Stem cell transplantation (SCT) is an important curative therapy for those who suffer from blood cancers. The goal of SCT is to re-establish the defective host immune system with donor-derived hematopoietic stem cells and provide the graft-versus-leukaemia effect, in which host malignant cells are targeted by donor lymphocytes due to donor/host genetic disparity. Graft-versus-Host-Disease (GVHD) is an often lethal complication that arises after SCT, which is characterised by donor T-cell-driven damage to healthy host organs due to the same genetic disparities between the graft and recipient tissues.
Cytokines are a large group of important effector molecules that play critical roles in the pathophysiology of GVHD. The skin, liver, lung and gastrointestinal tract are the main target tissues in GVHD, and organ damage is directly related to proinflammatory cytokines such as interleukin (IL)-1, IL-6, interferon (IFN)γ, and tumour-necrosis-factor (TNF). In contrast, cytokines such as IL-10, IFNλ, and transforming-growth-factor-β (TGF-β) have regulatory and protective roles. Interestingly, cytokines such as IL-22 and IL-17 have been found to have opposing effects based on the cellular source and site of secretion.
Intestinal organoids have been key to discovery of the protective functions of IFNλ and IL-22 therapy in gastrointestinal GVHD. A well-defined in vitro platform can help accelerate future drug discovery through high-throughput therapeutic target screening and validation. Hence, we developed an allogeneic T cell and intestinal organoid-based platform to simulate gut GVHD in vitro and study the effect of different immune cells on intestinal organoids and cytokine interactions in this setting. In this model, we show how co-culturing T-cells with intestinal organoids causes tissue damage in an allo-specific manner, mimicking in vivo gut GVHD in an in vitro setting.