Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease.
OBJECTIVE
Treatment with infliximab induces remission in about 70% of patients with steroid refractory Crohn's disease. Because Crohn's disease is considered to be mediated by uncontrolled activation of mucosal T lymphocytes, we hypothesised that infliximab could induce apoptosis of T lymphocytes.


METHODS
Induction of apoptosis in vivo was studied in 10 patients with therapy refractory Crohn's disease. In vitro, resting or stimulated Jurkat T cells were incubated with infliximab.


RESULTS
Infusion of infliximab (5 mg/kg) in steroid refractory patients with Crohn's disease induced a clinical response in 9/10 patients but did not influence expression of activation markers, homing receptors, memory cells, Fas expression, or Bax/Bcl-2 expression on peripheral blood T lymphocytes. In contrast, a significant increase in CD3 and TUNEL positive cells within colonic biopsies was detected 24 hours after infusion of infliximab, suggesting that infliximab stimulates apoptosis of activated T lymphocytes but not of resting T cells. To test this hypothesis, the effects of infliximab on Jurkat T cells were investigated. We observed that infliximab induced apoptosis and an increase in the Bax/Bcl-2 ratio of CD3/CD28 stimulated Jurkat T cells but not of unstimulated Jurkat cells.


CONCLUSIONS
Our data indicate that infliximab treatment causes a rapid and specific increase in apoptosis of T lymphocytes in the gut mucosa. These findings may explain the rapid and sustained therapeutic effects of infliximab in Crohn's disease.
ten Hove
T
T
Academic Medical Centre University of Amsterdam, Department of Experimental Internal Medicine, Amsterdam, the Netherlands. T.tenhove@amc.uva.nl
van Montfrans
C
C
Peppelenbosch
M P
MP
van Deventer
S J H
SJ
D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D003424:Crohn Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D006801:Humans; D000069285:Infliximab; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D019169:Jurkat Cells; D013601:T-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D018106:CD28 Antigens; D017252:CD3 Complex; D005765:Gastrointestinal Agents; D000069285:Infliximab