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Abstract
Allogeneic stem cell transplantation (allo-SCT) is a curative therapy for life threatening haematologic and non-haematologic malignancies, bone marrow failure, metabolic disorders and immuno-deficiency. Leukaemia patients receive an allo-SCT when chemotherapy has failed to induce or sustain remission. Allo-SCTs provide a potent immunotherapy in which donor T-cells kill residual host cancer cells (i.e Graft-versus-Leukaemia effect). The main impediment to achieving higher rates of successful allo-SCT is Graft-versus-Host Disease (GVHD) that occurs in 50-70% of allo-SCT recipients. GVHD is caused by donor allo-reactive T-cells that destroy host tissues (e.g. skin, liver, gut). Current treatments that act to suppress donor T-cell function mitigate GVHD at the expense of dampening GVL effects and adaptive immune responses. Therefore, novel anti-inflammatory therapeutics that mitigate GVHD without compromising GVL are required to improve the therapeutic benefit of allo-SCT.
Glycogen synthase kinase 3-beta (GSK3β) is a serine-threonine kinase that regulates several cell processes, including cell cycling, haematopoiesis, inflammation and cancerogenesis. GSK3β inhibitors were shown to exhibit anti-inflammatory effects in a number of in vivo models of inflammatory diseases such as asthma and autoimmune encephalomyelitis. Novel small molecules inhibitors of GSK3β are being investigated in pre-clinical and clinical studies targeting inflammatory conditions of the central nervous system (e.g. Alzheimer s disease). The potential of GSK3β inhibition to prevent GVHD has not been investigated.
To investigate the effect of GSK3β inhibition on GVHD, we used a xenogeneic mouse model of GVHD in which NSG mice are engrafted with human PB MNCs. These mice develop a fatal CD4+ T-cell driven GVHD-like syndrome that manifests in several organs. The results presented in this thesis demonstrate that GSK3β inhibition prevents GVHD in a humanized xenograft mouse model. GSK3β inhibition did not compromise stem cell engraftment or multilineage regeneration. Moreover, treatment with the GSK3β inhibitor did not abrogate the anti-tumour activity of donor T-cells.
Analysis of cellular and molecular mechanisms triggered by GSK3β inhibition revealed that GSK3β inhibition acted to suppress T-cell activation and expansion. GSK3β inhibition attenuated production of pro-inflammatory Th1 cytokines (e.g. TNFα, IFNγ), and promoted anti-inflammatory Th2 cytokine production, by activated T-cells. Global gene expression analysis demonstrated that GSK3β inhibition dysregulated critical T-cell-activating signalling pathways.
This research project provides novel pre-clinical data that rationalizes future investigations of GSK3β inhibitors as novel therapeutics for GVHD.