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  • Review Article
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Advances in graft-versus-host disease biology and therapy

Key Points

  • 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.

Abstract

Allogeneic haematopoietic stem cell transplantation is used to treat a variety of disorders, but its efficacy is limited by the occurrence of graft-versus-host disease (GVHD). The past decade has brought impressive advances in our understanding of the role of stimulatory and suppressive elements of the adaptive and innate immune systems from both the donor and the host in GVHD pathogenesis. New insights from basic immunology, preclinical models and clinical studies have led to novel approaches for prevention and treatment. This Review highlights the recent advances in understanding the pathophysiology of GVHD and its treatment, with a focus on manipulations of the immune system that are amenable to clinical application.

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Figure 1: The overall acute GVHD cascade.
Figure 2: Crucial factors in the development of chronic GVHD.
Figure 3: Some of the common pathways in T cell–APC interactions that are targeted by therapeutic interventions using antibodies or small molecules.
Figure 4: A general overview of promising therapies for GVHD.
Figure 5: Potential targets for cellular immunotherapies in GVHD.

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Acknowledgements

We thank the current and past members of our laboratories and our colleagues who have collaborated with us for their scientific contributions, and A. Baptiste for expert technical assistance in the preparation of the manuscript.

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Glossary

Allogeneic haematopoietic stem cell transplantation

A transplant with allogeneic haematopoietic stem cells (HSCs) is a treatment in which the transplanted HSCs are obtained from a normal donor. This approach can be used to treat either malignant or non-malignant disorders. Mismatches between the histocompatibility antigens of the donor and patient can lead to adverse events, such as rejection of the transplanted graft or pathological immune responses to normal tissues in the patient.

Conditioning regimen

(Also known as a preparative regimen). A combination of chemotherapy, radiation therapy and/or immunosuppressive medications that is designed not only to destroy residual malignant cells, but also to provide space for donor stem cell engraftment and to provide immunosuppression to prevent host rejection of the donor stem cells.

Myelosuppressive

Refers to conditioning regimens that abrogate bone marrow activity, resulting in a marked decrease in the production of blood cells and platelets.

Non-myeloablative

Refers to conditioning regimens that do not fully ablate bone marrow activity, resulting in no decrease (or at most a modest decrease) in the production of blood cells and platelets. Such regimens still help with engraftment and prevent the rejection of donor cells.

Graft-versus-tumour effects

(GVT effects). The antitumour activity of donor T cells against residual malignant cells of the graft recipient following (allogeneic) bone marrow transplantation.

Minor histocompatibility antigens

Normal proteins that are polymorphic in a given population. Even when a transplant donor and recipient are identical with respect to their MHC genes, the amino acid differences in minor proteins can cause graft solid-organ tissue to be slowly rejected.

Genetic drift

The process of change in the genetic composition of a population owing to chance or random events rather than natural selection, resulting in changes in allele frequencies over time.

Toll-like receptors

(TLRs). A family of membrane-spanning proteins that recognize pathogen-associated molecular patterns (which are shared by various microorganisms), as well as damaged host cell components. TLRs signal to the host that a microbial pathogen is present or that tissue damage has occurred. They are characterized by an ectodomain that has varying numbers of leucine-rich repeat motifs and a cytoplasmic Toll/IL-1 receptor (TIR) domain that recruits adaptors, such as myeloid differentiation primary-response protein 88 (MYD88) and TIR domain-containing adaptor protein inducing IFNβ (TRIF; also known as TICAM1).

Cytokine storm

An overproduction of pro-inflammatory mediators in a relatively short period of time in response to the stimulation of T cells, NK cells, monocytes and macrophages by pathogens, tissue injury or other immune insults. Typically, a cytokine storm consists of one or more positive feedback loops between cytokines and immune cells.

NOD-like receptors

(NLRs). The human NLR family comprises 22 members. They share a domain organization that usually includes an amino-terminal caspase-recruitment domain (CARD) or pyrin domain (PYD), followed by an intermediary nucleotide-binding oligomerization domain (NOD) and carboxy-terminal leucine-rich repeat motifs. NLRs are thought to survey the host cytosol and intracellular compartments for pathogen- and damage-associated molecular patterns to activate signalling pathways that contribute to the host innate immune response.

