Treatment of immune disease by mucosal delivery of antigents using genetically modified lactobacillus

a technology of lactobacillus and immune disease, which is applied in the field of immune disease treatment by mucosal delivery of antigents using genetically modified lactobacillus, can solve the problems of no adequate treatment, no side effects, and huge cost, and achieves the activation of antigen-specific regulatory t cells, increased oral tolerance, and high efficiency

Inactive Publication Date: 2010-04-29
ACTOGENIX
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]We demonstrate that the invention can induce oral tolerance with much more higher efficiency than with monotherapy with antigen or control L. lactis alone. In vivo activation of antigen-specific regulatory T cells was strongly enhanced. Specifically, mucosal delivery of a gliadin derived peptide, which is immunodominant for DQ8 mediated T-cell responses by genetically modified L. lactis, induces suppression of local and systemic DQ8 restricted T-cell responses. Treatment resulted in an antigen-specific decrease of the proliferative capacity of the splenocytes and inguinal lymph node cells, which was critically dependent on the production of IL-10 and TGF-β and associated with a significant induction of Foxp3+ regulatory T-cells. Because this approach of antigen-delivering bacteria has the capacity for potentiating oral tolerance even in the setting of established hypersensitivity, it is applicable for the treatment of celiac disease and other autoimmune and / or allergic diseases. The efficacy of the invention was demonstrated in autoimmune and allergic disease mouse models, as well as in the context of immune inactivation of therapeutics.

Problems solved by technology

Autoimmune, allergic and inflammatory diseases place a tremendous burden on the patient and society, resulting in decreased quality of life and huge costs.
Moreover, no adequate treatment exists without acceptable side effects or which is socially appropriate.
Nevertheless, these immunotherapies may be associated with increased risk of adverse effects, such as increased susceptibility to infection.
However, gastrointestinal degradation and low levels of absorption generally render this route of peptide and protein drug delivery ineffective.
Thus, there remains a problem in the art to effectively induce tolerance of antigens.

Method used

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  • Treatment of immune disease by mucosal delivery of antigents using genetically modified lactobacillus
  • Treatment of immune disease by mucosal delivery of antigents using genetically modified lactobacillus
  • Treatment of immune disease by mucosal delivery of antigents using genetically modified lactobacillus

Examples

Experimental program
Comparison scheme
Effect test

example a

Induction of OVA-Specific Tolerance by Genetically Modified Lactococcus lactis Delivering OVA to OVA-Sensitized Wild Type Mice

Introduction

[0099]For this purpose we genetically engineered OVA secreting LL (LL-OVA) and evaluated the induction of systemic tolerance in a therapeutic model for autoimmunity / allergy, namely the OVA immunization model.

Materials and Methods

[0100]Bacteria and media: The Lactococcus lactis MG1363 (LL) strain was genetically modified and used throughout this study. Bacteria were cultured in GM17E medium consisting of M17broth (Difco Laboratories, Detroit, Mich.) supplemented with 0.5% glucose and 5 μg / ml erythromycin (Abbott). Stock suspensions of LL strains were stored at −20° C. in 50% glycerol in GM17E medium. Stock suspensions were diluted 500-fold in GM17E medium and incubated at 30° C. overnight. Within 16 h they reached a saturation density of 2×109 colony forming units (CFU) per ml. Bacteria were harvested by centrifugation and resuspended in BM9 medium...

example b

Induction of Antigen-Specific Oral Tolerance by Genetically Modified Lactococcus lactis Delivering DQ8-Specific Immunodominant Gliadin Epitopes to Gluten-Sensitized Class II Transgenic Mice

Introduction

[0115]Celiac disease, also known as celiac sprue or gluten-sensitive enteropathy, is a chronic inflammatory disease that develops from an immune response to specific dietary grains that contain gluten. Celiac is a complex multigenic disorder that is strongly associated with the genes that encode the human leukocyte antigen variants HLA-DQ2 or HLA-DQ8. One of the most important aspects in the pathogenesis of Celiac is the activation of a T-helper 1 immune response. This arises when antigen-presenting cells that express HLA-DQ2 / DQ8 molecules present the toxic gluten peptides to CD4(+) T-cells. Both classes of gluten proteins, gliadins and glutenins, contain peptides that bind DQ2 and DQ8. It is generally accepted that the immune response, such as the production of IFN-γ from gluten-speci...

example c

Induction of Tolerance to Clotting Factor VIII and Factor IX Following Oral Administration of L. lactis Secreting Said Factors

Introduction

[0138]Several therapeutic (recombinant) proteins, such as interferon's, factor VIII / IX and antibodies (Remicade) are administered at high doses over prolonged treatment periods. However, a complication associated with their use is the development of protein-specific immune responses, such as antibodies. These antibodies (Abs), also called inhibitors, render the therapeutic proteins less effective. Examples include the formation of inhibitors for factor VIII / IX in hemophilia, erythropoietin (Epo) in patients undergoing therapy for chronic renal failure, and IFN- in patients undergoing treatment for multiple sclerosis. Here, we demonstrate that oral delivery of the Factor VIII (and Factor IX) by L. lactis suppresses inhibitor formation to said factor via the induction of antigen-specific CD4+ regulatory T cells.

Material and Methods

[0139]Bacteria and...

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Abstract

The present invention relates to the treatment of autoimmune and allergic diseases by mucosal delivery by micro-organism, in particular Lactococcus lactis, of secreted immunodominant antigens.

Description

[0001]The present invention relates to the treatment of autoimmune and allergic diseases by mucosal delivery by micro-organisms, in particular Lactococcus lactis, of secreted immunodominant antigens.FIELD OF THE INVENTION[0002]The immune system has the task of distinguishing between self and non-self. The mucosal immune system, present along the respiratory, gastrointestinal and genitourinary tracts, has the additional burden of coexisting with an abundance of bacteria and innocuous antigens, such as food, airborne antigens or the commensally bacterial flora. A key feature of the mucosal immune system is its ability to remain tolerant to these antigens while retaining the capacity to repel pathogens effectively. Introduction of antigen systemically, whether by injection or injury, leads to local infiltration of inflammatory cells and specific immunoglobulin production. By contrast, antigens introduced at mucosal surfaces, such as the gastrointestinal and genitourinary tracts, elicit...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/02C12N1/20C12N1/16A61K39/00A61P35/00A61P37/06
CPCA61K39/0008A61K39/001A61K39/35A61K39/36A61K49/00A61K2039/542A61K2039/55566C12R1/225A61K39/00A61K2039/523A61P11/06A61P19/02A61P21/04A61P25/00A61P27/02A61P29/00A61P3/10A61P35/00A61P37/02A61P37/04A61P37/06A61P37/08A61P5/14C12R2001/225C12N1/205
Inventor ROTTIERS, PIETER
Owner ACTOGENIX
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