Modulation of T-regulatory cells by small molecules: potential therapy for GvHD

Allogeneic haematopoietic stem cell transplantation (alloHSCT) is often curative for patients suffering from blood cancers. Nonetheless, significant morbidity and mortality are still prevalent. One major complication is graft versus host disease (GvHD) which occurs in 30-70% of patients. In this disease donor T-cells recognise the host as foreign and subsequently expand and attack the host’s tissues and organs. T-regulatory cells (Tregs) are a subpopulation of T-cells which promote anti-inflammatory immune responses and suppress T-cell activation and proliferation. It has been demonstrated that a high proportion of Tregs in the donor graft significantly reduce the occurrence of acute GvHD and increases overall survival. However, modern techniques have failed so far to routinely expand Tregs in the clinic due to many reasons including lineage instability and cost. This thesis explores the repurposing of two drugs, Atorvastatin and Vitamin D, which have an excellent safety profile, are cheap and easy to use, to boost Treg numbers and modulate distinct immune cell populations. The drug combination efficiently elevates Treg numbers, inhibits pathogenic CD4+ T-cells and suppresses Tcell proliferation. In addition, it induces a tolerogenic phenotype, at the transcriptional and translational level, in monocyte-derived dendritic cells. Atorvastatin and Vitamin D treatments are a viable approach to boost Treg numbers in the donor as well as combating GvHD in the recipient