title: Anti-interleukin-10R1 monoclonal antibody enhances bacillus Calmette-Guérin induced T-helper type 1 immune responses and antitumor immunity in a mouse orthotopic model of bladder cancer.
abstract: OBJECTIVE
  Proper induction of the T-helper type 1 immune response is required for effective bacillus Calmette-Guérin immunotherapy for bladder cancer. Interleukin-10 down-regulates the T-helper 1 response and is associated with bacillus Calmette-Guérin failure. We investigated whether blocking interleukin-10 receptor 1 would enhance the bacillus Calmette-Guérin induced T-helper type 1 immune response and anti-bladder cancer immunity in a mouse model.
  
  
  METHODS
  Splenocytes were incubated with bacillus Calmette-Guérin or bacillus Calmette-Guérin plus control IgG1, anti-interleukin-10 receptor 1 mAb or anti-interleukin-10 neutralizing mAb, followed by enzyme-linked immunosorbent assay of interferon-γ production. Bladder RNA was extracted after intravesical bacillus Calmette-Guérin plus intraperitoneal IgG1 or anti-interleukin-10 receptor 1 mAb and analyzed by reverse transcriptase and/or quantitative polymerase chain reaction. Urine was collected and analyzed by enzyme-linked immunosorbent assay. Mice bearing a luciferase expressing MB49 orthotopic tumor were treated with intravesical bacillus Calmette-Guérin plus intraperitoneal IgG1 or anti-interleukin-10 receptor 1 mAb. Tumor response was assessed by bioluminescent imaging and bladder weight measurement.
  
  
  RESULTS
  Bacillus Calmette-Guérin plus anti-interleukin-10R1 mAb induced significantly higher interferon-γ production by splenocytes than bacillus Calmette-Guérin plus anti-interleukin-10 mAb. Bacillus Calmette-Guérin plus anti-interleukin-10 receptor 1 mAb also induced significantly higher interferon-γ mRNA and protein in bladder and urine, respectively, in a dose dependent manner. Treatment with phosphate buffered saline, bacillus Calmette-Guérin plus control IgG1 and bacillus Calmette-Guérin plus anti-interleukin-10 receptor 1 mAb showed a 0% tumor-free rate with a 20% death rate, a 20% tumor-free rate with a 20% death rate and a 40% tumor-free rate with a 0% death rate, respectively. Bladder weight also revealed the effect of anti-interleukin-10 receptor 1 mAb on the bacillus Calmette-Guérin induced bladder tumor response.
  
  
  CONCLUSIONS
  Anti-interleukin-10 receptor 1 mAb enhanced the bacillus Calmette-Guérin induced T-helper type 1 immune response and anti-bladder cancer immunity. A humanized form of this mAb warrants future investigation for bacillus Calmette-Guérin treatment of bladder cancer.
authors.affiliation: Department of Urology, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Bockholt
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Knudson
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Henning
authors.forename: José L
authors.initials: JL
authors.lastname: Maymí
authors.forename: Peter
authors.initials: P
authors.lastname: Weady
authors.forename: George J
authors.initials: GJ
authors.lastname: Smith
authors.forename: Michael D
authors.initials: MD
authors.lastname: Eisenbraun
authors.forename: James D
authors.initials: JD
authors.lastname: Fraser
authors.forename: Michael A
authors.initials: MA
authors.lastname: O'Donnell
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D002295:Carcinoma, Transitional Cell / Q000276:immunology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D007167:Immunotherapy; D053709:Interleukin-10 Receptor alpha Subunit / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D001749:Urinary Bladder Neoplasms / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D053709:Interleukin-10 Receptor alpha Subunit