Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|IL-1 receptor antagonist（IL-1Ra）(Anakinra)|
|anti-IL-1b antibody (Canakinumab)|
|soluble IL-1R (Rilonacept)|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
|All life stages||High|
Key Event Description
The protection of host against microbial infection depends on both innate and acquired immunity. In particular, both T cell and antibody production by B cells play a principal role.
How It Is Measured or Detected
By comparison of the incidence of infection between individuals exposed to stressors and non-exposed individuals.
Domain of Applicability
The increased susceptibility to infection caused by IL-1RA or anti-IL-1 antibody has been reported in both humans and mice. (Fleischmann et al., 2003; De Benedetti et al., 2018; Hirsch et al., 1996)
Evidence for Perturbation by Stressor
Regulatory Significance of the Adverse Outcome
After L-1R antagonist or neutralizing antibody such as IL-1Ra (generic anakinra), canakinumab (anti-IL-1b antibody) and rilonacept (soluble IL-1R) became available to treat some of autoinflammatory syndromes, it became clear that these inhibitors increased the frequency of serious bacterial infection (De Benedetti et al., 2018; Genovese et al., 2004; Imagawa et al., 2013; Kullenberg et al., 2016; Lachmann et al., 2009; Lequerre et al., 2008; Migkos et al., 2015; Schlesinger et al., 2012; Yokota et al., 2017).
Auphan, N., DiDonato, J.A., Rosette, C., et al., 1995. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 270, 286-290.
Chatham, W.W., 2019. Glucocorticoid effects on the immune system.
De Benedetti, F., Gattorno, M., Anton, J., et al., 2018. Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. N Engl J Med 378, 1908-1919.
Genovese, M.C., Cohen, S., Moreland, L., et al., 2004. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 50, 1412-1419.
Guler, R., Parihar, S.P., Spohn, G., et al., 2011. Blocking IL-1alpha but not IL-1beta increases susceptibility to chronic Mycobacterium tuberculosis infection in mice. Vaccine 29, 1339-1346.
Horino, T., Matsumoto, T., Ishikawa, H., et al., 2009. Interleukin-1 deficiency in combination with macrophage depletion increases susceptibility to Pseudomonas aeruginosa bacteremia. Microbiol Immunol 53, 502-511.
Imagawa, T., Nishikomori, R., Takada, H., et al., 2013. Safety and efficacy of canakinumab in Japanese patients with phenotypes of cryopyrin-associated periodic syndrome as established in the first open-label, phase-3 pivotal study (24-week results). Clin Exp Rheumatol 31, 302-309.
Juffermans, N.P., Florquin, S., Camoglio, L., et al., 2000. Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis. J Infect Dis 182, 902-908.
Kullenberg, T., Lofqvist, M., Leinonen, M., et al., 2016. Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes. Rheumatology (Oxford) 55, 1499-1506.
Lachmann, H.J., Kone-Paut, I., Kuemmerle-Deschner, J.B., et al., 2009. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360, 2416-2425.
Lequerre, T., Quartier, P., Rosellini, D., et al., 2008. Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 67, 302-308.
Migkos, M.P., Somarakis, G.A., Markatseli, T.E., et al., 2015. Tuberculous pyomyositis in a rheumatoid arthritis patient treated with anakinra. Clin Exp Rheumatol 33, 734-736.
Schlesinger, N., Alten, R.E., Bardin, T., et al., 2012. Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions. Ann Rheum Dis 71, 1839-1848.
Tian, T., Jin, M.Q., Dubin, K., 2017. IL-1R Type 1-Deficient Mice Demonstrate an Impaired Host Immune Response against Cutaneous Vaccinia Virus Infection. 198, 4341-4351.
Yamada, H., Mizumo, S., Horai, R., et al., 2000. Protective role of interleukin-1 in mycobacterial infection in IL-1 alpha/beta double-knockout mice. Lab Invest 80, 759-767.
Yokota, S., Imagawa, T., Nishikomori, R., et al., 2017. Long-term safety and efficacy of canakinumab in cryopyrin-associated periodic syndrome: results from an open-label, phase III pivotal study in Japanese patients. Clin Exp Rheumatol 35 Suppl 108, 19-26.