Correspondence
Anti–Interleukin-12 Antibody for Active Crohn's Disease
N Engl J Med 2005; 352:627-628February 10, 2005
- Article
To the Editor:
Mannon et al. (Nov. 11 issue)1 describe the safety of anti–interleukin-12 antibody (anti–interleukin-12) for the treatment of active Crohn's disease. Among the 44 recipients of anti–interleukin-12 who could be evaluated at 18 weeks, no serious infections were reported.
These results are similar to those of the original studies of infliximab for the treatment of Crohn's disease and rheumatoid arthritis, in which serious infectious complications were not identified.2,3 The small number of patients enrolled, the exclusion of those at risk, and the limited follow-up for uncommon events are also similar. Through post-marketing surveillance, we learned that anti–tumor necrosis factor (TNF) therapy is associated with tuberculosis, listeriosis, and endemic fungal infections, as predicted by the inhibition of TNF.
Like TNF-α, interleukin-12 is important in interferon-γ production and defense against intracellular pathogens. The absence of interleukin-12 in humans has been linked to complicated infections due to mycobacteria and nontyphoidal salmonella species.4,5 None of these infections were found in this limited study.
The potential expansion of anticytokine therapeutics reminds us that we need improved screening, preventive measures, and a longitudinal registry of patients receiving these therapies in order to determine the true prevalence of serious infections.
5 ReferencesRobert Orenstein, D.O.
Mayo Clinic College of Medicine, Rochester, MN 55905
orenstein.robert@mayo. edu 1
Mannon PJ ,Fuss IJ ,Mayer L , et al. Anti-interleukin-12 antibody for active Crohn's disease. N Engl J Med 2004;351:2069-2079
Full Text | Web of Science | Medline2
Lipsky PE ,van der Heijde D ,St Clair EW , et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000;343:1594-1602
Full Text | Web of Science | Medline3
Present DH ,Rutgeerts P ,Targan S , et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999;340:1398-1405
Full Text | Web of Science | Medline4
MacLennan C ,Fieschi C ,Lammas DA , et al. Interleukin (IL)-12 and IL-23 are key cytokines for immunity against Salmonella in humans. J Infect Dis 2004;190:1755-1757
CrossRef | Web of Science | Medline5
Fieschi C ,Casanova JL . The role of interleukin-12 in human infectious diseases: only a faint signature. Eur J Immunol 2003;33:1461-1464
CrossRef | Web of Science | Medline
To the Editor:
The study reported by Mannon et al. shows the preliminary efficacy of anti–interleukin-12 in patients with active Crohn's disease. We wondered whether the title of the report should have been “Anti–Interleukin-12/23 for Active Crohn's Disease,” since interleukin-12 p40 is equally important in the biologic activity of these two cytokines. Much attention has been paid to the type 1/type 2 helper T-cell model of immunity in Crohn's disease, but preclinical data also support a role of interleukin-23 and the downstream T-cell cytokine interleukin-17.1 Transcripts for interleukin-23 p19 have been found to be elevated in the gut in patients with active Crohn's disease, and serum interleukin-17 levels have been shown to be elevated in active Crohn's disease.2 Moreover, inhibition of interleukin-17 receptor signaling is efficacious in reducing tissue neutrophils in colitis induced by trinitrobenzene sulfonic acid.3 Since interleukin-12 has been shown to down-regulate interleukin-17,4 serum interleukin-17 may be a good biomarker for determining whether anti–interleukin-12/23 p40 is working through interleukin-12, interleukin-23, or perhaps both pathways.
4 ReferencesJay K. Kolls, M.D.
Children's Hospital of Pittsburgh, Pittsburgh, PA 15213
jay.kolls@chp. edu Zili Zhang, M.D., Ph.D.
Oregon Health and Science University, Portland, OR 972391
Kolls JK ,Linden A . Interleukin-17 family members and inflammation. Immunity 2004;21:467-476
CrossRef | Web of Science | Medline2
Fujino S ,Andoh A ,Bamba S , et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 2003;52:65-70
CrossRef | Web of Science | Medline3
Zhang Z ,Oliver P ,Schwarzenberger P , et al. Interleukin-17 induces MIP-2 production and neutrophil infiltration in acute colitis induced by TNBS. J Pediatr Gastroenterol Nutr 2000;3:Suppl 2:S83-S83 abstract.4
Aggarwal S ,Ghilardi N ,Xie MH ,de Sauvage FJ ,Gurney AL . Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 2003;278:1910-1914
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Orenstein is correct in pointing out the risk of infection with anticytokine therapies. Our study was designed to reduce this risk, and as we stated, the risk of infection from longer-term use of anti–interleukin-12 remains to be established. Whether the infection experience with patients who have a genetic deficiency of interleukin-12 or its receptor will be recapitulated with recipients of anti–interleukin-12 is not known, but this is a logical place to focus future monitoring.
Drs. Kolls and Zhang highlight the fact that the antibody used in our study recognizes the same protein subunit (p40) that makes up part of the interleukin-12 (p40 and p35) and interleukin-23 (p40 and p19) heterodimers. Because interleukin-17 is produced by interleukin-23–stimulated memory T lymphocytes, Drs. Kolls and Zhang suggest that elevated interleukin-17 serum levels might be used as a marker of predominant interleukin-23 effects. Although interleukin-12 does not induce interleukin-17 production, it can inhibit interleukin-23–stimulated production of interleukin-17,1 so low serum levels of interleukin-17 would not discriminate between the absence of interleukin-23 and the presence of high levels of both interleukin-12 and interleukin-23. Perhaps future clinical-trial evaluation with the use of an anti-p19 antibody would better reveal the contribution of interleukin-23 as compared with that of interleukin-12 in candidate inflammatory states.
1 ReferencesPeter J. Mannon, M.D.
Ivan J. Fuss, M.D.
Warren Strober, M.D.
National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892
pmannon@niaid.nih. gov 1
Aggarwal S ,Ghilardi N ,Xie MH ,de Sauvage FJ ,Gurney AL . Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 2003;278:1910-1914
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Xiaowei Wei, Jianfeng Gong, Juan Zhu, Lingying Niu, Weiming Zhu, Ning Li, Jieshou Li. (2008) Therapeutic effects of triptolide on interleukin-10 gene-deficient mice with colitis. International Immunopharmacology 8:13-14, 1808-1812
CrossRef2
Hyun-Dong Chang, Andreas Radbruch. (2007) The pro- and anti-inflammatory potential of IL-12: the dual role of Th1 cells. Expert Review of Clinical Immunology 3:5, 709-719
CrossRef3
Zili Zhang, Mingquan Zheng, Julie Bindas, Paul Schwarzenberger, Jay K. Kolls. (2006) Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflammatory Bowel Diseases 12:5, 382-388
CrossRef
