Applications of trametinib to preparation of drug for treating pulmonary inflammatory diseases and drug for promoting Tfh cell differentiation

A technology of pulmonary inflammation and cell differentiation, applied in the medical field, can solve the problems of enhancing viral immune inflammatory response, harmful overall prognosis of the disease, unable to change the Tfh ratio, etc., to achieve the effect of promoting Tfh differentiation and good therapeutic effect.

Inactive Publication Date: 2020-08-14
XIEHE HOSPITAL ATTACHED TO TONGJI MEDICAL COLLEGE HUAZHONG SCI & TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] 1. Viral pneumonia suppresses the immune system (hormonal drugs), and cannot obtain high-quality protective antibodies. It can be used in emergencies, but it is harmful to the overall prognosis of the disease;
[0004] 2. For the treatment of new coronary pneumonia, specific treatment has proposed to use IL-6 antibody to reduce T cell reactivity and reduce the rate of severe disease, but IL-6 has a direct impact on Tfh function and development, directly affecting the production of protective antibodies, currently There is no relevant report that IL-6 has a protective effect on the long-term recovery of new coronary pneumonia;
[0005] 3. At present, there are only drugs for enhancing or inhibiting the overall function of T cells and antibodies for individual cytokines in clinical practice. The overall intervention of T cells cannot change the ratio of Tfh, and cannot simultaneously enhance viral immunity and suppress unnecessary inflammatory responses. Factors play multiple roles, and the use of corresponding antibodies for one purpose may lead to unnecessary complications. As far as virus immunity is concerned, there is no suitable monoclonal antibody for use
[0006] Trametinib is currently mainly used in the treatment of tumors, and it is not used in the treatment of inflammation

Method used

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  • Applications of trametinib to preparation of drug for treating pulmonary inflammatory diseases and drug for promoting Tfh cell differentiation
  • Applications of trametinib to preparation of drug for treating pulmonary inflammatory diseases and drug for promoting Tfh cell differentiation
  • Applications of trametinib to preparation of drug for treating pulmonary inflammatory diseases and drug for promoting Tfh cell differentiation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: Trametinib reduces IRF4 expression.

[0037] step:

[0038] Take a mouse spleen in a sterile environment, grind it with an appropriate amount of PBS buffer in a sterile table, filter the unground part through a 40μm sieve, centrifuge at 2000 rpm for 3 minutes, discard the supernatant, and use 1ml ACK for precipitation The red blood cells were lysed by the lysate for 3 minutes, diluted with PBS buffer and centrifuged again to obtain lymphocytes. After cell counting, the lymphocytes were planted in a flat-bottomed 96-well plate with 1640 complete medium at a density of about 0.5*106 cells / well, CD28 was added at a final concentration of 1ug / ml, and Trametinib of different concentrations was added. (The 96-well plate was coated with 4ug / ml CD3 in advance). After 2-3 days of activation, flow staining was performed to circle the CD4-positive living T cells and detect the expression of IRF4 ( figure 1 left), and statistics ( figure 1 right).

[0039] Result an...

Embodiment 2

[0041] Example 2: Trametinib inhibits the proliferation of total T cells.

[0042] step:

[0043] T cell medium was added to CTV cell cycle marker staining (invitrogen C34557) at a ratio of 1:1000, and stained in the dark for 20 minutes, then added complete medium and incubated for 5 minutes, discarded the supernatant after cell centrifugation, and resuspended with complete medium For cell culture, the two groups were respectively added with 100nM Trametinib or the same amount of solvent DMSO, and the cell proliferation was detected by flow cytometry three days later.

[0044] Result analysis:

[0045] Such as figure 2 In the study, the proliferation of T cells stimulated by Trametinib was significantly slowed down, and the number of T cell proliferation was much lower than that of the control group.

Embodiment 3

[0046] Example 3: Trametinib inhibits the differentiation of pro-inflammatory T cell subsets Th1 and Th17, and increases the differentiation of anti-inflammatory cell subsets Treg.

[0047] T cell sorting:

[0048] To obtain purified CD4+ T cells and T cell-depleted (CD3-negative) splenocytes, the Miltenyi magnetic bead sorting system was used to sort specific cell subsets. All operations were carried out in accordance with sterile requirements to prevent cell contamination, and were sorted according to the instructions of relevant Miltenyi kits.

[0049] 1. Prepare cell suspension:

[0050] After the operating room was sterilized by ultraviolet radiation, the mice were killed by cervical dislocation, and soaked in 75% alcohol for 5 minutes to reduce pollution; the midline abdominal incision was made to quickly remove the spleen tissue of the mice, and put them in the medium prepared in advance Move the culture dish into an ultra-clean bench, put the spleen into a 200-mesh f...

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Abstract

The invention relates to applications of trametinib to preparation of a drug for treating pulmonary inflammatory diseases and promotion of Tfh cell differentiation. The chemical formula is C26H23FIN5O4. The applications include an application of trametinib to promotion for Tfh cell differentiation and an application of trametinib to preparation of the drug for treating the pulmonary inflammatory diseases. The trametinib has beneficial effects as follows: cytokine storm caused by activation of T cells and mononuclear macrophages can be better inhibited, and meanwhile, Tfh differentiation, B cell maturation mediation and antibody production are promoted; and as abroad-spectrum immune regulation drug, the trametinib has an effect of promoting antibody production in the aspects of other viralpneumonia, virus infection or seedling inoculation.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to the application of trametinib in the preparation of medicines for treating pulmonary inflammatory diseases and the promotion of differentiation of Tfh cells. Background technique [0002] Viral immunization is to obtain high-quality blocking antibodies. Different subtypes of T cells perform different functions. In this process, the Tfh subtype is the most important, but at the same time there are too many other subtypes of pro-inflammatory T cells, which will secrete a large number of inflammatory factors , Inducing an excessive inflammatory response in the body, leading to complications: fever, organ damage, and even multiple organ failure, which is also the most serious complication of new coronary pneumonia (inflammatory factor storm). The current technical issues are as follows: [0003] 1. Viral pneumonia suppresses the immune system (hormonal drugs), and canno...

Claims

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Application Information

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IPC IPC(8): A61K31/519A61P11/00A61P31/12
CPCA61K31/519A61P11/00A61P31/12
Inventor 吴杰夏家红
Owner XIEHE HOSPITAL ATTACHED TO TONGJI MEDICAL COLLEGE HUAZHONG SCI & TECH UNIV
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