ALTERED LEVELS OF UROKINASE ON MONOCYTES AND IN SERUM OF CHILDREN WITH AIDS - EFFECTS ON LYMPHOCYTE-ACTIVATION AND SURFACE MARKER EXPRESSION

Urokinase (UK) type plasminogen activator is a serine protease produce d by activated human monocytes, Despite the well-documented roles play ed by UK in cell-mediated immunity in healthy humans, the roles played by Uh in the derangements of cell-mediated immune responses observed in HIV disease remain largely undefined, In these studies the numbers of peripheral Mood lymphocytes and monocytes bearing surface UK (UK+) as web as serum levels of UK (flow microfluorimetry and ELISA, respect ively) were determined in children with AIDS and in healthy HIV-negati ve children. The effects of exogenous UK on lymphocyte activation (cel l cycle analysis using Living cells) and surface marker (CD3, CD4, CD8 , and CD19) expression (flow microfluorimetry using fixed cells) were also studied. Data are expressed as percent total cells. Numbers of UK + lymphocytes in children with AIDS were similar to those observed in healthy children. In contrast, numbers of UK+ peripheral blood monocyt es were dramatically decreased (>70%) in the children with AIDS. Howev er, serum levels of UK were increased (nearly threefold) in these chil dren, When lymphocytes from these children were cultured with soluble UK, numbers of cells in S phase of cell cycle appeared suppressed, Inc ubation of fixed lymphocytes from either a child with AIDS or from a h ealthy child with exogenous UK appeared to increase numbers of cells e xpressing CD3, Incubation with UK had no effect on expression of any o ther surface marker (CD4, CD8, or CD19) using cells fi om the child wi th AIDS. In contrast, incubation with UK appeared to decrease (fivefol d) numbers of cells expressing CD19 and increase numbers of cells expr essing CDS and CD8 only when fixed lymphocytes from a healthy HN-negat ive child were used. The results suggest important roles for UK in reg ulation of lymphocyte surface markers in general and in CD3- and CD19- dependent lymphocyte activation pathways specifically. Furthermore, th ese studies add to a widening body of evidence implicating UK. dysregu lation in the pathogenesis of HIV disease and may point to pharmacolog ical opportunities involving Uh to delay or prevent progression of HIV infection into full-blown AIDS.