Low-dose interleukin 2 prevents the development of Epstein-Barr virus (EBV)-associated lymphoproliferative disease in scid/scid mice reconstituted i.p. with EBV-seropositive human peripheral blood lymphocytes.
When severe combined immune deficient (SCID) mice undergo i.p. injection with peripheral blood lymphocytes from normal human donors seropositive for EBV, a majority of these mice (hu-PBL-SCID mouse model) subsequently develop a fatal EBV+ lymphoproliferative disease (EBV-LPD) of human B-cell origin. Because T cells normally are critical in the control of EBV infection, we hypothesized that human T-cell dysfunction accounts for EBV-LPD in the hu-PBL-SCID mouse and that systemic administration of T-cell-derived cytokines would reestablish protective immunity against EBV-LPD. We show that the daily s.c. administration of a very low dose (500 international units) of polyethylene glycol-modified recombinant human interleukin 2 (PEG-IL-2) to hu-PBL-SCID mice can prevent the development of fatal EBV-LPD and significantly improves survival (78%), compared with the survival of hu-PBL-SCID mice treated with placebo (20%, P = 0.0008). Additional lymphocyte-depletion experiments showed that mouse natural killer cells and human CD8+ T cells provided cellular immunity necessary for the PEG-IL-2-mediated protective effect, whereas i.p. injection of human peripheral blood lymphocytes depleted of CD4+ T cells had no adverse effect when combined with PEG-IL-2 therapy and may have been beneficial. These data establish that 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 usefulness of this model for evaluating cytokine therapies in EBV-LPD. The use of low-dose IL-2 as a preventative immune therapy has potential application in immunocompromised individuals at high risk for EBV-LPD.
Baiocchi
R A
RA
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263-0001.
Caligiuri
M A
MA
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006566:Herpesviridae Infections / Q000517:prevention & control*; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D007376:Interleukin-2 / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000276:immunology*; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000382:microbiology* / Q000517:prevention & control; D051379:Mice; D016513:Mice, SCID; D011994:Recombinant Proteins; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014412:Tumor Virus Infections / Q000517:prevention & control*
D007376:Interleukin-2; D011994:Recombinant Proteins