SELECTIVE LOSS OF PERIPHERAL-BLOOD CD45RO(-LYMPHOCYTES CORRELATES WITH INCREASED LEVELS OF SERUM CYTOKINES AND ENDOTHELIAL CELL-DERIVED SOLUBLE CELL-ADHESION MOLECULES IN PATIENTS WITH CHRONIC IDIOPATHIC NEUTROPENIA OF ADULTS() T)

The present study was designed to investigate the hypothesis that sele ctive loss of peripheral blood CD45RO(+) T lymphocytes in patients wit h chronic idiopathic neutropenia of adults (CINA), previously reported from our laboratory, may be due to enhanced extravasation into the ti ssues. Serum levels of endothelial cell-derived soluble cell adhesion molecules (sELAM, sICAM and sVCAM), usually used as Indicators of endo thelial cell activation, were measured in 73 CINA patients and 32 heal thy volunteers using a micro-ELISA method. We found that patients had markedly elevated concentrations of all three soluble cell adhesion mo lecules studied compared to the controls, and serum levels of sELAM, s ICAM and, more importantly, sVCAM correlated inversely with the number s of both CD4(+)/CD45RO(+) and CD8(+)/CD45RO(+) T cell subsets. Using a micro-ELISA method, we also measured serum levels of two endothelial cell activators, interleukin (IL)-1 beta and TNF-alpha, and found tha t CINA patients had significantly higher cytokine concentrations than control subjects. Serum levels of IL-1 beta and TNF-alpha correlated p ositively with the values of all three soluble cell adhesion molecules and inversely with the numbers of CD4(+)/CD45RO(+) and CD8(+)/CD45RO( +) T cell subsets. Moreover, we measured serum levels of the chemokine RANTES by a micro-ELISA technique and found that CINA patients also h ad elevated concentrations of the molecule compared to controls. Serum RANTES correlated positively with IL-1 beta, TNF-alpha, sICAM, sVCAM and sELAM and inversely with the numbers of both CD4(+)/CD45RO(+) and CD8(+)/CD45RO(+) T cell subsets. These findings strongly suggest that CINA patients have an activated endothelium to which CD45RA(+) and CD4 5RO(+) T cells tether and roll, but firm adhesion and transendothelial migration are restricted to CD45RO(+) T cell subsets, as endothelial VCAM-1 interacts with the vascular leukocyte adhesion molecule-4 (VLA- 4) constitutively expressed on CD45RO(+) but not on CD45RA(+) T cells. Subsequent subendothelial and tissue migration of CD45RO(+) T cells m ay be facilitated by the chemokine RANTES, which acts mainly on CD45RO (+) T cells. We concluded that selective loss of peripheral blood CD45 RO(+) T lymphocytes in CINA patients is probably due, at least in part , to enhanced extravasation of both CD4(+)/CD45RO(+) and CD8(+)/CD45RO (+) T cell subsets into the tissues.