title: Synergy of chemotherapy and immunotherapy revealed by a genome-scale analysis of murine tuberculosis.
abstract: OBJECTIVE
  Although TB immunotherapy improves the results of conventional drug treatment, the effects of combining chemotherapy and immunotherapy have never been systematically evaluated. We used a comprehensive lung transcriptome analysis to directly compare the activity of combined chemotherapy and immunotherapy with that of single treatments in a mouse model of TB.
  
  
  METHODS
  Mycobacterium tuberculosis-infected mice in the chronic phase of the disease (day 30) received: (i) isoniazid and rifampicin (drugs) daily for 30 days; (ii) DNA immunotherapy (DNA), consisting of four 100 μg injections at 10 day intervals; (iii) both therapies (DNA + drugs); or (iv) saline. The effects were evaluated 10 days after the end of treatment (day 70 post-infection).
  
  
  RESULTS
  In all groups a systemic reduction in the load of bacilli was observed, bacilli became undetectable in the drugs and DNA + drugs groups, but the whole lung transcriptome analysis showed 867 genes exclusively modulated by the DNA + drugs combination. Gene enrichment analysis indicated that DNA + drugs treatment provided synergistic effects, including the down-regulation of proinflammatory cytokines and mediators of fibrosis, as confirmed by real-time PCR, ELISA, histopathology and hydroxyproline assay.
  
  
  CONCLUSIONS
  Our results provide a molecular basis for the advantages of TB treatment using combined chemotherapy and DNA immunotherapy and demonstrate the synergistic effects obtained with this strategy.
authors: The Centre for Tuberculosis Research, Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Ribeirao Preto, 14049-900, Brazil.
authors: Rodrigo F
authors: RF
authors: Rodrigues
authors: The Centre for Tuberculosis Research, Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Ribeirao Preto, 14049-900, Brazil zarate.blades@gmail.com.
authors: Carlos R
authors: CR
authors: Zárate-Bladés
authors: The Centre for Tuberculosis Research, Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Ribeirao Preto, 14049-900, Brazil.
authors: Wendy M
authors: WM
authors: Rios
authors: The Centre for Tuberculosis Research, Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Ribeirao Preto, 14049-900, Brazil.
authors: Luana S
authors: LS
authors: Soares
authors: The Centre for Tuberculosis Research, Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Ribeirao Preto, 14049-900, Brazil.
authors: Patricia R M
authors: PR
authors: Souza
authors: The Centre for Tuberculosis Research, Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Ribeirao Preto, 14049-900, Brazil.
authors: Izaíra T
authors: IT
authors: Brandão
authors: The Centre for Tuberculosis Research, Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Ribeirao Preto, 14049-900, Brazil.
authors: Ana P
authors: AP
authors: Masson
authors: The Centre for Tuberculosis Research, Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Ribeirao Preto, 14049-900, Brazil.
authors: Frederico G C
authors: FG
authors: Arnoldi
authors: Department of Pathology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirao Preto, São Paulo, 14049-900, Brazil.
authors: Simone G
authors: SG
authors: Ramos
authors: Université Paris-Descartes, Institut Cochin and INSERM U1016, CNRS (CMRS 8104), Paris, 75014, France.
authors: Franck
authors: F
authors: Letourneur
authors: Université Paris-Descartes, Institut Cochin and INSERM U1016, CNRS (CMRS 8104), Paris, 75014, France.
authors: Sébastien
authors: S
authors: Jacques
authors: Université Paris-Descartes, Institut Cochin and INSERM U1016, CNRS (CMRS 8104), Paris, 75014, France Hôpital Necker, Paris, 75015, France.
authors: Nicolas
authors: N
authors: Cagnard
authors: Université Paris-Descartes, Institut Cochin and INSERM U1016, CNRS (CMRS 8104), Paris, 75014, France.
authors: Gilles
authors: G
authors: Chiocchia
authors: The Centre for Tuberculosis Research, Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Ribeirao Preto, 14049-900, Brazil.
authors: Celio L
authors: CL
authors: Silva
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage; D003131:Combined Modality Therapy / Q000379:methods*; D004195:Disease Models, Animal; D004358:Drug Therapy / Q000379:methods*; D020869:Gene Expression Profiling; D007167:Immunotherapy / Q000379:methods*; D007538:Isoniazid / Q000008:administration & dosage; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000276:immunology*; D012293:Rifampin / Q000008:administration & dosage; D016896:Treatment Outcome; D014376:Tuberculosis / Q000628:therapy*; D019444:Vaccines, DNA / Q000008:administration & dosage
chemical_list: D000995:Antitubercular Agents; D019444:Vaccines, DNA; D007538:Isoniazid; D012293:Rifampin
keywords: drug therapy; gene expression profiling; lung transcriptome; vaccine therapy