IN-VIVO BLOCKADE OF TNF-ALPHA BY INTRAVENOUS-INFUSION OF A CHIMERIC MONOCLONAL TNF-ALPHA ANTIBODY IN PATIENTS WITH RHEUMATOID-ARTHRITIS - SHORT-TERM CELLULAR AND MOLECULAR EFFECTS

Due to the unknown etiology of RA, specific treatment is not available . Recently, in a double-blinded, placebo-controlled clinical trial, in vivo blockade of TNF-alpha by a single infusion of a chimeric TNF-alp ha-blocking mAb, cA2, has proven to be highly effective in the treatme nt of RA. In parallel to this trial, we tested the consequences of cA2 infusion in ex vivo and in vitro experiments. In this paper, we descr ibe an increase in CD4(+) and CD8(+) T lymphocyte counts on day 1 and a marked decrease in monocyte counts preferentially on day 7 after cA2 treatment, without major changes in 8 lymphocyte or NK cell counts. I n addition, we found an increased responsiveness of PBMC to CD28 mAb/P MA, but not to CD3 mAb, superantigen staphylococcus enterotoxin B, or PHA on day 1 after infusion. The increase in DNA synthesis of PBMC was paralleled by increased IL-2 mRNA and IL-4 mRNA expression and IL-2 p rotein secretion in culture supernatants after in vitro stimulation of PBMC with CD28 mAb/PMA. In PBMC, we did not find any significant chan ges in mRNA or protein expression of CD28 Ag or CD28 ligands, B7-1 and B7-2. Serum concentrations of IL-1 beta, IL-6, and soluble CD14 were significantly diminished after in vive TNF-alpha blockade. We did not see relevant changes in granulocyte function in vitro after cA2 infusi on. Finally, we observed a statistically significant decrease in sICAM -1 molecules in the serum of patients treated with verum compared with that in the serum of subjects given placebo. This change in sICAM-1 c oncentration was evident on days 1 and 7 after the infusion of 10 mg/k g cA2, whereas it occurred only on day 7 in the serum of patients trea ted with the low dose (1 mg/kg) of cA2.