Anti–Interleukin-12 Antibody for Active Crohn's Disease
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《新英格兰医药杂志》
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-, interleukin-12 is important in interferon- 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.
Robert Orenstein, D.O.
Mayo Clinic College of Medicine
Rochester, MN 55905
orenstein.robert@mayo.edu
References
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.
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.
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.
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.
Fieschi C, Casanova JL. The role of interleukin-12 in human infectious diseases: only a faint signature. Eur J Immunol 2003;33:1461-1464.
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.
Jay 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 97239
References
Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity 2004;21:467-476.
Fujino S, Andoh A, Bamba S, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 2003;52:65-70.
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.
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.
The authors reply: 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.
Peter 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
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-, interleukin-12 is important in interferon- 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.
Robert Orenstein, D.O.
Mayo Clinic College of Medicine
Rochester, MN 55905
orenstein.robert@mayo.edu
References
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.
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.
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.
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.
Fieschi C, Casanova JL. The role of interleukin-12 in human infectious diseases: only a faint signature. Eur J Immunol 2003;33:1461-1464.
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.
Jay 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 97239
References
Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity 2004;21:467-476.
Fujino S, Andoh A, Bamba S, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 2003;52:65-70.
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.
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.
The authors reply: 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.
Peter 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