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Aberrant Responsiveness to RANTES in Synovial Fluid T Cells from Patients with Rheumatoid Arthritis
NAOKO HISAKAWA, HIROTOSHI TANAKA, OSAMU HOSONO, RIKAKO NISHIJIMA, YOSHIYUKI OHASHI, SEIJI SAITO, KOJI NISHIYA, KOZO HASHIMOTO, and CHIKAO MORIMOTO
ABSTRACT.
Methods. Expression of CCR5 was studied by flow cytometry and immunoblotting. The chemotactic response of T cells to chemokines was studied in cell migration assay. Tyrosine phosphorylation of Crk-associated substrate lymphocyte-type (CasL) was evaluated in immunoprecipitation and immunoblotting. Results. SF T cells showed an increase in the population of CCR5, CXCR4, and CD45RO positive cells and exhibited an increase in chemotactic activity, which was not augmented with RANTES but stromal cell-derived factor-1a. Tyrosine phosphorylation per CasL molecule was markedly enhanced in SF T cells. In H9 cells, tyrosine phosphorylation of not only focal adhesion kinase but also CasL was induced after treatment with RANTES. Downmodulation of CCR5 by RANTES was decreased and recycling of CCR5 was accelerated in SF T cells when compared with peripheral blood (PB) T cells. When CD45RO positive PB T cells were cultured with interleukin 2, blunted responsiveness to RANTES-induced chemotaxis was reproduced as well as spontaneous chemotaxis, increased expression of CCR5, and aberrant receptor dynamics, after RANTES stimulation as observed in SF T cells. Conclusion. Synovial fluid T cells highly positive for CCR5 show aberrant characteristics; resistant to RANTES in terms of migration, but responsive in terms of dynamics of CCR5. (J Rheumatol 2002;29:1124-34) Key Indexing Terms:
RHEUMATOID ARTHRITIS
From the Division of Clinical Immunology, the Advanced Clinical Research Center, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan. Supported in part by the Grant-in-Aid from the Ministry of Health, Labour and Welfare, the Ministry of Education, Culture, Sports, Science and Technology, Japan. N. Hisakawa, MD, Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, the University of Tokyo, and Department of Internal Medicine, Kochi Medical School; H. Tanaka, MD, PhD, Associate Professor; O. Hosono, MD, PhD; R. Nishijima, MS, Research Associate; C. Morimoto, MD, PhD, Professor, Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, the University of Tokyo; S. Saito, MD, PhD, Associate Professor, Department of Orthopedics, Tokyo Women's Medical University, School of Medicine; K. Nishiya, MD, PhD, Associate Professor; K. Hashimoto, MD, PhD, Professor, Second Department of Internal Medicine, Kochi Medical School, Nankoku, Japan; Y. Ohashi, MD, PhD, Research Associate; C. Morimoto, MD, PhD, Professor, Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, the University of Tokyo, and Professor, Department of Tumor Immunology and AIDS Research, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Address reprint requests to Dr. C. Morimoto, Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo Submitted June 14, 2001; revision accepted December 29, 2001. |