title: Distinct phases of blood gene expression pattern through tuberculosis treatment reflect modulation of the humoral immune response.
abstract: BACKGROUND
  Accurate assessment of treatment efficacy would facilitate clinical trials of new antituberculosis drugs. We hypothesized that early alterations in peripheral immunity could be measured by gene expression profiling in tuberculosis patients undergoing successful conventional combination treatment.
  
  
  METHODS
  Ex vivo blood samples from 27 pulmonary tuberculosis patients were assayed at diagnosis and during treatment. RNA was processed and hybridized to Affymetrix GeneChips, to determine expression of over 47,000 transcripts.
  
  
  RESULTS
  There were significant ≥ 2-fold changes in expression of >4000 genes during treatment. Rapid, large-scale changes were detected, with down-regulated expression of 1261 genes within the first week, including inflammatory markers such as complement components C1q and C2. This was followed by slower changes in expression of different networks of genes, including a later increase in expression of B-cell markers, transcription factors, and signaling molecules.
  
  
  CONCLUSIONS
  The fast initial down-regulation of expression of inflammatory mediators coincided with rapid killing of actively dividing bacilli, whereas slower delayed changes occurred as drugs acted on dormant bacilli and coincided with lung pathology resolution. Measurement of biosignatures during clinical trials of new drugs could be useful predictors of rapid bactericidal or sterilizing drug activity, and would expedite the licensing of new treatment regimens.
authors.affiliation: Immunology and Infection Department, London School of Hygiene and Tropical Medicine, London, United Kingdom. jackie.cliff@lshtm.ac.uk
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Cliff
authors.forename: Ji-Sook
authors.initials: JS
authors.lastname: Lee
authors.forename: Nicholas
authors.initials: N
authors.lastname: Constantinou
authors.forename: Jang-Eun
authors.initials: JE
authors.lastname: Cho
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.forename: Katharina
authors.initials: K
authors.lastname: Ronacher
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: King
authors.forename: Pauline T
authors.initials: PT
authors.lastname: Lukey
authors.forename: Ken
authors.initials: K
authors.lastname: Duncan
authors.forename: Paul D
authors.initials: PD
authors.lastname: Van Helden
authors.forename: Gerhard
authors.initials: G
authors.lastname: Walzl
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Dockrell
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects; D015331:Cohort Studies; D015922:Complement C1q / Q000187:drug effects; D003175:Complement C2 / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004359:Drug Therapy, Combination; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects*; D007538:Isoniazid / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D011446:Prospective Studies; D012293:Rifampin / Q000627:therapeutic use; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D003175:Complement C2; D015922:Complement C1q; D007538:Isoniazid; D012293:Rifampin