IL-11 separates graft-versus-leukemia effects from graft-versus-host disease after bone marrow transplantation.
We recently showed that IL-11 prevents lethal graft-versus-host disease (GVHD) in a murine bone marrow transplantation (BMT) model of GVHD directed against MHC and minor antigens. In this study, we have investigated whether IL-11 can maintain a graft-versus-leukemia (GVL) effect. Lethally irradiated B6D2F1 mice were transplanted with either T cell-depleted (TCD) bone marrow (BM) alone or with BM and splenic T cells from allogeneic B6 donors. Animals also received host-type P815 mastocytoma cells at the time of BMT. Recipients were injected subcutaneously with recombinant human IL-11 or control diluent twice daily, from 2 days before BMT to 7 days after BMT. TCD recipients all died from leukemia by day 23. All control- and IL-11-treated allogeneic animals effectively rejected their leukemia, but IL-11 also reduced GVHD-related mortality. Examination of the cellular mechanisms of GVL and GVHD in this system showed that IL-11 selectively inhibited CD4-mediated GVHD, while retaining both CD4- and CD8-mediated GVL. In addition, IL-11 treatment did not affect cytolytic effector functions of T cells after BMT either in vivo or in vitro. Studies with perforin-deficient donor T cells demonstrated that the GVL effect was perforin dependent. These data demonstrated that IL-11 can significantly reduce CD4-dependent GVHD without impairing cytolytic function or subsequent GVL activity of CD8(+) T cells. Brief treatment with IL-11 shortly after BMT may therefore represent a novel strategy for separating GVHD and GVL.
Teshima
T
T
Department of Internal Medicine, University of Michigan Cancer Center, Ann Arbor 48109-0942, USA.
Hill
G R
GR
Pan
L
L
Brinson
Y S
YS
van den Brink
M R
MR
Cooke
K R
KR
Ferrara
J L
JL
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology*; D015704:CD4 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D018572:Disease-Free Survival; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy; D020350:Graft vs Tumor Effect / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D017370:Interleukin-11 / Q000502:physiology* / Q000627:therapeutic use; D007942:Leukemia, Experimental / Q000276:immunology / Q000628:therapy; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012513:Sarcoma, Experimental / Q000276:immunology / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology
D015704:CD4 Antigens; D007166:Immunosuppressive Agents; D017370:Interleukin-11; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019014:fas Receptor; D054353:Perforin