Regulation of human graft versus host disease by innate lymphoidcells

Abstract

Allogeneic haematopoietic stem cell transplant (HSCT) remains the only curative therapy for many malignant and non-malignant diseases. Its use, however, remains limited by the morbidity and mortality caused by graft versus host disease (GVHD). Treatment options, even where successful, often further immunosuppress the recipient and potentially reduce the effectiveness of the transplant.IL-22, a member of the IL-10 family of cytokines, is an exciting potential therapy. Its receptor is found on the key target tissues of graft versus host disease, but not on leucocytes, thereby potentially separating GVHD from the graft versus tumour effect. The role of IL-22 in GVHD, however, remains controversial. Innate lymphoid cells (ILCs), found at many of the body’s barrier surfaces, have been shown to be key producers of IL-22, but knowledge of their function in human GVHD is limited. This project has further explored the role of IL-22 and ILCs in human stem cell transplantation. ILCs were depleted from the peripheral blood by transplant conditioning, and were predominantly of donor origin by Day 28. No difference was demonstrated in ILC recovery betweenpatients who did and did not develop acute GVHD. No evidence was found of IL-22 induction by conditioning therapy, either full or reduced intensity, in the serum or skin, but serum IL-22 concentration was increased in GVHD. In addition,an IL-22 polymorphism study found a greater risk of death from GVHD where the donor had a ‘high IL-22 producer’ genotype.Finally rIL-22 was tested in a skin explant model of GVHD and supraphysiological concentrations of IL-22 reduced the GVHD Grade in 50% of experiments performed.This project has further elucidated the role of ILCs and IL-22 in human GVHD and supports the potential for a therapeutic role for rIL-22 in this context.