Immunomodulatory Peptides Derived from Heat Shock Proteins and Uses Thereof

a technology of immunomodulatory peptides and proteins, which is applied in the field of immunomodulatory peptides derived from heat shock proteins, can solve the problems of severe and in some cases generalized tissue damage, adverse effects, and decrease in patient's quality of life, and achieve the effects of reducing or inhibiting the inflammatory response, and modulating the immune response in the subj

Inactive Publication Date: 2008-08-07
ALBANI SALVATORE +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0041]The invention provides a method of modulating an immune response in a subject. As disclosed herein, an effective therapeutic strategy for ameliorating the inflammation-related symptoms of an immune-mediated disease, such as arthritis, can be achieved by modulating the underlying immune response, rather than by merely addressing the resulting inflammation. This strategy can be used to regulate the inflammatory response and is applicable to a variety of contexts in which immune modulation is desired, such as mucosal tolerization, DNA vaccination, anergy induction, active immunization, and ex vivo modulation of antigen-specific T cells.

Problems solved by technology

In particular, patients with an auto-immune diseases such as rheumatoid arthritis, systemic lupus erythematosis, and the like, often suffer from severe and in some cases generalized tissue damage.
Although administration of a steroidal drug, for example, can decrease the severity of the immune response is such patients, the long term use of such drugs can produce adverse effects, including decreasing the patient's quality of life.
Furthermore, the use of such drugs generally reduces the ability of an individual to mount an immune response, thus leaving the individual susceptible to short term infections that can produce severe consequences.

Method used

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  • Immunomodulatory Peptides Derived from Heat Shock Proteins and Uses Thereof
  • Immunomodulatory Peptides Derived from Heat Shock Proteins and Uses Thereof
  • Immunomodulatory Peptides Derived from Heat Shock Proteins and Uses Thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Cellular Immune Response to Recombinant E. coli dnaJ

[0099]Proliferative responses to recombinant E. coli hsp dnaJ (dnaJ) of peripheral blood mononuclear cells (PBMC) from 10 healthy subjects (“control”) and 21 patients with oligoarticular juvenile idiopathic arthritis (“oJIA”) were not significantly different (FIG. 1A). To evaluate whether dnaJ-specific T cells were enriched at the synovial sites of inflammation, synovial fluid mononuclear cells (SFMC) from all patients with oJIA were stimulated with dnaJ for 96 hr. The mean stimulation index (SI) of SFMC was significantly higher than the SI of the corresponding PBMC (p=0.01; FIG. 1A). In addition, following stimulation with dnaJ, the percentage of activated T cells, evaluated as CD3+ CD69+ cells, was significantly higher (p=0.0002) in SFMC with respect to PBMC (FIG. 1B).

[0100]To confirm that the increased response of SFMC to dnaJ was not secondary to a non-specific increase in SFMC reactivity, the proliferative responses of cells f...

example 2

Cellular Immune Response to Synthetic Peptides Derived from Recombinant E. coli dnaJ

[0104]In order to identify possible relevant epitopes on the bacterial dnaJ protein, PBMC and SFMC of patients with oJIA were incubated for 72 hr with dnaJ, and restimulated with autologous feeder cells the in presence or absence of selected E. coli derived MHC class II binder peptides for 96 hr. A total of 8 peptides were tested, including three peptides (pep4, pep22, pep 174) that are derived from the N-terminal region of E. coli dnaJ and present sequence homologies to each of the three human dnaJ isoforms (HDJ1, HDJ2, HSJ1; homologous peptides), and five peptides that are derived from the C-terminal region of E. coli dnaJ and do not present any homology with the human counterparts (pep61, pep209, pep242, pep264, pep 268; non-homologous peptides.

[0105]The stimulation of PBMC with E. coli derived peptides resulted in very low proliferative responses (SI6 in the presence of peptide 22, 61, 174, or 26...

example 3

Cellular Immune Responses to Human HSJ1, HDJ1, or HDJ2 Peptides Homologous or not Homologous to E. coli hsp dnaJ

[0108]In order to evaluate whether human homologous peptides could be the target of cross-recognition leading to self reactivity, human peptides derived from regions of HSJ1, HDJ1, or HDJ2 having sequence homology with E. Coli dnaJ were studied. SFMC of 14 patients with oJIA presenting a SI to the recombinant E. coli hsp dnaJ greater than 3 were restimulated for 96 hr with autologous cells in presence or absence of human peptide 2, 3, or 5, which are homologs of bacterial peptide 4; human peptide 20, 21, or 23, which are homologs of bacterial peptide 22; or human peptide 164, 167, or 176, which are homologs of bacterial peptide 174. SFMC proliferative responses, pro-inflammatory cytokine production, and anti-inflammatory IL-4 levels were overall similar between the peptides derived from human dnaJ proteins and the homologous bacterial peptides.

[0109]Table 3 shows the proli...

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Abstract

A method of modulating an immune response in a subject is disclosed. The invention is based on the discovery that an effective therapeutic strategy for ameliorating the inflammation-related symptoms of an immune-mediated disease, such as arthritis, can be achieved by modulation of the underlying immune response itself, rather than by merely addressing the resulting inflammation. This strategy can be used to regulate the inflammatory response and is applicable to a variety of contexts in which immune modulation is desired, such as mucosal tolerization, DNA vaccination, anergy induction, active immunization, and ex vivo modulation of antigen-specific T cells. In one embodiment, the method comprises administering to the subject a bacterial dnaJ peptide or a human homolog or a non-homologous human isoform thereof.

Description

CROSS REFERENCE TO RELATED APPLICATION(S)[0001]This application is a divisional application of U.S. application Ser. No. 10 / 001,938 filed Oct. 31, 2001, now pending; which claims the benefit under 35 USC § 119(e) to U.S. Application Ser. No. 60 / 245,181 filed Nov. 1, 2000, now abandoned. The disclosure of each of the prior applications is considered part of and is incorporated by reference in the disclosure of this application.GRANT INFORMATION[0002]This invention was made with Government support under Grant No. AR44850, awarded by the National Institutes of Health. The government has certain rights in this invention.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]The present invention relates generally to methods and compositions for modulating an immune response in a subject, and more specifically to compositions containing a bacterial dnaJ peptide or a human homolog or a non-homologous human isoform thereof, and to methods of using such compositions to stimulate an...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/00A61K38/00C12N15/09A61K39/02A61K39/108A61K39/39A61K45/00A61P1/04A61P19/02A61P29/00A61P31/00A61P35/00A61P37/00A61P37/02A61P43/00C07K14/195C07K14/245C07K14/39C07K14/46C07K14/47C12N1/15C12N1/19C12N1/21C12N5/10
CPCA61K38/00C07K14/4702C07K14/195A61P1/04A61P19/02A61P29/00A61P31/00A61P35/00A61P37/00A61P37/02A61P43/00
Inventor ALBANI, SALVATORECARSON, DENNIS A.PRAKKEN, BERENT J.MARTINI
Owner ALBANI SALVATORE
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