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Medicinal compositions containing fc receptor gamma-chain activator

a technology of gamma-chain activator and fc receptor, which is applied in the field of pharmaceutical compositions, can solve problems such as severe dysmyelination, and achieve the effect of clarifying the mechanism

Inactive Publication Date: 2005-08-11
KEIO UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0052] The term “activating Fyn tyrosine kinase” used herein refers to producing one or both of the following effects: increasing the enzyme activity of Fyn tyrosine kinase (qualitative increase) or increasing the expression level of Fyn itself (mRNA or protein) (quantitative increase). It is speculated that the qualitative increase requires CD45.
[0056] The term “stimulating myelinogenesis” used herein means: replacing or repairing removed myelin sheaths in demyelinating diseases; completing or repairing by replacement those myelin sheaths which were formed incompletely in dysmyelinating diseases; and stimulating foreign oligodendroglias or oligodendroglial precursor cells introduced into a patient's body so that they actually form myelin sheaths in the body to thereby enhance their forming ability in transplantation / regeneration medicine.

Problems solved by technology

Mice deficient in Fyn suffer severe decreases in MBP production, resulting in severe dysmyelination (9-11).

Method used

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  • Medicinal compositions containing fc receptor gamma-chain activator
  • Medicinal compositions containing fc receptor gamma-chain activator
  • Medicinal compositions containing fc receptor gamma-chain activator

Examples

Experimental program
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Effect test

example 1

FcRγ Expression in Oligodendroglia in Vitro

[0151] In the immune system, the activation of Src family tyrosine kinase signaling involves the interaction between molecules with cytoplasmic domains containing immunoreceptor tyrosine-based activation motifs (ITAM) (24; reviewed in 25). Src family tyrosine kinase phosphorylates the tyrosine residues within the ITAM, triggering intracellular signaling (26). Fyn, a member of the Src family, is critical in the initial events of myelination (9). This evidence suggests that an ITAM-bearing molecule, expressed in oligodendroglia during the initial events of myelination, may be involved in myelinogenesis. FcRγ, containing a cytoplasmic ITAM shown to be phosphorylated by Fyn (27), was examined as a candidate but this immunological molecule has not been previously shown to occur within oligodendroglial cells.

[0152] The following is the first report detailing the existence of FcRγ within the oligodenoroglial lineage. Total RNA was extracted from...

example 2

FcRγ Expression in Oligodedroglia in Vivo

[0155] In order to examine Fcγ expression within the CNS in vivo, the inventors performed immunohistochemistry on the brains of neonatal mice at variable ages (36,38,39). FcRγ-positive cells were detectable at birth (P0) within the subventricular zone (germinal matrix areas adjacent to the cerebral ventricles; SVZ) (FIG. 2-a). Four days after birth (P4), the expression pattern expanded into the white matter, becoming detectable within the corpus callosum (FIG. 2-b). By P7, or the age at which MBP and MAG become detectable by immunohistochemistry, FcRγ expression had been localized primarily to the white matter (FIG. 2-c). Interestingly, the expansion of the observed staining distribution strongly resembles the pattern of postnatal gliogenesis from SVZ (40). FcRγ-positive cells were also observed adjacent to the mouse-Musashi-1 (m-Msi-1)-positive neural stem cell layer of the lateral ventricle at P0 (41, FIG. 2-d,e), suggesting that FcRγ-posi...

example 3

FcRγ Signaling Stimulates MBP Expression

[0160] In order to examine the effect of FcRγ stimulation on the expression of MBP, the inventors artificially generated FcRγ signaling in OPC (28,29) by administration of an anti-FcRγ rabbit polyclonal antibody (47). Following 24 hours of the stimulation, cultured OPC with few processes demonstrated remarkable morphological changes to acquire well-developed processes (FIG. 4A-b). Such developments were not observed in the absence of the antibody (FIG. 4A-a). MBP expression was strongly stimulated by this signaling, as compared to controls in analysis by Western blotting (FIG. 4B; 48). Similar experiments on Fyn also showed increased expression in stimulated oligodendroglia (FIG. 4B). As Fyn is up-regulated two- to three-fold during oligodendroglia differentiation (19), the observations of the inventors, i.e. an up-regulation of Fyn expression and dramatic morphological changes, indicate that the FcRγ signaling induced OPC differentiation. Th...

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Abstract

The present invention provides pharmaceutical compositions comprising, as an active ingredient, a substance capable of activating the γ chain of Fc receptors (FcRγ) (provided that the substance is not an immunoglobulin for intravenous injection), and agents for stimulating myelinogenesis. The invention also provides agents for stimulating the differentiation of oligodendroglial precursor cells, agents for activating Fyn tyrosine kinase, and agents for stimulating the expression of myelin basic protein, all comprising a substance capable of activating FcRγ as an active ingredient. Further, the invention provides a method of detecting myelinogenetic oligodenroglias or precursor cells thereof which comprises using the expression of FcRγ in oligodendroglias or precursor cells thereof as an indicator.

Description

[0001] Pharmaceutical Compositions Comprising A Substance Capable of Activating FcRγ, Agents for Stimulating Myelinogenesis, Agents for Stimulating the Differentiation of Oligodendroglial Precursor Cells, Agents for Activating Fyn Tyrosine Kinase, Agents for Stimulating the Expression of Myelin Basic Protein, A Method of Detecting Oligodendroglias or Oligodendroglial Precursor Cells Capable of Myelinogenesis, A Method of Examining FcRγ Expression in Animal Brain Tissues or Cells, and Reagent Kits TECHNICAL FIELD [0002] The present invention relates to pharmaceutical compositions comprising a ligand for the γ chain of Fc receptors (FcRγ); agents for stimulating myelinogenesis; agents for stimulating the differentiation of oligodendroglial precursor cells; agents for activating Fyn tyrosine kinase; agents for stimulating the expression of myelin basic protein; a method of detecting myelinogenetic oligodendroglias or precursor cells thereof; a method of examining FcRγ expression in ani...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K45/00A61P43/00C07K16/28
CPCC07K16/283A61K45/00A61P25/00A61P29/00A61P43/00
Inventor NAKAHARA, JINASOU, HIROAKIAISO, SADAKAZU
Owner KEIO UNIV
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