Therapeutic Strategies to Prevent Graft-Versus-Host Disease

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for blood cancers. The success of allo-HSCT is restricted by the development of deadly graft- versus-host disease (GVHD), in 50% of allo-HSCT recipients. GVHD develops when donor T cells in the transplant (graft) become reactive against the recipient (host), triggering severe inflammatory damage. There are currently are no effective therapies for GVHD. Two key strategies for reducing GVHD are identifying biomarkers in allo-HSCT donors that may predict GVHD and developing therapeutics that target donor T cells. This thesis aimed to identify predictive donor GVHD biomarkers and develop novel therapeutic strategies to prevent GVHD that target reactive donor T cells. Purinergic signalling is an important extracellular signalling network that is implicated in GVHD. Activation of the purinergic ATP-gated P2X7 receptor enhances GVHD in mice. Although P2X7 is present on donor and host cells in allo-HSCT, how donor P2X7 impacts GVHD is unclear. Chapter 3 demonstrates that P2X7 activity on human leukocyte subsets important in GVHD is influenced by gain-of-function (GOF) and loss-of-function (LOF) single nucleotide polymorphisms (SNPs) in the human P2RX7 gene. To determine if donor P2RX7 genotype influenced GVHD, NOD-SCID-IL2Rγⁿᵘˡˡ (NSG) mice were injected with human peripheral blood mononuclear cells (hPBMCs) from GOF or LOF P2RX7 genotype donors. Donor P2RX7 genotype did not impact GVHD severity in humanised NSG mice.