Background/Purpose: Anti-TNF-alpha therapy has been a successful treatment strategy for rheumatoid arthritis (RA), but is associated with reduced resistance to infection. In mice, TNF is essential to control infection. We have developed a murine vaccine against TNF (mTNF-K) which protects mice from collagen-induced arthritis (CIA) to same extent as etanercept. We aimed at modelizing the infectious risk/benefit ratio of TNF-alpha neutralization by a vaccination strategy. Here we evaluated the consequence of TNF blockade by the mTNF-K in Listeria and Mycobacterium infection models.

Methods: Arthritis models were collagen-induced arthritis (CIA) in mice and collagen-antibodies induced arthritis (CAIA). In Listeria monocytogenes infection model, 4 groups of 10 C57Bl/6 mice were used and compared with a murine TNF KO group (same background). Wild type mice were treated either by mTNF-K, etanercept, KLH or PBS. Vaccines were emulsified in CFA (day 0) or IFA (days 13, 27 and 40) before injections. All groups were infected at day 44 by 10⁴ cfu of Listeria monocytogenes (LO28 strain). Mice groups were divided in two arms: one was euthanized 4 days post-infection, survival of the lasting mice was evaluated until day 11. In Mycobacterium infection model, the same protocol was applied with same groups before infection by 10⁴ cfu of Mycobacterium tuberculosis (H37Rv strain). Mice 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 the lung. Cellular infiltration was studied by immunohistological analysis.

Results: Our vaccine was efficient in improving clinical and histological signs of arthritis in CIA and CAIA. A sustained anti-TNF-alpha antibody production was obtained in mTNF-K vaccinated mice in all experiments. At day 4 post-infection by Listeria, mTNF-K and non-targeted-TNF treatments groups (KLH, PBS) presented lower bacterial burden in liver and spleen than TNF KO and etanercept groups. At day 11, all mice of PBS and mTNF-K groups survived to infection. Large lesions in livers were observed only within TNF KO and etanercept groups. At day 28 post-infection by Mycobacterium, bacterial burden, organ weights and cellular infiltrations (Neutrophils, B cells) were similar between mTNF-K and non-targeted-TNF treatments groups. On the contrary, etanercept group presented increased surface of liver granuloma and lower lung infiltration by iNOS+ cells than mTNF-K group. At day 56, etanercept group presented higher surface of lung granuloma than mTNF-K and KLH group.

Conclusion: Together, our results indicate that anti-TNF-alpha vaccine could protect mice from inflammatory arthritis without deeply altering host immunity against infection, suggesting the existence of two distinct pathophysiologic thresholds for TNF inhibition, one for arthritis improvement, the other for infection deregulation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-tnf-vaccination-protects-from-experimental-arthritis-without-affecting-resistance-to-mycobacterium-tuberculosis-or-listeria-monocytogenes-infection/