CN111000978B - Application of TLT-2 in preparation of medicine for treating tuberculosis - Google Patents
Application of TLT-2 in preparation of medicine for treating tuberculosis Download PDFInfo
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- CN111000978B CN111000978B CN201911154239.3A CN201911154239A CN111000978B CN 111000978 B CN111000978 B CN 111000978B CN 201911154239 A CN201911154239 A CN 201911154239A CN 111000978 B CN111000978 B CN 111000978B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
- A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
Abstract
The invention relates to the field of biological medicines, in particular to application of TLT-2 in preparation of a medicine for treating tuberculosis, and provides a novel immunotherapy scheme for comprehensive treatment of tuberculosis, the invention researches TLT-2 in active tuberculosis patients to find that the expression level of TLT-2 on mononuclear macrophages of tuberculosis patients is increased, and the TLT-2 on the surface of mouse mononuclear macrophages is blocked by TLT-2 recombinant protein to further research and find that TLT-2 can effectively reduce tubercle bacillus in the lungs of mice and promote anti-tubercular inflammatory reaction, so that TLT-2 is expected to be applied to comprehensive treatment of tuberculosis to prepare a form of the medicine for treating tuberculosis, reduce tubercle bacillus in the lungs of tuberculosis patients, reduce inflammation and finally achieve the aim of cellular immunotherapy.
Description
Technical Field
The invention relates to the field of biomedicine, in particular to application of TLT-2 in preparation of a medicine for treating tuberculosis.
Background
Tuberculosis is an infectious disease caused by mycobacterium tuberculosis and is common clinically. Tuberculosis is common among young people and rural people, and after tuberculosis infection, tubercle bacillus invades various body organs of patients, mostly invades lungs, so that tuberculosis is also called as pulmonary tuberculosis. In addition to infections of the lung, infections of the meninges, skin and cervical lymph may also occur. The causes of tuberculosis include infection between people, environmental pollution, spread of AIDS and the like, and the tuberculosis is mainly clinically manifested as cough, expectoration, hemoptysis, hypodynamia, low fever and other symptoms. Once tuberculosis occurs, the normal life and work of the patient can be seriously affected.
Currently, tuberculosis is treated mainly by chemical drugs, however, long-term chemotherapy easily causes drug resistance of mycobacterium tuberculosis. With the high drug-resistant rate and the spread of drug-resistant bacteria, the treatment of tuberculosis is more and more severe. Therefore, the development of new approaches to the treatment of tuberculosis and drug-resistant tuberculosis is urgent. In recent years, many attempts have been made in the field of biological therapy, such as cellular immunotherapy, cytokines, monoclonal antibodies, and the like. The cell therapy is to activate and amplify autologous or allogeneic immune effector cells in vitro and then return the cells to the patient, so as to kill target cells and improve the immune function of the patient. Cellular immunotherapy is an important component of the future refractory tuberculosis comprehensive treatment, and the prior art lacks an effective method for the cellular therapy of tuberculosis.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention mainly aims to provide the application of TLT-2 in preparing a medicine for treating tuberculosis.
Myeloid cell-Triggering receptor-like transcription factor-2 (TLT-2) is a member of the immunoglobulin superfamily of myeloid cell-Triggering Receptors (TREMs), and is a novel inflammation-Triggering receptor. According to the invention, the expression quantity of TLT-2 on mononuclear macrophages of tuberculosis patients is increased through research on the tuberculosis patients, and the TLT-2 on the surfaces of the mononuclear macrophages is blocked by TLT-2 recombinant protein for further research, so that the TLT-2 recombinant protein can effectively reduce pulmonary tubercle bacillus and promote anti-tuberculous inflammatory reaction, and the TLT-2 is expected to be applied to comprehensive treatment of tuberculosis.
Accordingly, the present invention provides, in a first aspect, a medicament for the treatment of tuberculosis, said medicament comprising myeloid cell triggering receptor-like transcription factor-2 (also known as TLT-2).
Through research, the following results are found: TLT-2 in humans recognizes and binds certain components of Mycobacterium tuberculosis, resulting in macrophage inability to eliminate Mycobacterium tuberculosis and inhibition of anti-tubercular inflammatory responses. Through exogenously administering the TLT-2 recombinant protein, because the TLT-2 recombinant protein is the same protein as the TLT-2 on the surface of the macrophage, the TLT-2 recombinant protein can also be combined with the mycobacterium tuberculosis, so that the combination of the mycobacterium tuberculosis and the TLT-2 on the surface of the macrophage is reduced, and the TLT-2 mediated inhibition effect of the macrophage is further reduced.
