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M J Verdonk

Publications and source records attributed to M J Verdonk.

7 recordsLinked to original sources
PubMed1996

Persistent CD3-crosslinking down-regulates interleukin-2 responsiveness in interleukin-2-competent cloned T cells: the possible involvement of protein kinase C.

To investigate the regulation of interleukin-2 (IL-2) responsiveness of T cells, a human CD4+ T-cell clone with constitutive expression of IL-2 receptors was stimulated with recombinant IL-2 (rIL-2) in the presence or absence of immobilized anti-CD3 monoclonal antibodies (alpha CD3imm MoAb). Incubation of T cells with alpha CD3imm MoAb decreased IL-2-induced proliferation which could not be ascribed to the modulation of IL-2 receptor expression nor to cell death. Phorbol-myristate-acetate (PMA), an activator of protein kinase C (PKC), also induced down-regulation of IL-2 responsiveness. The alpha CD3sol MoAb, inducing Ca(2+)-mobilization without activating PKC, did not inhibit IL-2 responsiveness whereas cyclosporine A (CsA), a drug that inhibits the Ca(2+)-dependent activation pathway, did not prevent the induction of IL-2 hyporesponsiveness induced by alpha CD3imm MoAb. It is concluded that modulation of IL-2 responsiveness of T cells via the T-cell receptor/CD3 complex (TCR/CD3) may be mediated by a PKC-activating signal.

Antibodies, Monoclonal↗
PubMed1995

Chloroquine inhibits T cell proliferation by interfering with IL-2 production and responsiveness.

Chloroquine (Chl) is an anti-rheumatic drug that is widely used in the treatment of rheumatoid arthritis (RA). It seems that T cells 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 T cell proliferation as induced with immobilized alpha CD3 MoAb in a concentration-dependent manner, at least partly through interfering with the production of IL-2 protein and the induction of IL-2 mRNA. Furthermore, Chl impedes the responsiveness of T cell clones to IL-2 since (1) the inhibition of alpha CD3 MoAb-induced proliferation by Chl could not be reversed by rIL-2 and (2) Chl directly blocks IL-2-driven proliferation of cloned T cells. Chl appeared to interfere with the internalization (50% inhibition) and degradation (total blockade) of rIL-2. Finally, the combination of Chl and CsA synergistically inhibited T cell proliferation. We conclude that Chl may inhibit functional properties of human T cells, although the drug is 100- to 1000-fold 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.

Antibodies, Monoclonal↗
PubMed1993

Activated synovial T cell clones from a patient with rheumatoid arthritis induce proliferation of autologous peripheral blood-derived T cells.

In order to investigate cellular interactions involved in the development of human autoimmune disease, a synovial fluid-derived T cell clone reactive with mycobacterial antigens, termed k38, was employed as a stimulus for autologous peripheral blood mononuclear cells (PBMC). Stimulator cells were used either activated with immobilized OKT3 mAb or in a resting state. Activated k38 cells triggered PBMC to proliferate. A T cell line prepared by coculturing autologous PBMC with irradiated activated k38 cells proliferated upon stimulation with activated k38 cells in the presence of PBMC as a source of accessory cells, as did T cell clones that were subsequently isolated from this line. Blocking studies revealed that proliferation of the anti-k38 line and anti-k38 clones in response to stimulation with clone k38 could be inhibited by monoclonal antibodies against a variety of cellular determinants including HLA class I and LFA-1 beta. It was demonstrated that the antigen reactivity of clone k38 was modulated by the presence of anti-k38 clones. These data provide a model for understanding the cellular interactions that may take place in vivo in the evolution of the chronic synovial inflammatory process.

Antibodies, Monoclonal↗
PubMed1993

Effects of inoculation with attenuated autologous T cells in patients with rheumatoid arthritis.

Injection of attenuated autoimmune T cells, T cell vaccination, has been used successfully in the prevention and treatment of experimental animal autoimmune disease. In order to determine whether such a procedure might be applied in rheumatoid arthritis (RA), a phase I study was conducted in thirteen RA patients with a mean disease duration of 12.8 years. All patients received a subcutaneous injection of attenuated autologous T lymphocytes from a CD4 positive clone (n = 4) or line (n = 9) isolated from synovial tissue (n = 3) or synovial fluid (n = 10). No toxic side effects were observed. On the average the patients showed a slight decrease in disease activity which was most marked at 8 weeks after the injection. Specific immune reactivity against the injected T cells was not detected, with the possible exception of one patient who was vaccinated with a clone selected in vitro with antigen and whose disease had begun one year earlier. In this patient a clear decrease in disease activity occurred, which was associated with a decrease in mitogen-induced proliferation of her peripheral blood mononuclear cells and in titres of serum rheumatoid factors. The results of this study show that inoculation of RA patients with autologous T cells is technically feasible and non-toxic, and may be associated with clinical and immunological effects. The data suggest that the potential of T cell vaccination should be further explored in diseases with defined antigen reactivity.

Adult↗
PubMed1992

T-cell receptor beta-chain gene rearrangements of T-cell populations expanded from multiple sites of synovial tissue obtained from a patient with rheumatoid arthritis.

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.

Aged↗
PubMed1991

Lack of T cell oligoclonality in enzyme-digested synovial tissue and in synovial fluid in most patients with rheumatoid arthritis.

The dominant presence of specific T-cell populations in the rheumatoid joint as detected by Southern blot analysis of T cell receptor (TCR) gene rearrangements would indicate local antigen recognition and T cell proliferation. We therefore studied TCR beta chain gene rearrangements using a C beta 2 probe in paired samples of T cell populations from synovial tissue and peripheral blood (n = 6) as well as synovial fluid (n = 16) and peripheral blood (n = 18) of patients with rheumatoid arthritis (RA). Peripheral blood mononuclear cells from healthy donors (n = 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 EcoRI and HindIII to detect rearrangements to C beta 1 and C beta 2, respectively. Extra bands were detected in all EcoRI-digested DNA samples prepared from 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 HindIII-digested 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 T cell 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 in vitro culture techniques on the result of TCR gene rearrangement analysis.

Adult↗