Induction of TNF-alpha autoantibody production by AutoVac TNF106: a novel therapeutic approach for the treatment of allergic diseases.
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.
Zuany-Amorim
Claudia
C
Novartis Horsham Research Centre, Novartis Pharmaceutical Ltd, Horsham, UK.
Manlius
Corinne
C
Dalum
Iben
I
Jensen
Martin R
MR
Gautam
Anand
A
Pay
Graham
G
Mouritsen
Søren
S
Walker
Christoph
C
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
D001323:Autoantibodies; D016085:Bronchoconstrictor Agents; D016207:Cytokines; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride; D007073:Immunoglobulin E; D010047:Ovalbumin