title: Induction of TNF-alpha autoantibody production by AutoVac TNF106: a novel therapeutic approach for the treatment of allergic diseases.
abstract: BACKGROUND
  Cytokines play an integral role in the coordination and persistence of allergic inflammatory processes and therefore represent prime targets for novel therapies in diseases such as asthma. Multiple attempts to generate low-molecular-weight cytokine inhibitors have failed, and the main attention has focused on the development of biological agents such as neutralizing antibodies. The present work describes a simple and effective method to induce the production of therapeutic anti-cytokine autoantibodies by active immunization against a modified endogenous cytokine.
  
  
  METHODS
  Balb/c mice were subcutaneously injected with AutoVac TNF106, a recombinant murine TNF-alpha molecule containing a foreign immunogenic T helper epitope, and the induction of neutralizing anti-TNF-alpha autoantibodies was analysed. These mice were then sensitized with ovalbumin (OVA), and the effect of neutralizing anti-TNF-alpha autoantibodies on the allergen-induced airway inflammation was analysed.
  
  
  RESULTS
  AutoVac TNF106-immunized mice developed high titres of neutralizing anti-TNF-alpha autoantibodies, which were maintained for at least 4 weeks after the last booster injection. Mice vaccinated with AutoVac TNF106 and further immunized against OVA showed diminished TNF-alpha levels in the bronchoalveolar lavage (BAL) fluid after OVA challenge. Moreover, pretreatment with AutoVac TNF106 resulted in significantly reduced numbers of eosinophils and neutrophils in BAL fluid in response to single or multiple allergen exposure.
  
  
  CONCLUSIONS
  The induction of anti-TNF-alpha autoantibody production by the AutoVac TNF106 technology not only confirmed the role of TNF-alpha in the induction of allergic inflammation but also offers a novel approach to block the activity of cytokines in order to treat allergic inflammatory conditions.
authors.affiliation: Novartis Horsham Research Centre, Novartis Pharmaceutical Ltd, Horsham, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Zuany-Amorim
authors.forename: Corinne
authors.initials: C
authors.lastname: Manlius
authors.forename: Iben
authors.initials: I
authors.lastname: Dalum
authors.forename: Martin R
authors.initials: MR
authors.lastname: Jensen
authors.forename: Anand
authors.initials: A
authors.lastname: Gautam
authors.forename: Graham
authors.initials: G
authors.lastname: Pay
authors.forename: Søren
authors.initials: S
authors.lastname: Mouritsen
authors.forename: Christoph
authors.initials: C
authors.lastname: Walker
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000628:therapy*; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D002452:Cell Count; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007114:Immunization; D007073:Immunoglobulin E / Q000276:immunology / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods*; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D011657:Pulmonary Eosinophilia / Q000276:immunology / Q000628:therapy; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000494:pharmacology
chemical_list: D001323:Autoantibodies; D016085:Bronchoconstrictor Agents; D016207:Cytokines; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride; D007073:Immunoglobulin E; D010047:Ovalbumin