ELEVATED TH1- OR TH0-LIKE CYTOKINE MESSENGER-RNA IN PERIPHERAL-CIRCULATION OF PATIENTS WITH RHEUMATOID-ARTHRITIS - MODULATION BY TREATMENT WITH ANTI-ICAM-1 CORRELATES WITH CLINICAL BENEFIT

The current studies examined whether cytokine patterns indicative of a n imbalance in Th1 and Th2 cells could be identified in PBMC of patien ts with active rheumatoid arthritis (RA). To investigate this possibil ity, a reproducible PCR technique to assess cytokine mRNA levels in PB MC was employed that minimized in vitro manipulation of the cells. Sev en of 14 RA patients had increased mRNA levels for IL-2, 5/14 for IFN- gamma, 3/14 for IL-4, and 4/14 for the IL-2R alpha-chain, compared wit h normal donors. Whereas 4 patients had elevated mRNA for IL-2 and IFN -gamma indicative of an increase in activated Th1 or Th0 cells, 1 of 1 4 patients expressed low levels of IL-2 and IFN-gamma and high levels of IL-4 mRNA. Seven RA patients were treated with a mAb to ICAM-1 (CD5 4). To determine whether changes in cytokine mRNA levels might be asso ciated with and/or account for the anti-inflammatory effect of anti-IC AM-1 mAb therapy, changes in cytokine mRNA levels were assessed and co rrelated with clinical improvement. Anti-ICAM-1 mAb administration was followed by a prompt and transient increase of IFN-gamma mRNA. Elevat ion of IFN-gamma mRNA expression throughout the treatment period refle cted a temporary increase in the number of circulating CD3(+)CD4(+) T cells, suggestive of altered circulatory patterns of activated Th1-lik e cells and was related to clinical efficacy. The results indicate tha t elevated cytokine mRNA levels characteristic for Th1 cells can be de tected in the PBMC in active RA and, furthermore, that anti-ICAM-1 mAb may be beneficial in RA by altering the recruitment of activated Th1- like cells into the synovium. This assumption further strengthens the hypothesis of a significant contribution of Th1-like cells to the path ogenesis of RA.