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Immunization-free methods for treating antigen-stimulated inflammation in a mammalian host and shifting the host's antigen immune responsiveness to a th1 phenotype

a technology of immune responsiveness and immunity, applied in the direction of antibody medical ingredients, drug compositions, immunological disorders, etc., can solve the problems of ineffective long-term cellular immunity and inflammation damage of host tissues, and canonical immunization does not effectively stimulate long-term cellular immunity

Inactive Publication Date: 2009-05-21
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

ISS-ODN effectively reduce granulocyte infiltration and antigen-specific IgE production, enhancing immune defenses against intracellular pathogens and reducing inflammation, while avoiding anaphylaxis and the need to identify sensitizing antigens.

Problems solved by technology

In susceptible individuals, the resulting inflammation can damage affected host tissues.
However, although effective in stimulating production of neutralizing antibodies, canonical immunization does not effectively stimulate longer term cellular immunity.

Method used

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  • Immunization-free methods for treating antigen-stimulated inflammation in a mammalian host and shifting the host's antigen immune responsiveness to a th1 phenotype
  • Immunization-free methods for treating antigen-stimulated inflammation in a mammalian host and shifting the host's antigen immune responsiveness to a th1 phenotype
  • Immunization-free methods for treating antigen-stimulated inflammation in a mammalian host and shifting the host's antigen immune responsiveness to a th1 phenotype

Examples

Experimental program
Comparison scheme
Effect test

example i

Murine Model for the Airway Hyperreactivity of Allergic Asthma

[0103]Sensitizing-antigen challenged mice of different strains model the airway hyperreactivity seen in allergic asthma. Suitable murine strains for use in modeling the disease include Balb / c mice (which are biased genetically toward the Th2 phenotype and produce enhanced concentrations of IL-4 and IL-5 in response to antigen challenge to CD4+ lymphocytes), C57BL / 6 mice (which are IL-5 deficient, for detailed study of IL-5 induced tissue damage in asthma) and W / Wv mice (which are mast cell deficient, for detailed study of mast cell activation in asthma).

[0104]Disease modeling mice are conveniently prepared by intraperitoneal or subcutaneous injection of a model sensitizing antigen, ovalbumin (“OVA”) in carrier (e.g., sterile saline or a carrier with adjuvant, such as alum), followed by antigen challenge with aerosolized antigen. For example, mice may be immunized with 25 μg OVA by subcutaneous injection (with or without a...

example ii

Reduction of Eosinophil Accumulation in Lung Tissue in a Murine Asthma Model by Administration of ISS-ODN

[0106]BALB / c mice, 6-10 weeks of age, were prepared as models of allergic asthma as described in Example I (subcutaneous injection of OVA followed by antigen challenge at a concentration of 50 mg OVA / ml PBS). Prior to each inhalation with OVA according to this scheme, sets of 8 mice each were treated as described in the Table below. Control mice were antigen challenged but untreated and naive mice were not challenged with antigen. All ISS doses were 100 μg per administration. Dexamethasone (a conventional steroidal anti-inflammatory used in the treatment of asthma) doses were 5 mg / kg / mouse. Priming doses of antigen were 25 μg OVA adsorbed to alum in 0.2 ml phosphate buffered saline (PBS). Challenge doses of antigen were 10 ml of 50 mg OVA / ml PBS. 1N=intranasal; IP=intraperitoneal; SC=subcutaneous and N / A=not applicable.

Set #Material ReceivedRoute and Timing1Naive mice (no antigen...

example iii

Antigen Dependent Reduction of Eosinophil Accumulation in Lung Tissue

[0114]To evaluate whether the eosinophil suppression demonstrated by the data in Example II is dependent upon immune stimulation by the ISS-ODN, mice were sensitized to OVA using a conventional, Th2 stimulatory adjuvant (alum), treated with ISS-ODN or a control, and measured for eosinophil suppression before ISS-ODN stimulation of the mouse immune system would be expected to occur.

[0115]More specifically, groups of four mice were immunized with 25 μg OVA in 1 mg alum by subcutaneous injection on days 1, 7, 14 and 21. This immunization protocol is known to stimulate a Th2 type response to the antigen in mice. On day 27, one group of animals received 100 μg of the DY1018 ISS-ODN described in Example I by intraperitoneal administration. A control group received the mutant DY1019 M-ISS-ODN described in Example I by the same route.

[0116]On day 28, the animals in each group received 10 mg OVA / ml phosphate buffered saline...

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PUM

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Abstract

The invention relates to methods for preventing or reducing antigen-stimulated, granulocytemediated inflammation in tissue of an antigen-sensitized mammal host by delivering an immunostimulatory oligonucleotide to the host. In addition, methods for using the immunostimulatory oligonucleotides to boost a mammal host's immune responsiveness to a sensitizing antigen (without immunization of the host by the antigen) and shifting the host's immune responsiveness to a Th1 phenotype to achieve various therapeutic ends are provided. Kits for practicing the methods of the invention are also provided.

Description

STATEMENT OF GOVERNMENT RIGHTS[0001]This invention was made with Government support under Grant No. AI37350, awarded by the National Institutes of Health. The Government may have certain rights in this invention.FIELD OF THE INVENTION[0002]The invention relates to methods and oligonucleotide compositions for use in reducing, or suppressing granulocyte-mediated inflammation in a host tissue and in modulating the host's immune responsiveness to an antigen.HISTORY OF THE RELATED ART[0003]In vertebrates, endothelial cell adhesion by granulocytes (eosinophils, basophils, neutrophils and mast cells) is followed by the release of inflammatory mediators, such as leukotrienes, major basic protein and histamine. In susceptible individuals, the resulting inflammation can damage affected host tissues.[0004]The most common pathologic inflammatory condition is asthma, which is characterized by marked eosinophil infiltration into respiratory airways, followed by inflammation-induced tissue damage....

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/711A61P37/02A61K47/28A61K39/35A61K47/36A61K47/42A61K47/44A61K47/48A61P11/06A61P21/00A61P27/02A61P27/16A61P29/00A61P37/08
CPCA61K39/35A61K2039/55561A61K2039/543A61K2039/53A61P11/06A61P21/00A61P27/02A61P27/16A61P29/00A61P37/02A61P37/08
Inventor RAZ, EYAL
Owner RGT UNIV OF CALIFORNIA
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