A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn's disease.
Recent clinical studies of Crohn's disease patients demonstrated dramatic clinical responses following one i.v. infusion of a chimeric mAb to TNF-alpha (cA2). To assess the role of TNF-alpha in mucosal cytokine regulation, the effects of TNF-alpha on lamina propria mononuclear cell (LPMC) Th1 production were determined. Increased IFN-gamma production was demonstrated in anti-CD2-stimulated LPMC cultured in TNF-alpha. To determine the effects of cA2 on cytokine production, TNF-alpha- and IFN-gamma-producing cells were quantitated in LPMC from five Crohn's disease patients treated with cA2. In all four patients who demonstrated clinical and endoscopic improvement, decreased numbers of LPMC producing IFN-gamma and TNF-alpha following CD2/CD28 activation paralleled improvement in disease activity over 8 wk. In one patient who did not improve, increased numbers of TNF-alpha- and IFN-gamma-secreting LPMC were observed. In three of four responding patients, CD2/CD28-activated PBMC demonstrated increased IFN-gamma production over 8 wk. These observations suggest that TNF-alpha may be a cofactor for mucosal Th1 responses, and improvement in clinical parameters and intestinal inflammation induced by cA2 in Crohn's disease may be mediated by down-regulation of mucosal Th1 cytokines.
Plevy
S E
SE
Cedars-Sinai Division of Gastroenterology, Inflammatory Bowel Disease Center, Los Angeles, CA 90048, USA.
Landers
C J
CJ
Prehn
J
J
Carramanzana
N M
NM
Deem
R L
RL
Shealy
D
D
Targan
S R
SR
D000276:Adjuvants, Immunologic / Q000502:physiology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D018801:CD2 Antigens; D002452:Cell Count; D002478:Cells, Cultured; D018920:Coculture Techniques; D003424:Crohn Disease / Q000209:etiology* / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007262:Infusions, Intravenous; D007371:Interferon-gamma / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology*
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D018801:CD2 Antigens; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma