MONONUCLEAR CELL RETENTION IN RHEUMATOID SYNOVIAL TISSUE ENGRAFTED INSEVERE COMBINED IMMUNODEFICIENT (SCID) MICE IS UP-REGULATED BY TUMOR-NECROSIS-FACTOR-ALPHA (TNF-(ALPHA)) AND MEDIATED THROUGH INTERCELLULAR-ADHESION MOLECULE-1 (ICAM-1)

The aim of this study was to assess regulation of mononuclear cell (MN C) traffic to human synovial tissue by TNF-alpha and IL-I and the invo lvement of ICAM-1 in MNC retention in rheumatoid synovial tissue. Huma n rheumatoid arthritis synovium was engrafted subcutaneously in 6-8-we ek-old SCID/CB17 mice. Three weeks later, we injected 20 x 10(6) human peripheral blood mononuclear cells (PBMC) previously labelled with (1 11)indium intraperitoneally into mice containing control or cytokine-i njected grafts. Total body scintigraphy was performed 72 h postinjecti on. The graft was removed and immunochemical analysis carried out to a ssess ICAM-1, vascular cell adhesion molecule-1 (VCAM-1) and E-selecti n expression. In some experiments, mice were treated intravenously wit h 500 mu g MoAb anti-ICAM-1 (BIRR-1) or an isotype-matched control MoA b before introduction of MNC. TNF-alpha, but not IL-1 alpha, enhanced MNC retention in the rheumatoid synovial graft 72 h post-injection (gr aft activity 989 +/- 1227 ct/min per 200 pixels or 3.36 +/- 4.16% of i nitial injected activity versus 411 +/- 157 ct/min per 200 pixels or 1 .13 +/- 0.45% in controls; P < 0.03). TNF-alpha enhanced ICAM-1 expres sion by synovial cells and endothelial cells, whereas VCAM-1 or E-sele ctin expression was not enhanced on either cell type. After MoAb treat ment of ICAM-1, synovial lymphocyte recruitment of TNF-alpha-treated m ice decreased significantly to levels below that of control mice (160 +/- 97 ct/min per 300 pixels, 0.54 +/- 0.33%; P < 0.01). Mononuclear c ell retention in rheumatoid synovial tissue engrafted into SCID mice w as up-regulated by TNF-alpha and blocked by MoAb to ICAM-1. These resu lts suggest that ICAM-1 is involved in mononuclear cell retention in r heumatoid synovium.