title: 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.
  
  
  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.
authors.affiliation: Núcleo de Pesquisa em Tuberculose, Departamento de Bioquímica e Imunologia, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Rogério S
authors.initials: RS
authors.lastname: Rosada
authors.forename: Ana P
authors.initials: AP
authors.lastname: Moreira
authors.forename: Fabiani G
authors.initials: FG
authors.lastname: Frantz
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
authors.forename: Aquilur
authors.initials: A
authors.lastname: Rahman
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Zárate-Bladés
authors.forename: Célio L
authors.initials: CL
authors.lastname: Silva
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
mesh_terms: 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
chemical_list: 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