GM-CSF and IL-2 induce specific cellular immunity and provide protection against Epstein-Barr virus lymphoproliferative disorder

Epstein-Barr virus-associated lymphoproliferative disease (EBV-LPD) is a po tentially life-threatening complication in immune-deficient patients. We ha ve used the severe combined immune deficient (SCID) mouse engrafted with hu man leukocytes (hu-PBL-SCID) to evaluate the use of human cytokines in the prevention of EBV-LPD in vivo. Daily low-dose IL-2 therapy can prevent EBV- LPD in the hu-PBL-SCID mouse, but protection is lost if murine natural kill er (NK) cells are depleted. Here we demonstrate that combined therapy with human GM-CSF and low-dose IL-2 is capable of preventing EBV-LPD in the hu-P BL-SCID mouse in the absence of murine NK cells. Lymphocyte depletion exper iments showed that human NK cells, CD8(+) T cells, and monocytes were each required for the protective effects of GM-CSF and IL-2 combination therapy. This treatment resulted in a marked expansion of human CD3(+)CD8(+) lympho cytes in vivo. Using HLA tetramers complexed with EBV immunodominant peptid es, a subset of these lymphocytes was found to be EBV-specific. These data establish that combined GM-CSF and low-dose IL-2 therapy can prevent the im mune deficiencies that lead to fatal EBV-LPD in the hu-PBL-SCID mouse deple ted of murine NK cells, and they point to a critical role for several human cellular subsets in mediating this protective effect.