituent component is hyaluronic acid or chitin.

[0008] (3) A composition for improving a disease involving type 2 immunity, comprising as an active ingredient N-acetyl-D-glucosamine or a substance containing N-acetyl-D-glucosamine as a constituent component.

[0009] (4) A composition for improving a disease involving type 2 immunity according to (3), characterized in that the substance having N-acetyl-D-glucosamine as a constituent component is hyaluronic acid or chitin.

[0010] (5) A composition for improving a disease involving type 2 immunity according to (3), characterized in that the disease involving type 2 immunity is atopic dermatitis, asthma, chronic sinusitis, or eosinophilic esophagitis.

[0011] (6) A composition for improving a disease involving type 2 immunity according to (3), which is orally administered. Effect of the Invention

[0012] The present invention provides a novel suppressant of type 2 immunity. Since type 2 immunity is a cause of allergic diseases, the suppressant of the present invention is useful for improving diseases involving type 2 immunity, such as allergic diseases. [Brief description of the drawings]

[0013] [Figure 1] Fluorescence microscopy images of small intestinal villi (left: bright field, right: dark field). [Diagram 2] A graph showing the percentage of small intestinal brush cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The present invention will be described in detail below. The type 2 immune suppressant of the present invention is characterized by containing, as an active ingredient, N-acetyl-D-glucosamine or a substance containing N-acetyl-D-glucosamine as a constituent. In the present invention, the term "type 2 immune suppressant" refers to a drug or composition that suppresses the type 2 immune response induced by brush cells. The type 2 immune suppressant of the present invention can be provided as, for example, a pharmaceutical composition or a food composition.

[0015] As the substance having N-acetyl-D-glucosamine as a component, a substance that functions as a ligand for GPRC5C can be used. Specific examples of the substance having N-acetyl-D-glucosamine as a component include hyaluronic acid and chitin.

[0016] Specific examples of the pharmaceutical composition include pharmaceutical compositions used for improving diseases associated with type 2 immunity (compositions for improving diseases associated with type 2 immunity). Diseases associated with type 2 immunity include atopic dermatitis, asthma, chronic sinusitis, eosinophilic esophagitis, etc.

[0017] When provided as a pharmaceutical composition, the type 2 immune suppressant of the present invention is usually administered orally. When administered orally, the type 2 immune suppressant of the present invention can be prepared in various dosage forms such as liquids, tablets, pills, powders, granules, and capsules.

[0018] The type 2 immunity suppressant of the present invention may contain, in addition to the active ingredient N-acetyl-D-glucosamine or a substance containing N-acetyl-D-glucosamine as a constituent, carriers, solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants, lubricants and other base materials, excipients, additives, secondary materials, bulking agents, etc. These ingredients are not particularly limited as long as they do not impair the type 2 immunity suppressing effect.

[0019] When provided as a food composition, the type 2 immune suppressant of the present invention can be prepared by adding the active ingredient N-acetyl-D-glucosamine or a substance containing N-acetyl-D-glucosamine as a constituent to a food or drink. The type of food or drink is not particularly limited, and examples thereof include seasonings, seasoned foods, processed grain products, processed meat products, processed fish products, soups, pickles, and prepared dishes.

[0020] The content of N-acetyl-D-glucosamine or a substance containing N-acetyl-D-glucosamine as an active ingredient in the type 2 immune suppressor is not particularly limited, and when N-acetyl-D-glucosamine is the active ingredient, it can be, for example, 0.01 to 100% by weight, preferably 0.1 to 10% by weight, and more preferably 1 to 5% by weight.

[0021] The subject of administration of the type 2 immune suppressant of the present invention may be a human or a non-human animal, such as a human, mouse, rat, rabbit, dog, or cat.

