Effect Of Neutralizing IL-17A and IL-17F Antibodies On Host Resistance To Acute Mycobacterium Tuberculosis Infection In Mice In Comparison With Neutralizing TNF-α Treatment

Michael Kammüller¹, Franco Di Padova², Christian Antoni³, Salah-Dine Chibout⁴, Timothy Wright⁵, Marie-Laure Bourigault⁶, Noria Segueni⁶, Stephanie Rose⁶, Bernhard Ryffel⁶ and Valerie Quesniaux⁶, ¹PCS - Discovery and Investigative Safety, Novartis Institutes for Biomedical Research, Basel, Switzerland, ²Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland, ³Novartis Pharmaceuticals Corporation, East Hanover, NJ, ⁴Novartis Institutes for Biomedical Research, Basel, Switzerland, ⁵Novartis Pharma AG, Basel, Switzerland, ⁶UMR7355 CNRS and University of Orleans, Orleans, France

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: interleukins (IL), mouse model and tuberculosis

Session Information

Title: Cytokines, Mediators, Cell-cell Adhesion, Cell Trafficking and Angiogenesis I

Session Type: Abstract Submissions (ACR)

Background/Purpose: Antibodies targeting IL-17A or IL-17RA are in clinical trials for the treatment of several autoimmune diseases. However, these therapies, by blocking critical mediators of innate and adaptive immunity, may carry the risk of an increased susceptibility to infections. While M. tuberculosis infections can be an important complication of anti-TNFα therapies, the role of the Th17/IL-17 pathway in host resistance to this intracellular pathogen is less clear.

Methods: The effect of neutralizing IL-17A or IL-17F during acute M. tuberculosis infection was evaluated in a 4-week aerosol mouse model. M. tuberculosis (strain H37Rv, 1000 CFU) infected C57BL/6 mice were treated once per week i.p. with 0.5 mg (approximately 20 mg/kg) of anti-mouse IL-17A or F antibodies, 0.25 mg (approximately 10 mg/kg) of anti-mouse TNFα antibody, and respective isotype control antibodies, starting 1 day before the infection. Disease symptoms, lung and spleen weight, pulmonary bacterial burden and lung histopathology were assessed at day 28.

Results: IL-17A or IL-17F blockade like the isotype controls did not alter body, lung, and spleen weights, pulmonary bacterial burden and lung histopathology after 28 days. On the other hand, in mice treated with a neutralizing anti-TNFα antibody, body weight was drastically decreased, while lung and spleen inflammation and pulmonary bacterial burden were clearly increased by day 28. These changes were associated with a worsening of the microscopic observations in the lung with the anti-TNFα antibody. TNFα-deficient mice succumbed by day 28 to severe infection under these experimental conditions.

Conclusion: Overall, these results confirm the importance of TNFα in host resistance to M. tuberculosis infection, and highlight that anti-IL-17A or anti-IL-17F cytokine blockade for 4 weeks in vivo do not impair immunity in an acute mouse M. tuberculosis infection model.

Disclosure:

M. Kammüller,