Advances in graft-versus-host disease biology and therapy

The acute and chronic forms of graft-versus-host disease (GVHD) have limited the success of allogeneic haematopoietic stem cell transplantation (HSCT), resulting in high rates of mortality and morbidity.The main focus of treatment approaches for GVHD include: direct targeting of alloreactive T cells and their subsets; inhibition of their function using cytokine-specific antibodies; inhibition of their signalling pathways; and interference with their recruitment and homing to target tissues.The activation of cellular and humoral components of the innate immune system owing to toxicity of the conditioning regimen or in response to certain gut microorganisms can augment acute GVHD. Strategies to decrease the toxicity of the conditioning regimen, manipulate the gut microbiome, control the release of damage-associated and pathogen-associated molecular patterns or inhibit the activity of their immune cell targets may be useful to prevent or treat GVHD.Recent studies have revisited the role of recipient versus donor and haematopoietic versus non-haematopoietic antigen-presenting cells (APCs) in the initiation of GVHD. This work suggests that several cell types may be responsible for alloantigen presentation in GVHD initiation. Therefore, strategies to impair antigen-presentation pathways in all APCs rather than deplete a single cell type may prove to be more effective in eliminating GVHD.Our improved understanding of the role of B cells in acute and particularly chronic GVHD — in conjunction with improved tools for targeting B cells (such as those directed towards B cell receptors or their signalling pathways, B cell cytokine responsiveness and B cell–T cell cooperativity) — will allow the development of novel approaches for future clinical intervention in GVHD.The inhibition of co-stimulatory molecules and their receptors remains a logical approach for the treatment or prevention of GVHD. The role of T cell co-inhibitory pathways, such as the programmed cell death protein 1 (PD1)–PD1 ligand 1 (PDL1) pathway, in GVHD is currently being investigated.Immune regulatory cells — such as natural or induced regulatory T cells, tolerogenic dendritic cells, natural killer (NK) cells, NKT cells and myeloid-derived suppressor cells — can suppress GVHD in preclinical models. Several therapeutic approaches that exploit regulatory cells have already shown efficacy in early-stage clinical trials. Such strategies include: the in vivo infusion of regulatory T cells; the administration of low-dose interleukin-2 or histone deacetylase inhibitors to support the expansion of regulatory T cell populations in vivo; and the use of conditioning regimens that provide a relative increase in regulatory populations.The future basic research and clinical trials in GVHD should specifically focus on approaches that inhibit GVHD while sparing (or even augmenting) graft-versus-tumour effects.