Treatment strategy for connective tissue diseases using evaluation of P-glycoprotein on lymphocytes

2007 Fiscal Year Final Research Report Summary

• Project/Area Number: 18591130
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: NAKATUSKA Kiesuki University of Occupational and Environmental Health, Japan, School of Medicine, assistant professor (00291633)
• Co-Investigator(Kenkyū-buntansha): SAITO Kazuyoshi University of Occupational&Environmental Health, School of Medicine, associate professor (30279327) ; TANAKA Yoshiya University of Occupational&Environmental Health, School of Medicine, professor (30248562)
• Project Period (FY): 2006 – 2007
• Keywords: drug resistance / P-glycoprotein / Lymphocytes / 遺伝子発現調節

Research Abstract

The quick judgment of steroid-resistance and immunosuppressants effectiveness is important in the treatment of connective tissue diseases including SLE. P-glycoprotein (P-gp) expression on lymphocytes in according to disease activity induces steroid-resistance. P-gp cut-off value for steroid-unresponsiveness patients (low responders, LR), who satisfied BILAG A2 sections or A 1+B2 sections, was 1000 molecules/cell by ROC analysis. LR with P-gp<1000 molecules/cell had P-gp-high-expressing-subgroup (P-HES) with high levels of CD69. Control of disease activity in LR succeeded by enough intensive immunosuppressive treatments to get both P-gp decrease and P-HES elimination. The measurement of P-gp on lymphocytes could make assess steroid-resistance and could be indicator of treatment strategy in acute phase SLE. P-gp also causes drug-resistance by exclusion of intracellular drugs from peripheral blood lymphocytes (PBL) in RA. P-gp expression levels were correlated with disease activity, increased in activated PBL with high CD69, increased in refractory RA patients with DAS28>5.1 despite taking at least 2 drugs, and significantly higher in corticosteroids (CS) users and MTX non-users. Drug-exclusion via P-gp from PBL was suppressed by P-gp reduction with biological agents and P-gp inhibition with tacrolimus. P-gp overexpression under MTX suggests that present MTX isn't enough to suppress activated PBL, and CS loading enhances treatment resistance. In refractory RA, MTX loading, biological agents and tacrolimus might result in overcoming treatment resistance then in reduction of CS and complications.