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 potentially life-threatening complication in immune-deficient patients. We have used the severe combined immune deficient (SCID) mouse engrafted with human 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 killer (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-PBL-SCID mouse in the absence of murine NK cells. Lymphocyte depletion experiments 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(+) lymphocytes in vivo. Using HLA tetramers complexed with EBV immunodominant peptides, 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 immune deficiencies that lead to fatal EBV-LPD in the hu-PBL-SCID mouse depleted of murine NK cells, and they point to a critical role for several human cellular subsets in mediating this protective effect.
Baiocchi
R A
RA
Department of Medicine, Division of Hematology/Oncology, The Ohio State University, Columbus, Ohio 43210, USA.
Ward
J S
JS
Carrodeguas
L
L
Eisenbeis
C F
CF
Peng
R
R
Roychowdhury
S
S
Vourganti
S
S
Sekula
T
T
O'Brien
M
M
Moeschberger
M
M
Caligiuri
M A
MA
D000818:Animals; D004195:Disease Models, Animal; D020031:Epstein-Barr Virus Infections / Q000276:immunology / Q000517:prevention & control*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology; D017708:Leukocyte Transfusion; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D016513:Mice, SCID; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D014183:Transplantation, Heterologous
D007376:Interleukin-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor