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https://hdl.handle.net/2440/121910
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Type: | Journal article |
Title: | Recipient BCL2 inhibition and NK cell ablation form part of a reduced intensity conditioning regime that improves allo-bone marrow transplantation outcomes |
Author: | Jiao, Y. Davis, J.E. Rautela, J. Carrington, E.M. Ludford-Menting, M.J. Goh, W. Delconte, R.B. Souza-Fonseca-Guimaraes, F. Koldej, R. Gray, D. Huang, D. Kile, B.T. Lew, A.M. Ritchie, D.S. Huntington, N.D. |
Citation: | Cell Death and Differentiation, 2019; 26(8):1516-1530 |
Publisher: | Nature Publishing Group |
Issue Date: | 2019 |
ISSN: | 1350-9047 1476-5403 |
Statement of Responsibility: | Yuhao Jiao, Joanne E. Davis, Jai Rautela, Emma M. Carrington, Mandy J. Ludford-Menting ... Benjamin T. Kile ... et al. |
Abstract: | Allogeneic hematopoietic stem cell transplantation (alloSCT) is used to treat over 15,000 patients with acute myeloid leukemia (AML) per year. Donor graft-versus-leukemia (GVL) effect can prevent AML relapse; however, alloSCT is limited by significant toxicity related to conditioning intensity, immunosuppression, opportunistic infections, and graft-versus-host disease (GVHD). Reducing the intensity of conditioning regimens prior to alloSCT has improved their tolerability, but does not alter the pattern of GVHD and has been associated with increased rates of graft rejection and relapse. Here, using a murine pre-clinical model, we describe a novel recipient conditioning approach combining reduced intensity conditioning with either genetic or pharmacological inhibition of NK cell numbers that permits efficient donor engraftment and promotes GVL without inducing GVHD. We show that NK cell-specific deletion of Bcl2 or Mcl1 in mice, or pharmacological inhibition of BCL2 impairs radio-resistant NK cell-mediated rejection of allogeneic engraftment and allows reduction of conditioning intensity below that associated with GVHD priming. The combination of reduced intensity conditioning and NK cell targeting in mice allowed successful donor T cell engraftment and protective immunity against AML while avoiding GVHD. These findings suggest that reduced conditioning in combination with targeted therapies against recipient NK cells may allow the delivery of effective alloSCT against AML while reducing the toxicities associated with more intensive conditioning including GVHD. |
Keywords: | Killer Cells, Natural Animals Mice, Inbred BALB C Mice, Inbred C57BL Humans Mice Sulfonamides Proto-Oncogene Proteins c-bcl-2 Antineoplastic Agents Bone Marrow Transplantation Transplantation, Homologous Administration, Oral Cell Differentiation Structure-Activity Relationship Dose-Response Relationship, Drug HEK293 Cells Bridged Bicyclo Compounds, Heterocyclic |
Rights: | © ADMC Associazione Differenziamento e Morte Cellulare 2018. |
DOI: | 10.1038/s41418-018-0228-y |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1049407 http://purl.org/au-research/grants/nhmrc/1066770 http://purl.org/au-research/grants/nhmrc/1057852 http://purl.org/au-research/grants/nhmrc/1027472 http://purl.org/au-research/grants/nhmrc/1088703 http://purl.org/au-research/grants/nhmrc/10461276 |
Published version: | http://dx.doi.org/10.1038/s41418-018-0228-y |
Appears in Collections: | Aurora harvest 8 Molecular and Biomedical Science publications |
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