© 2017 Yuhao JiaoAllogeneic haematopoietic stem cell transplantation (allo-HSCT) is used to treat a range of haematological malignancies. However, the use of allo-HSCT is limited due to significant toxicity related to conditioning intensity, opportunistic infection, graft failure, and graftversus host disease (GVHD). Standard conditioning regimen including myeloablative total body irradiation (TBI) is considered to be the trigger for pro-inflammatory cytokine release and further induce acute GVHD (aGVHD). To decrease the risk of aGVHD, a reduced intensity conditioning (RIC) regimen was introduced to clinical practice because of its lower toxicity. However, the insufficient suppression of host immune system caused by RIC might lead to higher chances of graft failure. In this case, to identify the risk factors to graft rejection after RIC regimen was crucial. And by targeting the major contributor to graft failure post-transplantation, RIC can be utilised to prevent aGVHD while high donor engraftment can still be achieved. Recipient natural killer (NK) cells were found to be significantly more radio-resistant than other cytotoxic lymphocytes following TBI and thus could be a considerable contributor to acute allograft rejection. MHC-mismatched transplantation allo-BMT mouse models were utilised in this project to determine the extent by which radio-resistant recipient NKs are involved in causing acute allograft rejection. By using wild-type (WT) and the NK cell deficient (Bcl2fl/fl Ncr1-iCre) mice as recipients, donor cells were rapidly rejected in WT recipients with RIC-allo-BMT, whereas Bcl2fl/fl Ncr1-iCre recipients that were irradiated with the RIC 2×400 rad TBI achieved long-term engraftment and lower aGVHD clinical scores. This positive outcome with reduced TBI dose was attributed to lesser donor T cell expansion, lower pro-inflammatory cytokine levels and higher myeloid cell reconstitution in the NK cell deficient recipients, compared to recipients that had undergone transplantation with myeloablative TBI (2×600 rad). These findings clearly indicate that recipient radio-resistant NK cells are the main cause of graft failure and can be targeted to lower conditioning intensity and promote engraftment. Besides the Bcl2fl/fl Ncr1-iCre mouse models, other NK cell deficient or aberrant models were also studied in order to understand further how NK cells can regulate aGVHD and donor engraftment. Using an alternative approach with greater clinical relevance, WT mice administered with the BCL2-inhibitor S63845 and/or the MCL1-inhibitor ABT-199 exhibited similar outcomes as the BCL2- and MCL1-deficient mouse models. Inhibitor treatment prior to allogeneic transplantation with RIC regimen reduced the number of host residual NK cells. And in this case, mice that had the inhibitor treatment and RIC-allo-BMT had reduced risk of graft failure and could also be free from aGVHD. Another key finding of this study, which has significant potential for clinical translation was validation of the therapeutic graft-versus-leukaemia (GVL) effect in the RIC-allo-BMT models. Either genetically modified NK cell deficient mouse RIC-allo-HSCT models or inhibitor treatment mouse RIC-allo-HSCT models were proven to have intact GVL effect. Therefore, the less sufficient anti-neoplastic efficacy of RIC regimen could be compensated by the intact GVL effect. And most importantly, the overall mortality related to leukaemia relapse of the NK cell deficient RIC-allo-BMT models was significantly lower than the WT RIC-allo-BMT models
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