F Daum

Effects of infliximab on apoptosis and reverse signaling of monocytes from healthy individuals and patients with Crohn's disease.

Objectives: Infliximab, an anti-tumor necrosis factor (TNF) monoclonal antibody, might exert some of its long-term therapeutic effects in Crohns disease (CD) by interacting directly with cells of the immune system such as monocytes and T lymphocytes via membrane TNF and by inducing apoptosis. Accordingly, the effects of inflix-imab on monocyte apoptosis and down-regulation of proinflammatory cytokines (reverse signaling) were assessed. Methods: To assess apoptosis, monocytes from healthy individuals (controls) and CD patients were incubated in the presence or absence of infliximab or the apoptotic agent gliotoxin for 24 hours. Annexin V staining and the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-FITC nick end labeling assay were used to measure early and late apoptosis. To measure the effects of infliximab on reverse signaling, monocytes from healthy individuals pretreated in vitro with infliximab were stimulated with lipopolysaccharide or staphylococcal enterotoxin A, and the induction of the proinflammatory cytokines, TNF-α, interleukin (IL)-1β, IL-6, and IL-8 was measured by reverse transcription polymerase chain reaction. The effect of in vivo infliximab treatment of monocytes was similarly determined by comparing the responses of monocytes from CD patients before and immediately after infliximab infusion. Results: Infliximab did not induce apoptosis of monocytes from either healthy individuals or CD patients but rather stabilized them. However, monocytes from healthy individuals treated with infliximab in vitro, or from CD patients infused with infliximab, produced significantly less TNF and other proinflammatory cytokines when stimulated with the bacterial products lipopolysaccharide and staphylococcal enterotoxin A. Conclusions: Apoptosis of monocytes is not responsible for the therapeutic effects of infliximab. However, some of the therapeutic effects of infliximab may be caused by its ability to down-regulate proinflammatory cytokines production by monocytes exposed to bacterial antigens.

Immunomodulatory therapy for pediatric inflammatory bowel disease: changing patterns of use, 1990–2000

OBJECTIVE:To identify changes over the past decade in physicians’ attitudes regarding the use of immunomodulatory agents for the treatment of children with inflammatory bowel disease (IBD), we surveyed the membership of the North American Society for Pediatric Gastroenterology and Nutrition and compared the responses to those from an identical survey performed in 1990.METHODS:Surveys were mailed to 718 physicians in January, 2000. All surveys returned by mid-February were analyzed, and results compared to those obtained in the 1990 survey.RESULTS:Thirty-nine percent (278/718) of surveys were returned, compared to 27% (105/385) in 1990. Overall, 93% of the current surveys respondents agreed with the statement “immunomodulatory agents are effective in the treatment of children and adolescents with IBD.” Compared to 1990, significant increases (p < 0.0001) were noted in the percentage of respondents who prescribe immunomodulatory agents to children with all forms of IBD. Indications for immunomodulation that showed significant increases (p < 0.001) since 1990 included treatment of perianal and nonperianal fistulae; growth failure; use as initial, primary therapy; and use as prophylaxis against postoperative recurrence. 6-Mercaptopurine and azathioprine continue to be the agents prescribed by the greatest percentage of respondents. More physicians are willing to use immunomodulatory agents in children younger than 5 yr, and duration of use is longer than in 1990. Currently, physicians seem to favor the use of immunomodulatory agents over colectomy for children with either intractable ulcerative or Crohns colitis. Most respondents remain concerned about potential bone marrow and immune suppression, but concerns regarding malignancy, teratogenicity, and infertility have lessened.CONCLUSION:These survey findings document that pediatric gastroenterologists have widely accepted the use of immunomodulators in the treatment of children and adolescents with IBD.

Immunology of inflammatory bowel disease: Summary of the proceedings of the subcommittee on immunosuppressive use in IBD

As outlined, scanty data exist with regard to immunologic therapy in children with IBD despite the fact that the pediatric population affords a unique opportunity for clinical evaluation. Children are less affected by modifying conditions such as smoking, alcohol ingestion, and the long-term use of medications, and because of their specific needs for ponderal and linear growth, children might benefit most from immunological therapy that has been proven to be steroid sparing. Therefore, clinical trials to evaluate the efficacy of 6-MP and/or azathioprine in growing children with Crohns disease would appear to provide a fruitful avenue for collaborative research. Efforts to organize a multicenter evaluation of these agents have been initiated. The studies are crucial in evaluating the efficacy and safety of immunosuppressive therapy in the pediatric population with IBD.

Inhibiting thiopurine methyltransferase (TPMT) activity with mesalamine improves therapeutic 6MP metabolites in children with Crohn's disease (CD)

Inhibiting thiopurine methyltransferase (TPMT) activity with mesalamine improves therapeutic 6MP metabolites in children with Crohns disease (CD)