Suppression of microglial activation with innate lymphoid cells

A technology of lymphoid cells and microglia, applied to medical preparations containing active ingredients, peptide/protein ingredients, allergic diseases, etc., can solve problems such as unclear long-term effects

Pending Publication Date: 2021-05-14
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The long-term effects of these therapies are unclear because mesenchymal stem cells survive only a few months in the body (Volkman and Offen, 2017, Stem Cells, 35(8):1867-1880)

Method used

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  • Suppression of microglial activation with innate lymphoid cells
  • Suppression of microglial activation with innate lymphoid cells
  • Suppression of microglial activation with innate lymphoid cells

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0153] The invention also provides the following non-limiting embodiments.

[0154] Embodiment 1 is a method of reducing or inhibiting microglial activation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of activated type II innate lymphoid cells (ILC2 ).

[0155] Embodiment 1a is a method of reducing the permeability of the blood-brain barrier (BBB) ​​in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of activated type II innate lymphoid cells (ILC2).

[0156] Embodiment 2 is the method according to embodiment 1 or 1a, wherein the ILC2 is obtained by combining the ILC2 with at least one selected from IL-33, IL-25, IL-2, IL-7 or combinations thereof Cytokine exposure to activate.

[0157] Embodiment 2a is the method according to embodiment 2, wherein said ILC2 is activated by contacting said ILC2 with two cytokines selected from the group con...

Embodiment approach 21c

[0228] Embodiment 21c is a method of identifying an agent useful for reducing BBB permeability in a subject in need thereof, the method comprising:

[0229] (1) contacting innate lymphoid cells (ILC2) with the agent; and

[0230] (2) measuring the level of Timp1 produced by said ILC2;

[0231] wherein an increase in the amount of Timpl produced by the ILC2 compared to a control level indicates that the agent is useful for reducing BBB permeability in a subject in need thereof.

[0232] Embodiment 22 is the method according to any one of embodiments 1 to 13, the pharmaceutical composition according to any one of embodiments 14 to 16, or the method according to any one of embodiments 17 to 21c The method, wherein the ILC2 expresses one or more of CD90, ICOS, IL7Ra (CD127), CD161, ST2, stem cell antigen 1 (Sca1), IL2Ra (CD25) and CRTH2 and is negative for the expression of Lin.

[0233] Embodiment 22a is the method of embodiment 22, wherein the ILC2 expresses two of CD90, ICOS,...

Embodiment 1

[0249] Example 1. Enrichment of ILC2 in meninges

[0250] Transcription factor markers of CD45+Lin–FCεr1a–DX5–CD90+IL7rα+ cells ( figure 1 A) Used to resolve ILC1 (Tbet+), ILC2 (Gata3Hi) and ILC3 (RORγt+Gata3– / lo) subpopulations. First, meningeal innate lymphoid cells (mILCs) were analyzed to determine the most abundant type. Naïve mouse brains were carefully dissected and immediately fixed in 4% paraformaldehyde. After fixation at 4°C for 48 hours (hr), the brain was incubated in 30% sucrose in H 2 O in solution for 24 hr and then stored at -80 °C. The calvaria was placed in 20 ml of fluorescence activated cell sorting (FACS) buffer (DMEM / F-12 + 2% FBS) in a petri dish and the meninges were carefully peeled off using forceps. Place the meninges in a 70 μm cell strainer and gently dissociate using the reverse side of the plunger of a syringe with (minimum 100) strokes. Cells were then washed three times through the filter to further release cells from the dissociated t...

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Abstract

Compositions and methods of using ILC2 to reduce microglial activation or to reduce blood-brain barrier (BBB) permeability are described. Also described are methods and compositions that use an agent that increases the number of activated ILC2 to reduce microglial activation or BBB permeability.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 698,545, filed July 16, 2018, the disclosure of which is incorporated herein by reference in its entirety. technical field [0003] The present invention generally relates to methods and compositions for inhibiting microglia activation. In particular, the present invention relates to compositions and methods for inhibiting microglial activation or disruption of the blood-brain barrier by administering type II innate lymphoid cells or agents that increase the number or activity of type II innate lymphoid cells. Background technique [0004] As the name suggests, innate lymphoid cells (ILCs) display features of both innate and adaptive immunity. Although ILCs arise from a common lymphoid precursor and differentiate into subpopulations resembling T helper cells, ILCs do not undergo the somatic recombination that underlies the receptor diversi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K35/17A61P25/00
CPCA61K35/17A61P25/00A61K38/20A61K2035/122A61K2035/124A61P29/00A61P37/06A61K38/2013A61K38/2026A61K2300/00
Inventor A·巴塔查里亚G·R·阿莱曼慕尼黑N·C·德雷基P·索罗斯H·贝恩
Owner JANSSEN PHARMA NV
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