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Application of inhibiting autophagy of mesenchymal stem cells in autoimmune diseases

An autoimmune and mesenchymal stem cell technology, applied in the direction of allergic diseases, genetic material components, medical preparations containing active ingredients, etc., can solve the problems of weakening the therapeutic effect of inflammatory diseases and reducing immune function

Active Publication Date: 2018-06-05
SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, inflammatory cells and inflammatory factors in the inflammatory microenvironment also act on MSCs, reducing their immune function and weakening their therapeutic effect on inflammatory diseases

Method used

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  • Application of inhibiting autophagy of mesenchymal stem cells in autoimmune diseases
  • Application of inhibiting autophagy of mesenchymal stem cells in autoimmune diseases
  • Application of inhibiting autophagy of mesenchymal stem cells in autoimmune diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Inhibition of autophagy in mesenchymal stem cells enhances their immunosuppressive ability against experimental allergic meningitis (EAE)

[0084] METHODS: Mice aged 6-8 weeks were randomly divided into groups and immunized with synthetic myelin protein peptides to establish an animal model of experimental allergic cerebrospinal meningitis (EAE). Prophylactic treatment with vehicle (PBS), control MSCs (shNC-MSCs) and autophagy-inhibited MSCs (shBecn1-MSCs) were used on the 3rd and 8th day of modeling, respectively, and on the 10th and 15th day of modeling PBS, shNC-MSCs and shBecn1-MSCs were used for therapeutic treatment, respectively, and the incidence of the three groups of mice was observed.

[0085] Scoring criteria: 0: no disease; 1: tail weakness; 2: slight hindlimb weakness; 3: severe hindlimb paralysis; 4: quadriplegia; 5: dying or dying.

[0086] Results: The disease scores of mice in the suppressed autophagy treatment group were significantly improved after ...

Embodiment 2

[0089] Inhibition of MS autophagy on CD4 + T cell role detection

[0090] Method: According to the results of Example 1, it was further determined to inhibit MS autophagy on CD4 + The role of T cells, that is, detection and analysis of CD4 in EAE mice treated with PBS, shNC-MSCs and shBecn1-MSCs + T cells,

[0091] Results: The experiment found that the shBecn1-MSCs treatment group EAE mice CD4 + The level of T cell activation was significantly lower than that of the shNC-MSCs treatment group, and the expression levels of T cell activation markers CD25 and CD69 were lower than those of the shNC-MSCs treatment group (see image 3 A, 3B).

[0092] detect CD4 + After the proliferation of T cells in vivo, it was found that BrdU+ CD4 in the target organ spinal cord and peripheral immune organ spleen in the shBecn1-MSCs treatment group EAE mice + T cells, proliferating CD4 + T cells, significantly less than those treated with shNC-MSCs (see Figure 4 A).

[0093] Further us...

Embodiment 3

[0096] Inhibition of autophagy can enhance the immunosuppressive function of mesenchymal stem cells

[0097] Method: Activated CD4 + T cells were co-cultured with shNC-MSCs and shBecn1-MSCs. CFSE and 3H incorporation methods were used to detect the proliferation of T cells, and real-time quantitative polymerase chain reaction was used to detect the expression levels of effector molecules that MSCs exerted immunosuppressive functions.

[0098] Result: CD4 + The ratio of T cells to MSCs ranged from 10:1 to 50:1, and shBecn1-MSCs could inhibit CD4 more strongly than shNC-MSCs + Proliferation of T cells (see Figure 5 A, 5B).

[0099] Experiments have shown that the mRNA expression of COX-2 is up-regulated after autophagy is inhibited, and the expression of COX-2 is further up-regulated under the combined stimulation of inflammatory factors TNF-α and IFN-γ (see Figure 6 A), This result was further confirmed at the protein level using Western blotting (see Figure 6 B).

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Abstract

The invention discloses an application of inhibiting autophagy of mesenchymal stem cells in autoimmune diseases. Specifically, the present invention relates to the use of an autophagy inhibitor of mesenchymal stem cells for preparing a composition that enhances the immunosuppressive ability of mesenchymal stem cells; and / or for preparing a pharmaceutical combination for preventing or treating autoimmune diseases thing. The present invention also relates to a method for taking a safe and effective amount of mesenchymal stem cell autophagy inhibitor as an active ingredient of a pharmaceutical composition, and using it for treating autoimmune diseases. The method for inhibiting autophagy of mesenchymal stem cells so as to enhance their immunosuppressive function can be applied to the treatment of autoimmune diseases, and has good application prospects and economic benefits.

Description

technical field [0001] The invention relates to a method for enhancing the immunosuppressive function of mesenchymal stem cells based on inhibiting autophagy, and belongs to the technical field of medicine. Background technique [0002] Autoimmune diseases are a kind of diseases caused by the body's immune response to self-antigens, resulting in damage to its own tissues. It is generally believed that abnormal inflammatory reactions occur at the tissue damage caused by various autoimmune diseases, such as rheumatoid arthritis ( rheumatoid arthritis, RA), multiple sclerosis (multiple sclerosis, MS) and systemic lupus erythematosus (systemic lupus erythematosus, SLE). RA is characterized by synovial inflammation accompanied by articular bone and cartilage damage, MS is an inflammatory lesion characterized by demyelination of the central nervous system, and SLE is an immune complex deposition. Chronic activation of the immune system results in multisystem autoimmune disease, o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/06A61K31/52A61K48/00A61P37/06
Inventor 张雁云党时鹏金敏万兵
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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