Furthermore, the drug for treating tuberculosis also comprises a pharmaceutically acceptable auxiliary agent of the myeloid cell triggering receptor-like transcription factor-2, and the drug can be used in combination with the pharmaceutically acceptable auxiliary agent, so that the safety, effectiveness and stability of the drug can be improved while the treatment effect is ensured.
The invention also provides the application of the marrow cell triggering receptor-like transcription factor-2 in the preparation of drugs for treating tuberculosis.
Furthermore, the myeloid cell triggering receptor-like transcription factor-2 is a human recombinant myeloid cell triggering receptor-like transcription factor-2 protein, and is more suitable for the comprehensive treatment of human tuberculosis; specifically, TLT-2 is used to treat tuberculosis by reducing the number of Mycobacterium tuberculosis in the body and promoting anti-tubercular inflammatory response in the body.
Furthermore, the dosage form of the medicine is an injection administration dosage form or a gastrointestinal administration dosage form, so that the application range of the medicine is increased; specifically, the administration form by gastrointestinal tract includes common powders, tablets, granules, capsules, solutions, emulsions, suspensions, and the like; the injection dosage forms include common injections (such as intravenous injection, intramuscular injection, subcutaneous injection, and intradermal injection).
Furthermore, when the preparation form of the medicine is an injection preparation, the medicine is mixed with normal saline to prepare a solution when in use.
Compared with the prior art, the invention has the beneficial effects that:
the TLT-2 in active tuberculosis patients is researched and found, the expression quantity of the TLT-2 on mononuclear macrophages of tuberculosis patients is increased, the TLT-2 recombinant protein blocks the TLT-2 on the surfaces of the mononuclear macrophages of mice for further research and finding, the TLT-2 recombinant protein can effectively reduce tubercle bacillus in the lungs of the mice and promote anti-tubercular inflammatory reaction, and the TLT-2 is suggested to be applied to comprehensive treatment of tuberculosis to prepare a medicament for treating tuberculosis so as to reduce the tubercle bacillus in the lungs of tuberculosis patients and relieve inflammation. Meanwhile, TLT-2 is a human recombinant protein, so that rejection does not exist, and the method is more suitable for comprehensive treatment of tuberculosis.
Drawings
Figure 1 shows TLT-2 expression on mononuclear macrophages from tuberculosis patients (×, p < 0.001);
FIG. 2 shows the variation of the number of Mycobacterium tuberculosis in the lung and spleen of a mouse after TLT-2 recombinant protein blocks TLT-2 on the surface of mouse mononuclear macrophage (FIG. 2A is a graph showing the number of Mycobacterium tuberculosis in the lung, and FIG. 2B is a graph showing the number of Mycobacterium tuberculosis in the spleen);
FIG. 3 is a graph showing the inflammatory infiltration of mouse lung after TLT-2 recombinant protein blocks TLT-2 on mouse monocyte macrophage surface (a, c, e is 10X visual field, b, d, f is 20X visual field corresponding to a, c, e, wherein control is blank group, BCG + NaCl is positive control group, BCG + rmTLT2 is experimental treatment group).
Detailed Description
The following further describes the embodiments of the present invention. It should be noted that the description of the embodiments is provided to help understanding of the present invention, and is not intended to limit the present invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1 analysis of TLT-2 expression level on mononuclear macrophages of tuberculosis patients
1. Collecting a detection sample:
collecting subject peripheral blood: active tuberculosis patients (noted ATB) and healthy persons (noted HC).
2. The detection method specifically comprises the following steps:
(1) 3mL human peripheral venous whole blood with saline 1:1 proportion, and slowly adding the diluted whole blood onto the liquid surface of 2ml of Ficoll lymphocyte separation solution.
(2) The cells were centrifuged at 1800rpm for 30min to obtain a mononuclear cell layer (leukocyte layer with PBMC).
(3) Sucking tunica albuginea cells, blocking with 1% BSA buffer solution, flow-staining to label TLT-2 (CD 11b-Pacificblue, TLT-2-PE, staining at 4 ℃ for 30min, fixing with 1% paraformaldehyde, and detecting the expression level of TLT-2 as TLT2 + CD11b + Percentage statistics for Cells).
3. The experimental results are as follows:
as shown by the results in FIG. 1, TLT-2 expression was increased on mononuclear macrophages in tuberculosis patients compared to healthy controls. Suggesting that TLT-2 on mononuclear macrophages may play an important role in the context of tuberculosis infection.
Example 2 TLT-2 experiment for blocking mouse monocyte macrophage surface by TLT-2 recombinant protein
1. Preparation of the experiment: mouse TLT-2 recombinant protein; mycobacterium bovis BCG;7H10 medium; physiological saline; c57BL mice.
