A radio-resistant perforin-expressing lymphoid population controls allogeneic T cell engraftment, activation, and onset of graft-versus-host disease in mice

Joanne E Davis; Michael Harvey; Nicholas A Gherardin; Rachel Koldej; Nicholas Huntington; Paul Neeson; Joseph A Trapani; David S Ritchie

doi:10.1016/j.bbmt.2014.11.003

A radio-resistant perforin-expressing lymphoid population controls allogeneic T cell engraftment, activation, and onset of graft-versus-host disease in mice

Biol Blood Marrow Transplant. 2015 Feb;21(2):242-9. doi: 10.1016/j.bbmt.2014.11.003. Epub 2014 Nov 12.

Authors

Joanne E Davis¹, Michael Harvey², Nicholas A Gherardin³, Rachel Koldej⁴, Nicholas Huntington⁵, Paul Neeson⁶, Joseph A Trapani⁷, David S Ritchie⁸

Affiliations

¹ 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.
² Haematology and Immunology Translational Research Laboratory, Cancer Immunology Research Department, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
³ 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.
⁴ 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.
⁵ Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
⁶ 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.
⁷ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
⁸ 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.

PMID: 25459639
DOI: 10.1016/j.bbmt.2014.11.003

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.

Keywords: Bone marrow transplantation; Donor lymphoid cell; Engraftment; Graft-versus-host disease; Natural killer cells; Perforin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Marrow Transplantation*
Female
Gene Expression
Graft Survival*
Graft vs Host Disease / prevention & control*
Host vs Graft Reaction / radiation effects
Immunologic Memory
Killer Cells, Natural / cytology
Killer Cells, Natural / immunology
Killer Cells, Natural / radiation effects*
Lymphocyte Activation
Lymphocyte Depletion
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Pore Forming Cytotoxic Proteins / deficiency
Pore Forming Cytotoxic Proteins / genetics
Pore Forming Cytotoxic Proteins / immunology*
Radiation Tolerance
T-Lymphocytes / cytology
T-Lymphocytes / immunology*
Transplantation, Homologous
Whole-Body Irradiation

Substances

Pore Forming Cytotoxic Proteins
perforin, mouse