SUMMARY Chloroquine (Chi) is an anti‐rheumatic drug that is widely used in the treatment of rheumatoid arthritis (RA). It seems that T ceils are important in the pathogenesis of RA, but it is not known whether Chl acts via inhibition of T cell function. We here present evidence that Chl, just like cyclosporine A (CsA), inhibits Tcell proliferation as induced with immobilized αCD3 MoAb in a concentration‐dependent manner, at least partly through interfering with the production of IL‐2 protein and the induction of IL‐2 inRNA. Furthermore, Chi impedes the responsiveness of T cell clones to IL‐2 since (1) the inhibition of αCD3 MoAb‐induced proliferation by Chi could not be reversed by rlL‐2 and (2) Chi directly blocks IL‐2‐driven proliferation of cloned T cells. Chi appeared to interfere with the internalization (50% inhibition) and degradation (total blockade) of rIL‐2. Finally, the combination of Chi and CsA synergistically inhibited T ceil proliferation. We conclude that Chi may inhibit functional properties of human T cells. although the drug is 100‐to 1000‐folds less potent than CsA in inhibiting T cell proliferation and IL‐2 production, respectively. It is speculated that the in vitro. effects of Chl might be relevant in explaining the anti‐rheumatic effect of this drug in patients with RA.

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SUMMARYThe dominant presence of specific T-ectl populations in the rheumatoid joint as detected by Southern blot analysis ofT cell receptor (TCR) gene rearrangements would indicate local antigen recognition and T cell proliferation. We therefore studied TCR /{chain gene rearrangements using a C/*2 probe in paired samples ofT cell populations from synovial tissue and peripheral blood (/j = 6) as well as synovial fluid («=16) and peripheral blood («=18) of patients with rheumatoid arthritis (RA). Peripheral blood mononuclear cells from healthy donors {ri-7) served as a control. T cells were studied directly after isolation or after non-specific expansion with OKT3 monoclonal antibody (MoAb) and T cell growth factor (TCGF). DNA samples were digested with EcoR\ and IlindUl to detect rearrangements to C/il andC/i2, respectively. Extra bands were detected in all /ftvjRI-digested DNA samples prepared fVom both freshly isolated and non-specifically expanded T cell populations of patients and healthy donors, possibly representing "common" (V-) D-J rearrangements. Dominant rearrangements were found in only two out of 16 synovial fluid T cell populations (one freshly isolated and one expanded) and not in peripheral blood or synovial tissue derived T cell populations, No extra bands were detected in ///rtdlll-digcsted DNA samples. To investigate the effect of in vitro culture techniques on rearrangement patterns we studied DNA samples prepared from synovial tissue T cells obtained both by outgrowth from tissue with TCGF or by enzyme digestion and subsequent expansion either with TCGF or with OKT3 MoAb and TCGF. Whereas the latter Tcell population yielded "common" rearrangements, the former T cell populations yielded different dominant rearrangements. These data indicate that oligoclonality of the T cell populations in synovial tissue and synovial fluid of patients with RA is a rare event. The data also show the influence of m vitro culture techniques on the result of TCR gene rearrangement analysis.

In this study T-cell receptor (TcR) beta-chain gene rearrangements of T-cell lines prepared from multiple sites (n = 92) of synovial tissue derived from both knees of a patient with rheumatoid arthritis were analysed. In the majority of T-cell lines, dominant TcR beta-chain gene rearrangements were detected, involving C beta 1 as well as C beta 2. The dominant rearrangement patterns of T-cell lines from different tissue fragments showed significant variability, but some of the DNA restriction fragments were shared by T-cell lines from multiple sites in both knees. The latter observation suggests that identical T-cell clones may be present at different sites in the synovial tissue and in different joints. However, since many T-cell lines yielded different rearrangement patterns, these data also indicate considerable heterogeneity of T cells in the joints. Apart from theoretical implications, this TcR heterogeneity of T cells within an individual patient also has practical consequences for studies on synovial T cells obtained by biopsy.