2. The experimental steps are as follows:
(1) Centrifugally collecting the BCG subjected to liquid culture, and grinding the BCG by using a tissue grinding rod to prepare a single BCG bacterial suspension;
(2) Calculating the bacterial concentration by detecting the turbidity of single bacterial suspension of BCG, and calculating the bacterial concentration by using BCG 1x10 6 Dose of mice intravenously infected;
(3) 1ug of TLT-2 recombinant protein per mouse was injected into the abdominal cavity, and the control group was Nacl injection;
(4) The effect was boosted 7 days after infection with another injection of 1 ug/TLT-2 recombinant protein.
(5) And (3) judging the curative effect: the experiment was terminated 21 days, the mice were dissected, the lungs and spleen were removed, and the organs were milled to give a tissue milling solution, which was diluted to 1:10 was lysed using 0.01% Triton100, 100uL of lysate was plated on 7H10 plates, and individual colonies grown on the plates were counted after 21 days of 37 ℃ culture. The number of tubercle bacillus in the lung and spleen of the mice treated with the TLT-2 recombinant protein was determined by using the NaCl-treated group as a control (FIG. 2). The tissue blocks of the lung portions were taken, fixed with 10% formalin, and subjected to HE staining of pathological sections, and the inflammatory infiltration pattern of the mouse lung was observed (fig. 3).
3. The experimental results are as follows:
as shown in the results of FIG. 2, the amount of Mycobacterium tuberculosis in the lung and spleen of mice was significantly reduced after the TLT-2 recombinant protein blocked the TLT-2 on the surface of mouse mononuclear macrophage compared to the NaCl-treated group, indicating that the immune mechanism of bacterial clearance in mice was enhanced after the TLT-2 on the surface of mouse mononuclear macrophage was blocked.
As shown in the results of FIG. 3, the enhanced pulmonary inflammatory response of mice after blocking TLT-2 on the surface of mouse mononuclear macrophages by the TLT-2 recombinant protein, compared with the NaCl-treated group, indicates that the anti-tuberculosis immunity inflammatory effect of mice in vivo is enhanced after blocking TLT-2.
The results show that the TLT-2 recombinant protein can effectively reduce tubercle bacillus in the lung of a mouse, promote anti-tubercular inflammatory reaction, facilitate comprehensive treatment of tuberculosis, and prompt that the TLT-2 recombinant protein is expected to be applied to comprehensive treatment of tuberculosis.
The embodiments of the present invention have been described in detail above, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made in the embodiments without departing from the principles and spirit of the invention, and these embodiments are still within the scope of the invention.
Claims (5)
1. Application of medullary cell triggering receptor-like transcription factor-2 in preparing medicine for treating tuberculosis is provided.
2. The use of claim 1, wherein the myeloid cell-triggering receptor-like transcription factor-2 is a human recombinant myeloid cell-triggering receptor-like transcription factor-2 protein.
3. The use according to claim 1, wherein the treatment of tuberculosis is a reduction in the number of mycobacterium tuberculosis in the body.
4. The use according to claim 1, wherein the treatment of tuberculosis is the promotion of an anti-tubercular inflammatory response in vivo.
5. The use according to claim 1, wherein the medicament is in the form of an injection or a gastrointestinal tract.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102892426A (en) * | 2010-03-04 | 2013-01-23 | 宏观基因有限公司 | Antibodies reactive with b7-h3, immunologically active fragments thereof and uses thereof |
| CN107106679A (en) * | 2014-08-08 | 2017-08-29 | 艾利妥 | Anti- TREM2 antibody and its application method |
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| SG189365A1 (en) * | 2010-10-13 | 2013-05-31 | Bioniche Urology Ip Inc | Compositions de membranes cellulaires et d'acide ribonucléique bactériens, et leurs procédés de fabrication et d'utilisation |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102892426A (en) * | 2010-03-04 | 2013-01-23 | 宏观基因有限公司 | Antibodies reactive with b7-h3, immunologically active fragments thereof and uses thereof |
| CN106279416A (en) * | 2010-03-04 | 2017-01-04 | 宏观基因有限公司 | The antibody reactive with B7 H3, its immunologic competence fragment and application thereof |
| CN107106679A (en) * | 2014-08-08 | 2017-08-29 | 艾利妥 | Anti- TREM2 antibody and its application method |
Non-Patent Citations (2)
| Title |
|---|
| Jinai Li et al.TLT2 Suppresses Th1 Response by Promoting IL-6 Production in Monocyte Throμgh JAK/STAT3 Signal Pathway in Tuberculosis.《Frontiers in Immunology》.2020,第11卷第1-13页. * |
| 一株鼠抗人TLT-2单克隆抗体的研制及其生物学特性的鉴定;徐俊驰 等;《现代免疫学》;20111231;第31卷(第5期);第374-378页 * |
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