Histamine-releasing factor (HRF), hrf-receptor and methods of modulating inflammation

a technology of hrf and receptor, which is applied in the field of hrf, hrf receptor and methods of modulating inflammation, can solve the problems of hrf, if any, being elusive for decades in the role of hrf in allergic and other immune diseases, and low levels of phosphorylation, so as to reduce the binding of hrf/tctp, reduce the probability, severity, frequency, duration or preventing a subject, and reduce the probability of hr

Inactive Publication Date: 2013-04-04
LA JOLLA INST FOR ALLERGY & IMMUNOLOGY
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Benefits of technology

[0026]The invention further provides methods of reducing or decreasing the probability, severity, frequency, duration or preventing a subject from having an acute or chronic food allergy, allergic reaction, hypersensitivity, an inflammatory response or inflammation. In one embodiment, a method includes administering to a subject a compound that inhibits or reduces binding of HRF / TCTP to an immunoglobulin thereby decreasing the probability, severity, frequency, duration or preventing the subject from having an acute or chronic food allergy, allergic reaction, hypersensitivity, inflammatory response or inflammation.

Problems solved by technology

However, this failure may be due to low levels of phosphorylation and limited cell numbers used.
However, the role of HRF, if any, in allergic and other immune diseases has been elusive for decades.
In addition to these, the study of HRF has another formidable obstacle: how can the extracellular (=cytokine) and intracellular functions of HRF be distinguished?
Simple overexpression (by transgenic approach), knockout, or knockdown of the HRF gene cannot resolve this problem.
Even conditional knockout techniques will not provide an answer, as the intracellular function of HRF / TCTP in the targeted cells might be affected at the same time.
However, several challenges of OVA were needed for mast cell accumulation and diarrhea development after transfer (Knight et al., Am. J. Physiol. Gastrointest.
However, these studies were based on histamine releasing activity of serum on basophils, not on direct measurement of HRF.
In addition, the impact of spontaneous release of histamine from basophils on food allergy pathogenesis has not been studied.

Method used

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  • Histamine-releasing factor (HRF), hrf-receptor and methods of modulating inflammation
  • Histamine-releasing factor (HRF), hrf-receptor and methods of modulating inflammation
  • Histamine-releasing factor (HRF), hrf-receptor and methods of modulating inflammation

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0226]This example includes a description of various materials and methods.

Mice

[0227]C57BL / 6 and Balb / c mice were purchased from the Jackson Laboratory (Maine). FcεRIα− / − mice (Dombrowicz et al., Cell 75:969 (1993)) on a Balb / c background, FcεRIγ− / − mice (Takai et al., Cell 76:519 (1994)) on a C57BL / 6 background, μMT mice (Kitamura et al., Nature 350:6317 (1991)) on a C57BL / 6 background, and KitW-sh / W-sh (Grimbaldeston et al., Am. J. Pathol. 167:835 (2005)) on a C57BL / 6 background. Such knockout mice are usually backcrossed to Balb / c or C57BL / 6 mice for >10 generations.

Purification and Preparation of IgE and IgG

[0228]For purification of IgE, Ishizaka's method (Ishizaka, Methods Enzymol. 116:76 (1985)) was utilized such that IgE was enriched from ascites or culture supernatants by ammonium sulfate precipitation (40-55%). IgE-containing fractions were then purified by DEAE-agarose (GE Healthcare Bio-Sciences AB) column chromatography, followed by gel filtration using Sephacryl S-300 (...

example 2

[0248]This example includes a description of a subset of mouse IgE and IgG molecules, and that human IgE binds to HRF.

