Divergent effects of methotrexate on the clonal growth of T and B lymphocytes and synovial adherent cells from patients with rheumatoid arthritis.
AUTOR(ES)
Nakajima, A
RESUMO
OBJECTIVE: To define the mechanisms whereby methotrexate (MTX) manifests its effects in patients with rheumatoid arthritis. METHODS: T and B cells from peripheral blood and rheumatoid synovial tissues, synovial adherent cells, and the human fibrosarcoma cell line HT1080 and its mutant (defective in an enzyme in the nucleotide salvage pathway) were tested for clonal growth when cultured with MTX. Normal human fibroblasts and those with a deficiency in a salvage pathway were cultured with MTX in the presence or absence of purine and pyrimidine bases. RESULTS: Clonal growth of T and B cells, but not synovial cells, was inhibited by clinically relevant concentrations of MTX. Slowly proliferating fibroblast lines were resistant to MTX, whereas their rapidly proliferating counterparts were not. However, mutant fibroblast lines deficient in a salvage pathway were sensitive to MTX despite slow proliferation. Similarly, while skin fibroblasts were resistant to MTX, germline mutant fibroblasts deficient in a salvage pathway were sensitive to small concentrations of MTX. CONCLUSION: T and B lymphocytes, but not synovial cells, may be the target of MTX in vivo. Resistance to MTX may be associated with slow proliferation and the ability to synthesise nucleotides via salvage pathways. MTX can inhibit proliferation of even slowly growing cells by restricting the supply of nucleotides obtained via a salvage pathway, by removal of purine and pyrimidine bases, or by inducing a deficiency in a salvage pathway. It may be possible to manipulate the therapeutic effect of MTX by adjusting the amounts of purines and pyrimidines available to the cells in vivo.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1010144Documentos Relacionados
- Clonal heterogeneity of synovial fluid T lymphocytes from patients with rheumatoid arthritis.
- Natural killer (NK) cell activity of peripheral blood, synovial fluid, and synovial tissue lymphocytes from patients with rheumatoid arthritis and juvenile rheumatoid arthritis.
- The cytotoxicity of leukocytes and lymphocytes from patients with rheumatoid arthritis for synovial cells.
- Detection of cytokine producing cells in the synovial membrane from patients with rheumatoid arthritis.
- Studies on blood T and B lymphocytes in rheumatoid arthritis.