Cellular and pharmacological modulation of T-cell alloreactivity for the prevention of graft-versus-host disease

Allogeneic hematopoietic stem cell transplantation is a common therapeutic option for treating many malignant hematological diseases. Its efficacy is partly mediated by the destruction of the recipient’s cancer cells by donor T lymphocytes present in the graft, through graft-versus-tumor (GVT) effects. However, donor T cells can also target healthy tissues, causing graft-versus-host disease (GVHD), one of the major complications of allogeneic transplantation.
A primary focus of research is to limit T-cell alloreactivity to prevent GVHD, while preserving the GVT effects that are essential to sustain cancer remission.
In this thesis project, we evaluated two strategies for modulating donor T-cell alloreactivity. First, we used TNF-α to enhance the immunoregulatory function of regulatory T cells and investigated the ability of manipulated Tregs to prevent GVHD in a humanized mouse model. Second, we assessed the impact of an inhibitor of the NF-κB-inducing kinase (NIK), an enzyme involved in the non-canonical NF-κB signaling pathway. As NIK was shown to be involved in GVHD pathogenesis, we evaluated the NIK inhibitor SMI1 (Genentech) in a humanized mouse model of GVHD.