P2X7

An ATP-gated cation channel that is expressed by haematopoietic cells and participates in cell proliferation and apoptosis. It belongs to the family of purinoceptors for ATP and is responsible for the ATP-dependent lysis of macrophages through the formation of membrane pores.

Inflammasome

A large multiprotein complex formed by a NOD-like receptor (NLR), the adaptor protein ASC and pro-caspase 1. The assembly of the inflammasome leads to the activation of caspase 1, which cleaves pro-interleukin-1β (pro-IL-1β) and pro-IL-18 to generate the active pro-inflammatory cytokines.

Germinal centre

A highly specialized and dynamic microenvironment located in peripheral lymphoid tissues (for example, the spleen or lymph nodes). It is the main site of B cell maturation, which leads to the generation of memory B cells and plasma cells that produce high-affinity antibodies.

TH1 cells

(T helper 1 cells). TH1 cells secrete interferon-γ and tumour necrosis factor to promote cell-mediated immunity by supporting the classical activation of macrophages and the proliferation of cytotoxic CD8+ T cells.

Janus kinases

(JAKs). Kinases that are activated downstream of cytokine receptor ligation. Activated JAKs phosphorylate various signal transducer and activator of transcription (STAT) molecules, which in turn translocate to the nucleus, where they transactivate various genes involved in cell differentiation, survival, apoptosis and proliferation.

Tolerogenic DCs

A subpopulation of dendritic cells that can promote antigen-specific peripheral and central tolerance by inducing antigen-specific regulatory T cells, T cell anergy and the deletion of antigen-specific cytotoxic T cells.

Mixed lymphocyte reaction

A tissue-culture technique for testing T cell reactivity and antigen-presenting cell (APC) activity. A population of T cells is cultured with MHC-mismatched APCs, and the proliferation of the T cells is determined by measuring the incorporation of 3H-thymidine into the DNA of dividing cells.

Invariant NKT cells

(iNKT cells). A subset of T cells that possess a semi-invariant T cell receptor. In both mice and humans, iNKT cells recognize ligands presented by CD1d.

Indoleamine 2,3-dioxygenase

(IDO). An intracellular haem-containing enzyme that catalyses the oxidative catabolism of tryptophan. Insufficient availability of tryptophan can lead to T cell apoptosis or anergy.

Alternatively activated macrophages

(Also known as M2 macrophages). Macrophages that are stimulated by interleukin-4 (IL-4) or IL-13 and express arginase 1, the mannose receptor CD206 and IL-4 receptor-α. Pathogen-associated molecular patterns expressed by helminths may also drive the alternative activation of macrophages.

Mesenchymal stem cells

(MSCs; also known as marrow stromal cells). Bone marrow-derived multipotent stem cells that can differentiate into various cell types of mesenchymal origin, including osteoblasts, chondrocytes and adipocytes. MSCs have been shown to have immunomodulatory and immunosuppressive effects.

Azacitidine

A pyrimidine nucleoside analogue of cytidine that inhibits DNA methyltransferase, thereby blocking DNA methylation. The hypomethylation of DNA that results from azacitidine treatment may activate an array of genes, such as tumour suppressor genes that have been silenced by hypermethylation, resulting for example in an antitumour effect. Azacitidine is also incorporated into RNA, thereby disrupting normal RNA function and impairing the activity of tRNA (cytosine-5)-methyltransferase.

Extracorporeal photopheresis

A form of photodynamic therapy in which mononuclear cells are separated from blood by leukopheresis and chemically treated with a photosensitizer such as 8-methoxypsoralen, exposed to ultraviolet light, and re-infused into the patient. The mechanism of action has been proposed to involve alloreactive T cell depletion and TReg cell induction.

Statins

A family of inhibitors of hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase), an enzyme that catalyses the conversion of HMG-CoA to L-mevalonate. Statins are mainly used as cholesterol-lowering drugs, but they also have immunoregulatory and anti-inflammatory properties. L-mevalonate and its metabolites are implicated in cholesterol synthesis and other intracellular pathways.

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Blazar, B., Murphy, W. & Abedi, M. Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol 12, 443–458 (2012). https://doi.org/10.1038/nri3212

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