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06.11 Anti-tnf-α vaccination protects from experimental arthritis without negatively affecting resistance to mycobacterium tuberculosis infection
  1. Eric Assier1,2,
  2. Nadia Belmellat1,2,
  3. Luca Semerano1,2,3,
  4. Bernhard Ryffel4,
  5. Patrice Decker1,2,
  6. Valérie Quesniaux4,
  7. Marie-Christophe Boissier1,2,3
  1. 1Inserm UMR 1125, Bobigny France
  2. 2Sorbonne Paris Cité Université Paris, Bobigny France
  3. 3Assistance Publique – Hôpitaux de Paris (AP-HP) GH HUPSSD, Bobigny France
  4. 4CNRS UMR7355, INEM, Orléans, France

Abstract

Background TNF-α-blocking therapy is a successful treatment strategy for rheumatoid arthritis (RA), but is associated with reduced resistance to tuberculosis. We have developed a vaccine against mouse TNF-α (TNF-KLH) which protects mice from collagen-induced arthritis (CIA) and collagen-antibodies-induced arthritis (CAIA). We aimed at modelizing the infectious risk/benefit ratio of TNF-α neutralisation by comparing different strategies of TNF-α targeting in experimental Mycobacterium tuberculosis infection.

Materials and methods 4 groups (TNF-KLH, etanercept, KLH, PBS) of 10 C57BL/6 mice were compared with TNF deficient mice (TNF -/-). Vaccines were emulsified in IFA before i.m. administration (days −44, –31, −17 and −4). Other treatments were given from D0. All groups were infected at day 0 by 104 cfu of Mycobacterium tuberculosis (H37Rv virulent strain). Mouse groups were divided in two arms: one was euthanized 28 days post-infection, the lasting mice were euthanized 56 days post-infection. Bacterial burden was evaluated in lungs. Cellular infiltration was studied by immunohistological analysis.

Results A sustained anti-TNF-α antibody production was obtained in vaccinated mice. At day 28 of Mycobacteria infection, bacterial burden, organ weights, neutrophils and B cells infiltration were similar between TNF-KLH, KLH and PBS groups. At this time point, histological analysis showed higher surface of granuloma in liver of etanercept and TNF-/- groups than TNF-KLH group. At day 56 post infection, etanercept group presented higher surface of liver and lung granuloma than TNF-KLH and KLH groups. These observations were in accordance with a progression of the disease in etanercept group, whereas such effect was not retrieved in TNF-KLH and immunocompetent groups (KLH, PBS).

Conclusion Our results indicate that anti-TNF-α vaccination could protect mice from inflammatory arthritis without deeply altering host immunity against infection, suggesting the existence of two distinct pathophysiologic thresholds for TNF-α inhibition, one for arthritis improvement, the other for infection facilitation. These thresholds might be dependend on the TNF inhibition strategy.

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