[0022] The dosage of N-acetyl-D-glucosamine or a substance containing N-acetyl-D-glucosamine as an active ingredient of a suppressor of type 2 immunity is not particularly limited as long as it is within a range capable of suppressing type 2 immune responses in a subject to administration. When N-acetyl-D-glucosamine is used as the active ingredient, the daily dosage can be, for example, about 0.1 to 300 g per adult human (body weight: 60 kg). EXAMPLES

[0023] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0024] 〔method〕 1. Generation of Trpm5-tdTomato transgenic (Tg) mice The inventors previously generated Trpm5-tdTomato transgenic mice, which express the red fluorescent protein tdTomato under the control of the Trpm5 promoter, which is specifically expressed in brush cells in the small intestine, based on C57BL / 6J mice, making it possible to identify brush cells, which exist at low frequencies in the small intestinal epithelium, by fluorescence microscopy.

[0025] 2. Administering the Solution to Mice The solutions in the drinking water bottles were administered to Trpm5-tdTomato Tg mice for one week, and the amount of water consumed was measured. Eight male or female mice aged 22 to 23 weeks were used, and the administered solutions and the number of mice are shown below. ·Water [n=2] GlcNAc 150 mM [n=3] Succinic acid 150 mM (adjusted to pH 5.5) [n=1] Succinic acid and GlcNAc mixed solution, both 150 mM (adjusted to pH 5.5) [n=2]

[0026] 3. Preparation of Mouse Cryosections The mice were fasted 18 hours before the end of administration of the solution. After administration of the solution, the mice were cervically dislocated, and the digestive tract (duodenum to large intestine) was removed and fixed overnight at 4°C in 4% PFA / PBS solution. It was then stored overnight at 4°C in 30% sucrose / PBS solution. The small intestine was then excised, embedded in OCT compound, and frozen in liquid nitrogen to prepare a block. The section was cut to a thickness of 10 μm using a cryostat and attached to a slide glass to prepare a section.

[0027] 4. Calculation of Brush Cell Proportion Sections were observed under a fluorescence microscope, and villi were selected in the bright field and their lengths were measured. The number of brush cells was then counted in the dark field, where the red fluorescence of tdTomato was regarded as brush cells (Figure 1). At least 50 villi were observed per individual, and the number of brush cells per mm of villi (tuft cells / mm of villus) was calculated as an index of the proportion of brush cells.

[0028] [Results / Discussion] Water consumption The amount of water consumed was approximately 30g ± 5g per week regardless of the type of solution, with no significant difference being observed depending on the solution.

[0029] Effects of succinic acid administration Mice administered succinic acid showed an increase in brush cell number compared to water (Figure 2). This was consistent with previous research showing that the reception of succinic acid produced by the parasite by brush cells promotes type 2 innate immune responses. This process creates a positive feedback loop, which increases the number of brush cells themselves.

[0030] Effect of GlcNAc administration Administration of GlcNAc solution in either water or succinic acid reduced the number of small intestinal brush cells in mice (Fig. 2). Given that recent studies have shown that GlcNAc is a ligand for GPRC5C expressed in hematopoietic stem cells, it is possible that GlcNAc activates GPRC5C in small intestinal brush cells, suppressing type 2 immunity. [Industrial Applicability]

[0031] The present invention can be used in the pharmaceutical industry.

Claims

1. 1. A suppressant of type 2 immunity, characterized by containing, as an active ingredient, N-acetyl-D-glucosamine or a substance having N-acetyl-D-glucosamine as a constituent component.

2. The method of claim 1, wherein the substance having N-acetyl-D-glucosamine as a constituent component is hyaluronic acid or chitin.

3. A composition for improving a disease involving type 2 immunity, comprising as an active ingredient N-acetyl-D-glucosamine or a substance having N-acetyl-D-glucosamine as a constituent component.

4. 4. The composition for improving a disease involving type 2 immunity according to claim 3, characterized in that the substance having N-acetyl-D-glucosamine as a constituent component is hyaluronic acid or chitin.

5. The composition for improving a disease involving type 2 immunity according to claim 3, characterized in that the disease involving type 2 immunity is atopic dermatitis, asthma, chronic sinusitis, or eosinophilic esophagitis.

6. The composition for improving a disease involving type 2 immunity according to claim 3, characterized in that it is orally administered.

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