| Co-Investigator(Kenkyū-buntansha) |
OKADA Yosuke University of Occupational & Environmental Health, Japan, School of Medicine, Assistant professor, 医学部, 講師 (80333243)
SAITO Kazuyoshi University of Occupational & Environmental Health, Japan, School of Medicine, Assistant professor, 医学部, 講師 (30279327)
TSUKADA Junichi University of Occupational & Environmental Health, Japan, School of Medicine, Associate professor, 医学部, 助教授 (20227367)
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| Budget Amount *help |
¥13,600,000 (Direct Cost: ¥13,600,000)
Fiscal Year 2003: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2002: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 2001: ¥6,000,000 (Direct Cost: ¥6,000,000)
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| Research Abstract |
Systemic lupus erythematosus (SLE) is a representative autoimmune disease, which is involved in multiple organs such as skin, kidney, central nervous system, lung and so on, and sometimes results in severe prognosis. However, the precise pathological mechanisms of each organ involvement and specific treatments for them remain unclear. We have intensively studied the mechanism of circulating T cell migration into tissues through binding with endothelial cells. Recent progress in the field clarifies certain homing molecules on T cells and endothelial cells could define organ-specific homing of T cells. In this study, we first estimated the molecules on peripheral T cells in SLE patients with skin involvement. T cells, especially Th2 cells and Tc2 cells, of SLE with skin involvement characteristically highly expressed cutaneous lymphocyte-associated antigen (CLA), whereas T cells of SLE without skin lesion possessed marginal amounts of CLA, indicating that CLA might play a role in skin ra
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sh of SLE. Next, we assessed expression of specific gene on endothelial cells purified from skin, bone/bone marrow, lung, kidney, joint, thyroid and brain, using gene chip analyses. Each endothelial cells express very interesting genes and among them, for instance, endothelial cells from synovial membrane highly expressed CD40L, enkephalin, tetranectin, C1-inhibitor, CSF-1, IL-1R, SDF-1 and so on. Based on these chip analyses would warrant further studies in the context of organ-tropism. Finally, we assessed cell surface co-stimulatory molecules on SLE T cells. Interestingly, CD28 was reduced or decreased on active SLE T cells, whereas CD29 was highly up-regulated on them. When CD29 was crosslinked by specific antibodies, T cells were efficiently activated through FAK-tyrosine kinase and CD40L and CD69 were rapidly induced on the cells. Combined with other results, CD29 could play a potent role in SLE T cell activation, in an independent manner on CD28, resulting in organ involvement such as lupus nephritis. Taken together, to clarify the mechanisms of organ-tropic involvement in SLE, as shown in the study, could lead to more specific therapeutic approaches to SLE. Less
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