Medicine (RMH) - Theses
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ItemManipulation of Natural Killer cells to improve stem cell transplant outcomes( 2019)Allogeneic haematopoietic stem cell transplantation (alloHSCT) is an effective and potentially curative treatment for many haematological malignancies due to its graft-versus-leukemia (GVL) effect. In order to achieve sustained engraftment after donor cell infusion, conditioning regimens before transplantation are required to deplete recipient immune cells. Myeloablative total body irradiation before transplantation is commonly used as an immunosuppressive method to allow recipients achieve donor cell engraftment. However, myeloablative conditioning (MAC) is organ toxic and tissue damage resulting from high dose of irradiation triggers pro-inflammatory cytokine release and inflammation inducing donor T cells activation, expansion then attack of host organs, which is defined as graft-versus-host disease (GVHD), the major complication and contributing factor to treatment-related mortality (TRM) after transplantation. Therefore, to improve prognosis and apply alloHSCT to patients who are not eligible for alloHSCT based on conventional intensive conditioning regimens, reduced intensity conditioning (RIC) was developed in recent years. Researchers have found patients with RIC treatment exhibited reduced TRM, but higher relapse rate compared to the MAC group, and results from experiments on mouse models revealed recipients that received RIC rejected the donor graft. In summary, although RIC has the potential to mitigate GVHD post-transplantation due to reduced toxicity to organs, it is insufficient to ensure sustained engraftment and GVL effect on its own. Previous studies have proven that the GVL effect is intertwined with GVHD, therefore it is a clinical aim to achieve a balance between the two, ensuring engraftment and tumor cell eradication, meanwhile mitigating complications and prolonging survival. RIC is less toxic to organs and has the potential to reduce GVHD but cause graft failure due to insufficient inhibition of the recipient immune system. Our previous study has found that Natural Killer (NK) cells were the primary residual cell population after reduced TBI, and more radio-resistant than CD8+ T cells in recipient mice. Mouse alloHSCT recipients with complete inhibition of NK cell cytotoxic function via perforin knock out exhibited rapid donor cell engraftment but early onset of acute GVHD. Moreover, NK cell adoptive therapy is becoming increasingly utilized as an anti-tumor immunotherapy, in addition to the supplementation of donor T cells in a HSCT scenario. Recent studies demonstrated infusion of donor NK cells is beneficial to promote donor cell engraftment and augment GVL effect while reduce GVHD by inhibiting alloreactive donor T cells and killing recipient APCs. Collectively, although RIC is less toxic to organs and has the potential to reduce GVHD, it is insufficient to deplete recipient immune cells resulting in graft failure after alloHSCT. Manipulation of recipient and donor NK cells combined with RIC using murine models allows us to explore the optimal method to maintain donor cell engraftment with preserved GVL effect and minimal GVHD, which may be further applied to clinical trials. We hypothesized that improved alloHSCT outcomes could be achieved using reduced intensity conditioning (RIC) in combination with pharmacological inhibition of recipient NK cells and introduction of donor NK cells to 1) promote engraftment; 2) reduce GVHD; and 3) exert GVL effect.