Exploring the complications of hematopoietic stem cell transplantation : a laboratory and clinical study

Abstract

This thesis is comprised of two parts, both exploring complications of hematopoietic stem cell transplantation. The first part investigated the immunosuppressive mechanisms of human mesenchymal stromal cells (MSCs) in graft versus host disease (GVHD) murine models. MSCs have been documented to possess the capability to suppress proliferation of T lymphocytes which is implicated in acute GVHD, which accounts for around 20% mortality amongst matched sibling and matched unrelated transplants (CIBMTR, 2013). A number of mechanisms have been described using in vitro or in vivo studies either by human MSCs administered to humanized murine models of GVHD or murine MSCs given to GVHD mice. This part involved exploration of the various mechanisms of immunosuppression using human MSCs administered to murine GVHD models and monitoring GVHD clinical score, survival, donor T cell alloreactivity, homing of MSCs to lymphoid organs and target organs of GVHD, and their corresponding histopathologic changes. Elucidation of the role of chemokine receptors and ligands, members of the ephrin family of receptors and ligands, inducible nitric oxide synthase and phosphorylated STAT 5 proteins in the immunosuppressive capacity of MSCs were also studied. This study attempted to form a coherent explanation of these mechanisms spanning clinicopathologically and in terms of the immune response of lymphoid organs and target tissues of acute GVHD. Apart from these, investigation of some of the receptors, ligands and soluble mediators reported to be produced by MSCs and use lymphoid organs and target tissues of GVHD to test these forming a coherent picture of how MSCs exert immunosuppression in GVHD in an in vivo setting were performed.

The second part of this thesis involved retrospective studies on Human Herpes Virus 6 and 7 (HHV-6, HHV-7) and Norovirus infections in paediatric hematopoietic stem cell transplant recipients. Their incidence in a tertiary hospital in Hong Kong, profile of patients affected, predisposing or reactivation risk factors, manifestations and management options were analysed and discussed. These data may provide clinicians recommendations when their patients become infected with these viruses post bone marrow transplantation in the future.