Interleukin 18 preserves a perforin-dependent graft-versus-leukemia effect after allogeneic bone marrow transplantation.
We have recently shown that early administration of interleukin 18 (IL-18) after bone marrow transplantation (BMT) attenuates acute graft-versus-host disease (GVHD) in a lethally irradiated parent into F1 (B6-->B6D2F1) BMT model. In this study, we investigated whether IL-18 can maintain graft-versus-leukemia (GVL) effect in this context. B6D2F1 mice received transplants of T-cell-depleted (TCD) bone marrow (BM) and splenic T cells from either syngeneic (H2(b/d)) or allogeneic B6 (H2(b)) donors. Recipient mice were treated with recombinant murine IL-18 or the control diluent. Initial studies demonstrated that IL-18 treatment did not affect the proliferative responses or the cytolytic effector functions of T cells after BMT. In subsequent experiments, animals also received host-type P815 mastocytoma cells at the time of BMT. All syngeneic BM transplant recipients died from leukemia by day 18. The allogeneic BM transplant recipients effectively rejected their leukemia regardless of treatment and IL-18 significantly reduced GVHD-related mortality. Examination of the cytotoxic mechanisms with perforin-deficient donor T cells demonstrated that perforin is critical for the GVL effect. Taken together these data demonstrate that IL-18 can attenuate acute GVHD without impairing the in vitro cytolytic function or the in vivo GVL activity after allogeneic BMT.
Reddy
Pavan
P
Blood and Marrow Transplantation Program, Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA.
Teshima
Takanori
T
Hildebrandt
Gerhard
G
Duffner
Ulrich
U
Maeda
Yoshinobu
Y
Cooke
Kenneth R
KR
Ferrara
James L M
JL
D000818:Animals; D016026:Bone Marrow Transplantation; D005260:Female; D020544:Graft vs Leukemia Effect / Q000187:drug effects*; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D020382:Interleukin-18 / Q000494:pharmacology / Q000627:therapeutic use*; D034801:Mastocytoma / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D018365:Neoplasm, Residual; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011828:Radiation Chimera; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014184:Transplantation, Homologous
D006183:H-2 Antigens; D020382:Interleukin-18; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011994:Recombinant Proteins; D054353:Perforin