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


RESULTS
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.
Rosada
Rogério S
RS
Núcleo de Pesquisa em Tuberculose, Departamento de Bioquímica e Imunologia, Universidade de São Paulo, São Paulo, Brazil.
Moreira
Ana P
AP
Frantz
Fabiani G
FG
Puri
Raj K
RK
Rahman
Aquilur
A
Standiford
Theodore J
TJ
Zárate-Bladés
Carlos R
CR
Silva
Célio L
CL
Hogaboam
Cory M
CM
D036002:ADP Ribose Transferases / Q000276:immunology / Q000494:pharmacology*; D000818:Animals; D001427:Bacterial Toxins / Q000276:immunology / Q000494:pharmacology*; D001761:Bleomycin / Q000633:toxicity; D005098:Exotoxins / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use*; D000922:Immunotoxins / Q000627:therapeutic use*; D018793:Interleukin-13 / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors / Q000276:immunology / Q000494:pharmacology*; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D001761:Bleomycin; D005098:Exotoxins; D000922:Immunotoxins; D018793:Interleukin-13; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C521502:IL13-PE38