Role of CTA1R7K-COL-DD as a novel therapeutic mucosal tolerance-inducing vector for treatment of collagen-induced arthritis.

Abstract

OBJECTIVE:

To determine whether a cholera toxin-derived, novel immunomodulating fusion protein, CTA1R7K-COL-DD, carrying the class II major histocompatibility complex H-2q-restricted type II collagen peptide aa 259-274, can induce therapeutic tolerance and prevent collagen-induced arthritis (CIA) when administered intranasally in DBA/1 mice, and to assess whether ADP-ribosylation at the mucosal membranes exerts a regulatory function such that the outcome of tolerance or immune enhancement can be controlled.

METHODS:

DBA/1 mice with CIA were treated intranasally with CTA1R7K-COL-DD. The therapeutic effect was monitored for 46 days after the onset of disease. Clinical scoring of disease, histologic examination of inflammation, and bone erosion were assessed, and cytokine levels were determined in the serum or supernatants from splenocytes stimulated with recall antigen.

RESULTS:

The protective effect of CTA1R7K-COL-DD resulted in roughly 60% of the mice having no clinical signs or histologic evidence of disease after treatment, and those with CIA had significantly milder disease with less bone erosion. The protective status was associated with lower serum titers of IgG1, IgG2a, IgG2b, and IgG3 anticollagen and a substantial decrease in the production of interleukin-6 (IL-6), IL-17, and interferon-gamma, while levels of IL-10 were markedly up-regulated both in the serum and at the T cell level.

CONCLUSION:

The enzymatically inactive mutant fusion protein CTA1R7K-COL-DD provided substantial therapeutic protection against CIA following intranasal administration. The mechanism behind the effect appears to be mediated by peptide-specific regulatory T cells induced by mucosal exposure to the peptide containing CTA1R7K-COL-DD vector. In addition, ADP-ribosylation at the mucosal membranes acts as a key regulator controlling mucosal tolerance or immunity.

• Authors: Annemarie Hasselberg, Karin Schön, Andrej Tarkowski, Nils Lycke
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 60 Issue 6 Pg. 1672-82 (Jun 2009) ISSN: 0004-3591 [Print] United States
• PMID: 19479868 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CTA1-DD protein, recombinant
• CTA1R7K-COL-DD
• Immunoglobulin G
• Interleukin-17
• Interleukin-6
• Peptide Fragments
• Recombinant Fusion Proteins
• Interleukin-10
• Cholera Toxin
• ADP Ribose Transferases

Topics

• ADP Ribose Transferases (metabolism)
• Administration, Intranasal
• Animals
• Arthritis, Experimental (chemically induced, metabolism, prevention & control)
• CD4-Positive T-Lymphocytes (metabolism)
• Cholera Toxin (administration & dosage, genetics, therapeutic use)
• Disease Models, Animal
• Drug Tolerance (physiology)
• Immunoglobulin G (metabolism)
• Interleukin-10 (metabolism)
• Interleukin-17 (metabolism)
• Interleukin-6 (metabolism)
• Male
• Mice
• Mice, Inbred DBA
• Mucous Membrane (metabolism)
• Peptide Fragments (genetics, physiology, therapeutic use)
• Plasmids
• Recombinant Fusion Proteins (administration & dosage, genetics, therapeutic use)