Use of adenosine receptor signaling to modulate permeability of blood-rain barrier

A technology of adenosine receptor and blood-brain barrier, applied in the direction of medical preparations containing active ingredients, antibodies, antibody medical components, etc., can solve the problems of poor understanding of molecular mechanisms, limited endocytosis of BBB transport capacity, etc. To achieve the effect of enhanced treatment and improved treatment

Inactive Publication Date: 2013-07-24
CORNELL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Vector-based delivery technologies have two major disadvantages: 1) BBB transport capacity is limited by receptor expression and 2) endocytic events are limited in the BBB endothelium, which is a physiological characteristic of
[0014] Despite the importance of this barrier, the molecular mechanisms controlling BBB integrity and / or permeability are poorly understood

Method used

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  • Use of adenosine receptor signaling to modulate permeability of blood-rain barrier
  • Use of adenosine receptor signaling to modulate permeability of blood-rain barrier
  • Use of adenosine receptor signaling to modulate permeability of blood-rain barrier

Examples

Experimental program
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Effect test

Embodiment

[0156] The following examples are provided to illustrate embodiments of the invention, but are in no way intended to limit the scope thereof.

[0157] Example 1 - Mice

[0158] cd73 has been described previously - / - Mice (Thompson et al., "Crucial Role for Ecto-5'-Nucleotidase (CD73) in Vascular Leakage During Hypoxia," J. Exp. Med. 200:1395-1405 (2004), which is hereby incorporated by reference in its entirety) And it has been backcrossed with C57BL / 6 for 14 generations. cd73 - / - Mice have no apparent susceptibility to infection and appear to be normal based on the size and cellular composition of their lymphoid organs and their T and B cell responses in in vivo and in vitro assays (Thompson et al., "Crucial Role for Ecto-5'-Nucleotidase( CD73) in Vascular Leakage During Hypoxia," J. Exp. Med. 200:1395-1405 (2004), which is hereby incorporated by reference in its entirety). Purchase C57BL / 6 and tcra with C57BL / 6 background from Jackson Laboratories - / - mice. Mice were b...

Embodiment 2-E

[0159] Example 2 - EAE induction and scoring

[0160] By subjecting mice to Swanborg, "Experimental Autoimmune Encephalomyelitis in Rodents as a Model for Human Demyelinating Disease," Clin. Immunol. Immunopathol. 77:4-13 (1995) and Bynoe et al., as hereby incorporated by reference in its entirety. Epicutaneous Immunization with Autoantigenic Peptides Induces T Suppressor Cells that Prevent Experimental Allergic Encephalomyelitis, "Immunity 19:317-328 (2003) described in the myelin oligodendrocyte glycoprotein ("MOG") EAE induction protocol to induce EAE. Briefly, MOG was injected subcutaneously into each flank 35-55 1:1 emulsion (50 μl) of peptide (3 mg / ml in PBS) (Invitrogen) and complete Freund's adjuvant (CFA, Sigma). Pertussis toxin (PTX, 20 ng) (Biological Laboratories Inc.) was reinjected intravenously (200 μl in PBS) at the time of immunization and 2 days later. Mice were scored daily for EAE based on severity of disease symptoms; 0=no disease, 0.5-1=tail weakness / li...

Embodiment 3

[0161] Example 3-T cell preparation and adoptive transfer

[0162] For MOG in CFA without PTX 35-55 Peptide primed mice. One week later, lymphocytes were harvested from the spleen and lymph nodes and mixed with ACK buffer (0.15M NH 4 Cl, 1mM KHCO 3 , 0.1mM EDTA, pH7.3) to lyse red blood cells. Combine cells with CD8(TIB-105), IA b,d,v,p,q,r (212.A1), FcR(2.4-G2), B220(TIB-164), NK1.1(HB191) antibodies were then incubated with BioMag goat anti-mouse IgG, IgM and goat anti-rat IgG (Qiagen). After negative magnetic enrichment, use CD4 directly +Cells may be further sorted into specific subpopulations. For sorting, cells were stained with antibodies to CD4 (RM4-5) and CD73 (TY / 23), and in some experiments CD25 (PC61), and then separated using a FACSAria (BD Biosciences). Typically >99% pure after sorting. For adoptive transfer, wash all CD4 + Or sort T cells and resuspend in sterile PBS. Recipient mice received ≤2.5×10 intravenously 6 cells in 200 μl sterile PBS.

[01...

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Abstract

The present invention relates to a method of increasing blood brain barrier ("BBB") permeability in a subject. This method involves administering to the subject an agent or agents which activate both of the A1 and A2A adenosine receptors. Also disclosed is a method to decrease BBB permeability in a subject. This method includes administering to the subject an agent which inhibits or blocks the A2A adenosine receptor signaling. Compositions relating to the same are also disclosed.

Description

[0001] This application claims the benefit of US Provisional Patent Application Serial No. 61 / 383,628, filed September 16, 2010, which is hereby incorporated by reference in its entirety. [0002] This invention was made with government support under grants K22A1057854 and R01NS063011 awarded by the National Institutes of Health. The government has certain rights in this invention. technical field [0003] The present invention relates to the regulation of blood-brain barrier permeability. Background of the invention [0004] The barrier to blood entering the central nervous system ("CNS") is collectively referred to herein as the blood-brain barrier ("BBB"). The BBB is a very tight layer of endothelial cells that covers 400 miles of capillaries and blood vessels in the brain (Ransohoff et al., "Three or More Routes for Leukocyte Migration Into the Central Nervous System," Nature Rev. Immun. 3:569-581 (2003)) . The blood-brain barrier (BBB) ​​is composed of brain endothel...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N5/07C12N5/16
CPCA61K39/395A61K31/437A61K31/519A61K31/706C07K16/00A61K31/7076C07K16/18A61K39/39533A61K45/06A61P1/14A61P3/00A61P25/04A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P43/00A61K2300/00
Inventor M·S·拜内
Owner CORNELL UNIVERSITY
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