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• W77508032 abstract "Allogeneic stem cell transplantation (SCT) is the therapy of choice, and only curative treatment available, for many haematological malignancies. Haematopoietic stem cells (HSCs) can reconstitute the entire haematopoietic system and this mechanism is harnessed to advantage in SCT. However, this procedure is limited by serious complications such as graft failure and graft-versus-host disease (GVHD). Graft failure can occur as a result of an inadequate number of transplanted HSCs or failure of an adequate number of cells to survive. Therefore, it is important to study HSCs biology in the context of SCT. GVHD occurs when the donor graft recognises the recipient as foreign and mounts an immune response against it. Alloreactive responses parallel to those involved in GVHD can also occur in the natural context of pregnancy-induced microchimerism which is implicated in the predisposition to auto-immune diseases. Thus, understanding the immune regulators of alloreactive responses in GVHD in the context of SCT and pregnancy-induced microchimerism will allow the development of rational therapeutics to improve clinical outcomes. Autophagy is a survival mechanism allowing the recycling of cytoplasmic protein. We investigated the role of autophagy in long-term HSC (LT-HSC) function at homeostasis and during the clinically relevant stress of granulocyte-colony stimulating factor (G-CSF)-induced HSC mobilisation. We demonstrated that autophagy was required for LT-HSC maintenance, function and effective G-CSF-induced HSC mobilisation. These data highlight the clinical importance of this process. Chronic GVHD (cGVHD) is a late complication of SCT which represents an increasing burden in the clinic with limited effective treatments available. cGVHD can occur with or without prior existing acute GVHD (aGVHD) symptoms, however the pathophysiology of cGHVD in these settings is poorly understood. We demonstrated that subclinical aGVHD induces a failure of MHC class II antigen presentation by donor dendritic cells which leads to a failure in regulatory T cell (Treg) development and cGVHD. These data highlight the potential for adoptive Treg therapy as a novel approach to inhibit or reverse cGHVD post allogeneic SCT. The most frequent situation where allogeneic interactions occur is pregnancy. During gestation, maternal cells traffic to the foetus leading to the natural phenomenon of microchimerism. Although their persistence in offspring has been associated with several autoimmune disorders, the precise role of maternal cells in these disorders remains unclear. We showed that the persistence of maternal allogeneic T cells changed the foetal Treg development in mesenteric lymph nodes, leading to early signs of inflammation in the gut. Therefore, we defined a common mechanism for predisposition to auto-immune diseases whereby alloreactive maternal microchimeric T cells indirectly predispose the offspring to autoimmune disease. Thus, strongly alloreactive maternal microchimeric T cells can indirectly predispose the offspring to autoimmune disease. Overall, the data presented in this thesis identifies multiple novel avenues and understanding in the mechanisms of HSCs function in the context of SCT, in the development and treatment of cGVHD and also in the predisposition of autoimmune diseases." @default.
• W77508032 created "2016-06-24" @default.
• W77508032 creator A5036297185 @default.
• W77508032 date "2015-03-06" @default.
• W77508032 modified "2023-09-24" @default.
• W77508032 title "Immune mediators of alloreactive responses in allogeneic stem cell transplantation and in pregnancy-induced microchimerism" @default.
• W77508032 doi "https://doi.org/10.14264/uql.2014.165" @default.
• W77508032 hasPublicationYear "2015" @default.
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