title: A radio-resistant perforin-expressing lymphoid population controls allogeneic T cell engraftment, activation, and onset of graft-versus-host disease in mice.
abstract: Immunosuppressive pretransplantation conditioning is essential for donor cell engraftment in allogeneic bone marrow transplantation (BMT). The role of residual postconditioning recipient immunity in determining engraftment is poorly understood. We examined the role of recipient perforin in the kinetics of donor cell engraftment. MHC-mismatched BMT mouse models demonstrated that both the rate and proportion of donor lymphoid cell engraftment and expansion of effector memory donor T cells in both spleen and BM were significantly increased within 5 to 7 days post-BMT in perforin-deficient (pfn(-/-)) recipients, compared with wild-type. In wild-type recipients, depletion of natural killer (NK) cells before BMT enhanced donor lymphoid cell engraftment to that seen in pfn(-/-) recipients. This demonstrated that a perforin-dependent, NK-mediated, host-versus-graft (HVG) effect limits the rate of donor engraftment and T cell activation. Radiation-resistant natural killer T (NKT) cells survived in the BM of lethally irradiated mice and may drive NK cell activation, resulting in the HVG effect. Furthermore, reduced pretransplant irradiation doses in pfn(-/-) recipients permitted long-term donor lymphoid cell engraftment. These findings suggest that suppression of perforin activity or selective depletion of recipient NK cells before BMT could be used to improve donor stem cell engraftment, in turn allowing for the reduction of pretransplant conditioning.
authors.affiliation: ACRF Translational Research Laboratory, The Department of Research, The Royal Melbourne Hospital, Melbourne, Victoria, Australia; Haematology and Immunology Translational Research Laboratory, Cancer Immunology Research Department, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia. Electronic address: Joanne.Davis@mh.org.au.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Davis
authors.affiliation: Haematology and Immunology Translational Research Laboratory, Cancer Immunology Research Department, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Harvey
authors.affiliation: Haematology and Immunology Translational Research Laboratory, Cancer Immunology Research Department, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Gherardin
authors.affiliation: ACRF Translational Research Laboratory, The Department of Research, The Royal Melbourne Hospital, Melbourne, Victoria, Australia; Haematology and Immunology Translational Research Laboratory, Cancer Immunology Research Department, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Rachel
authors.initials: R
authors.lastname: Koldej
authors.affiliation: Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Huntington
authors.affiliation: ACRF Translational Research Laboratory, The Department of Research, The Royal Melbourne Hospital, Melbourne, Victoria, Australia; Haematology and Immunology Translational Research Laboratory, Cancer Immunology Research Department, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Neeson
authors.affiliation: Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
authors.affiliation: ACRF Translational Research Laboratory, The Department of Research, The Royal Melbourne Hospital, Melbourne, Victoria, Australia; Haematology and Immunology Translational Research Laboratory, Cancer Immunology Research Department, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia; Clinical Haematology and Bone Marrow Transplantation Service, Department of Clinical Oncology and Haematology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.
authors.forename: David S
authors.initials: DS
authors.lastname: Ritchie
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D005260:Female; D015870:Gene Expression; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006789:Host vs Graft Reaction / Q000528:radiation effects; D007156:Immunologic Memory; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000528:radiation effects*; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052899:Pore Forming Cytotoxic Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011836:Radiation Tolerance; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D052899:Pore Forming Cytotoxic Proteins; C483886:perforin, mouse
keywords: Bone marrow transplantation; Donor lymphoid cell; Engraftment; Graft-versus-host disease; Natural killer cells; Perforin