LOW-DOSE INTERLEUKIN-2 PREVENTS THE DEVELOPMENT OF EPSTEIN-BARR-VIRUS(EBV)-ASSOCIATED LYMPHOPROLIFERATIVE DISEASE IN SCID SCID MICE RECONSTITUTED IP WITH EBV-SEROPOSITIVE HUMAN PERIPHERAL-BLOOD LYMPHOCYTES/

When severe combined immune deficient (SCID) mice undergo i.p. injecti on with peripheral blood lymphocytes from normal human donors seroposi tive for EBV, a majority of these mice (hu-PBL-SCID mouse model) subse quently develop a fatal EBV(+) lymphoproliferative disease (EBV-LPD) o f human B-cell origin. Because T cells normally are critical in the co ntrol of EBV infection, we hypothesized that human T-cell dysfunction accounts for EBV-LPD in the hu-PBL-SCID mouse and that systemic admini stration of T-cell-derived cytokines would reestablish protective immu nity against EBV-LPD. We show that the daily s.c. administration of a very low dose (500 international units) of polyethylene glycol-modifie d recombinant human interleukin 2 (PEG-IL-2) to hu-PBL-SCID mice can p revent the development of fatal EBV-LPD and significantly improves sur vival (78%), compared with the survival of hu-PBL-SCID mice treated wi th placebo (20%, P = 0.0008). Additional lymphocyte-depletion experime nts showed that mouse natural killer cells and human CD8(+) T cells pr ovided cellular immunity necessary for the PEG-IL-2-mediated protectiv e effect, whereas i.p. injection of human peripheral blood lymphocytes depleted of CD4(+) T cells had no adverse effect when combined with P EG-IL-2 therapy and may have been beneficial. These data establish tha t very low-dose PEG-IL-2 therapy can overcome the immune deficiencies that lead to EBV-LPD in the hu-PBL-SCID mouse and point to the usefuln ess of this model for evaluating cytokine therapies in EBV-LPD. The us e of low-dose IL-2 as a preventative immune therapy has potential appl ication in immunocompromised individuals at high risk for EBV-LPD.