Therapeutic efficacy of Cintredekin Besudotox (IL13-PE38QQR) in murine lung fibrosis is unaffected by immunity to Pseudomonas aeruginosa exotoxin A.

Abstract

BACKGROUND:

We have previously explored a therapeutic strategy for specifically targeting the profibrotic activity of IL-13 during experimental pulmonary fibrosis using a fusion protein comprised of human IL-13 and a mutated form of Pseudomonas aeruginosa exotoxin A (IL13-PE) and observed that the intranasal delivery of IL13-PE reduced bleomycin-induced pulmonary fibrosis through its elimination of IL-13-responsive cells in the lung. The aim of the present study was to determine whether the presence of an immune response to P. aeruginosa and/or its exotoxin A (PE) would diminish the anti-fibrotic properties of IL13-PE.

METHODOLOGY/PRINCIPAL FINDINGS:

Fourteen days after P. aeruginosa infection, C57BL/6 mice were injected with bleomycin via the intratracheal route. Other groups of mice received 4 doses of saline or IL13-PE by either intranasal or intraperitoneal application, and were challenged i.t. with bleomycin 28 days later. At day 21 after bleomycin, all mice received either saline vehicle or IL13-PE by the intranasal route and histopatological analyses of whole lung samples were performed at day 28 after bleomycin. Intrapulmonary P. aeruginosa infection promoted a neutralizing IgG2A and IgA antibody response in BALF and serum. Surprisingly, histological analysis showed that a prior P. aeruginosa infection attenuated the development of bleomycin-induced pulmonary fibrosis, which was modestly further attenuated by the intranasal administration of IL13-PE. Although prior intranasal administration of IL13-PE failed to elicit an antibody response, the systemic administration of IL13-PE induced a strong neutralizing antibody response. However, the prior systemic sensitization of mice with IL13-PE did not inhibit the anti-fibrotic effect of IL13-PE in fibrotic mice.

CONCLUSIONS:

Thus, IL13-PE therapy in pulmonary fibrosis works regardless of the presence of a humoral immune response to Pseudomonas exotoxin A. Interestingly, a prior infection with P. aeruginosa markedly attenuated the pulmonary fibrotic response suggesting that the immune elicitation by this pathogen exerts anti-fibrotic effects.

• Authors: Rogério S Rosada, Ana P Moreira, Fabiani G Frantz, Raj K Puri, Aquilur Rahman, Theodore J Standiford, Carlos R Zárate-Bladés, Célio L Silva, Cory M Hogaboam
• Journal: PloS one (PLoS One) Vol. 5 Issue 1 Pg. e8721 (Jan 15 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 20090941 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Toxins
• Exotoxins
• IL13-PE38
• Immunotoxins
• Interleukin-13
• Recombinant Fusion Proteins
• Virulence Factors
• Bleomycin
• ADP Ribose Transferases
• Pseudomonas aeruginosa exotoxin A

Topics

• ADP Ribose Transferases (immunology, pharmacology)
• Animals
• Bacterial Toxins (immunology, pharmacology)
• Bleomycin (toxicity)
• Exotoxins (immunology, pharmacology, therapeutic use)
• Immunotoxins (therapeutic use)
• Interleukin-13 (therapeutic use)
• Mice
• Mice, Inbred C57BL
• Pulmonary Fibrosis (chemically induced, drug therapy)
• Recombinant Fusion Proteins
• Virulence Factors (immunology, pharmacology)