[0249]A previous report indicated that IgE polyclonal antibody does not interact with HRF (Wantke, et al., J Allergy Clin Immunol 103, 642 (April 1999)). To evaluate the possibility of IgE / HRF interactions, a panel of IgE mAbs was examined. N-terminally glutathione S-transferase (GST)-tagged mouse HRF protein (GST-mHRF) or GST were immobilized onto enzyme-linked immunosorbent assay (ELISA) plates and incubated with IgE mAbs. Bound IgE was detected with anti-IgE-biotin and streptavidin-horseradish peroxidase conjugates. GST-mHRF, but not GST, bound C38-2, IGELa2, and 5 other IgE mAbs (FIG. 1A). By contrast, C48-2 and 12 other IgE mAbs failed to bind GST-mHRF using OD4506 (C-terminally hexahistidine-tagged mHRF) was used as a capturing agent.

[0250]Interaction of the C38-2 and IGELa2 IgE mAbs with mHRF was also demonstrated by co-immunoprecipitation from a mixture of Ig...

example 3

[0255]This example includes a description of studies indicating that the N-terminal 19 residue peptide of HRF inhibits the HRF / IgE interaction.

[0256]To map the Ig-interaction site within the mHRF molecule, an ELISA panel of N- or C-terminally truncated GST-mHRF proteins (FIG. 3A) was used as capturing agents and two HRF-reactive IgE mAbs (C38-2 and aOE) and two HRF-reactive IgG mAbs (JK18 and JK31) as binding probes. C38-2 and aOE IgE molecules were incubated in wells coated with full-length or truncated forms of GST-mHRF. After blocking, JK18 and JK31 IgGs were incubated. The bound IgGs were detected by incubation with horseradish peroxidase-conjugated anti-mouse IgG antibody. The absorbance at 450 nm was measured after development of the color.

[0257]HRF-reactive IgE and IgG mAbs gave similar binding patterns (FIGS. 3B and 4). C-terminal truncations of mHRF up to residue 19 did not affect Ig binding, but a further truncation abrogated Ig binding. Thus, a major Ig-binding site was m...

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Abstract

Methods of treating a food allergy, allergic reactions, hypersensitivity, inflammatory responses, inflammation are provided. In one method, histamine releasing factor (HRF)/translationally controlled tumor protein (TCTP) is contacted with a compound that inhibits or reduces binding of HRF/TCTP to an immunoglobulin in order to treat the food allergy, allergic reaction, hypersensitivity, inflammatory response, or inflammation. Methods of reducing or decreasing the probability, severity, frequency, duration or preventing a subject from having an acute or chronic food allergy, allergic reaction, hypersensitivity, an inflammatory response or inflammation, are also provided. In one method, histamine releasing factor (HRF)/translationally controlled tumor protein (TCTP) is contacted with a compound that inhibits or reduces binding of HRF/TCTP to an immunoglobulin in order to reduce or decrease the probability, severity, frequency, duration or prevent a subject from having an acute or chronic food allergy, allergic reaction, hypersensitivity, an inflammatory response or inflammation.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of priority of application Ser. No. 61 / 319,652 filed Mar. 31, 2010, and application Ser. No. 61 / 326,079, filed Apr. 20, 2010, both of which applications are expressly incorporated herein by reference in their entirety.GOVERNMENT SUPPORT[0002]This work was supported in part by Grant AI050209 from the National Institutes of Health. The government has certain rights in the invention.INTRODUCTION[0003]Histamine-releasing factor (HRF, also known as translationally controlled tumor protein (TCTP), p21, p23, Q23, and fortilin), is a highly conserved, multi-functional protein with both intracellular and extracellular functions.[0004]HRF exhibits amino acid sequence identities of over 40% between distantly related species (Bommer et al., Int. J. Biochem. Cell Biol. 36:379 (2004); Hinojosa-Moya et al., J. Mol. Evol. 66:472 (2008)). Fifteen of approximately 170 residues are completely or nearly completely conserved in TCTP proteins ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C07K16/18
CPCA61K38/1709C07K14/52C07K2319/00G01N2500/02G01N2800/24C07K2317/76C07K16/18A61K2039/505C07K7/08C07K14/47C07K2317/24A61K39/3955
Inventor KAWAKAMI, TOSHIAKIKAWAKAMI, YUKO
Owner LA JOLLA INST FOR ALLERGY & IMMUNOLOGY
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