Investigation of the prognostic value of TNF-alpha gene polymorphism among patients treated with infliximab, and the effects of infliximab therapy on TNF-alpha production and apoptosis.
OBJECTIVE
Infliximab, a chimeric anti-tumor necrosis factor (TNF) antibody, is highly effective for the treatment of Crohn's disease (CD) and rheumatoid arthritis (RA). Our experiments focused on RA and CD patients receiving infliximab. Since cytokine production is largely determined by genetic factors, the promoter polymorphisms of TNF-alpha were examined among these patients. Additionally, the changes caused by infliximab in the TNF-alpha-producing ability and apoptosis of peripheral blood mononuclear cells (PBMCs) were investigated.


METHODS
The TNF-alpha genotypes were analyzed by PCR-RFLP. The in vitro TNF-alpha production of the PBMCs was detected by flow cytometric analysis. The TNF-alpha concentration in the supernatant was measured by bioassay. Apoptosis was detected by annexin V-fluorescein isothiocyanate labeling.


CONCLUSIONS
8 of the 12 nonresponder patients carried the TNF A allele associated with high TNF-alpha production. We suggest that the determination of TNF polymorphism may help identify more suitable candidates for infliximab treatment. Although in vitro infliximab treatment for 48 h resulted in significant (44.2 +/- 1.17%) apoptosis in PBMCs, in ex vivo samples from RA patients who received infliximab, apoptosis was only 13.3 +/- 1.6%. Furthermore, infliximab did not result in irreversible inhibition of the TNF-alpha-producing ability or in the significant apoptosis of PBMCs.
Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
Attila
A
Balog
Gergely
G
Klausz
János
J
Gál
Tamás
T
Molnár
Ferenc
F
Nagy
Imre
I
Ocsovszky
Zsófia
Z
Gyulai
Yvette
Y
Mándi
D000483:Alleles; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics*; D001782:Blood Donors; D003424:Crohn Disease / Q000188:drug therapy / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D005838:Genotype; D006801:Humans; D000069285:Infliximab; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011379:Prognosis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab