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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. Here, the authors review the most promising strategies for preventing or treating graft-versus-host disease after allogeneic haematopoietic stem cell transplantation. Approaches that target alloreactive T cells are often favoured, but those that exploit regulatory cell populations are now showing increasing success. 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.

Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD ( n =54, all grades III or IV) or SR-cGVHD ( n =41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1–7) and SR-cGVHD (1–10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3–90.7%, 95% confidence interval (CI)) and 97.4% (92.3–100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.

Microbiome-derived metabolites influence intestinal homeostasis and regulate graft-versus-host disease (GVHD), but the molecular mechanisms remain unknown. Here we show the metabolite sensor G-protein-coupled receptor 43 (GPR43) is important for attenuation of gastrointestinal GVHD in multiple clinically relevant murine models. GPR43 is critical for the protective effects of short-chain fatty acids (SCFAs), butyrate and propionate. Increased severity of GVHD in the absence of GPR43 is not due to baseline differences in the endogenous microbiota of the hosts. We confirm the ability of microbiome-derived metabolites to reduce GVHD by several methods, including co-housing, antibiotic treatment, and administration of exogenous SCFAs. The GVHD protective effect of SCFAs requires GPR43-mediated ERK phosphorylation and activation of the NLRP3 inflammasome in non-hematopoietic target tissues of the host. These data provide insight into mechanisms of microbial metabolite-mediated protection of target tissues from the damage caused allogeneic T cells. The microbial metabolite sensor GPR43 has been previously shown to be a crucial modulator of immune responses. Here the authors show GPR43 is required for controlling disease pathology severity in the context of experimental models of GVHD.

Chatila and colleagues demonstrate a critical role for Notch canonical and non-canonical signaling in controlling peripheral T reg cell function. Receptors of the Notch family direct the differentiation of helper T cell subsets, but their influence on regulatory T cell (T reg cell) responses is obscure. We found here that lineage-specific deletion of components of the Notch pathway enhanced T reg cell–mediated suppression of type 1 helper T cell (T H 1 cell) responses and protected against their T H 1 skewing and apoptosis. In contrast, expression in T reg cells of a gain-of-function transgene encoding the Notch1 intracellular domain resulted in lymphoproliferation, exacerbated T H 1 responses and autoimmunity. Cell-intrinsic canonical Notch signaling impaired T reg cell fitness and promoted the acquisition by T reg cells of a T H 1 cell–like phenotype, whereas non-canonical Notch signaling dependent on the adaptor Rictor activated the kinase AKT–transcription factor Foxo1 axis and impaired the epigenetic stability of Foxp3 . Our findings establish a critical role for Notch signaling in controlling peripheral T reg cell function.

Autonomous artificial intelligence (AI) models for deciding treatment strategies are available but rarely applied prospectively in clinical settings. Here we present a prospective study of deploying daGOAT, an algorithm we have developed, as a conditional autonomous AI agent to prescribe a drug to prevent severe (grade 3−4) acute graft-versus-host disease (acute GvHD) following human leukocyte antigen (HLA)-mismatched haematopoietic cell transplantation (ClinicalTrials.gov, NCT05600855). During the enrollment period physicians invite 85% of eligible patients to participate and 88% of the invited patients agree. Among the 110 enrolled participants who receive HLA-haploidentical transplants, daGOAT predicts intermediate to high risk of severe acute GvHD in 57 participants between days +17 and +23 posttransplant and prescribes ruxolitinib in addition to the existing regimen to intensify immune suppression. The initial compliance with AI prescription is 98% (56/57), with dose and/or schedule deviating from the AI prescription within one month in a total of eight participants. In conclusion, we show that many physicians and patients are receptive to using conditional autonomous AI to prescribe a drug and that the decision for pharmaceutical intervention could be facilitated by autonomous AI. Autonomous artificial intelligence (AI) models to replace human decision-making in medical intervention need thorough testing. Here authors present the results of a clinical trial, NCT05600855, in which daGOAT, a conditional autonomous artificial intelligence agent successfully makes the decision whether to prescribe an immune suppressive drug to prevent severe acute graft-versus-host disease following HLA-mismatched haematopoietic cell transplantation.

Acute graft-versus-host disease (GVHD) is characterized by severe tissue damage that is a life-threatening complication of allogeneic hematopoietic stem cell transplantation. Due to their immunosuppressive properties, mesenchymal stem cells (MSC) have been increasingly examined for the treatment of immune-related diseases. We aimed to assess the immunosuppressive effects of human amnion-derived MSC (AMSC) in a xenogeneic GVHD NOD/Shi-scid IL2rγnull mouse model using human peripheral blood mononuclear cells (PBMC). Additionally, we used human bone marrow-derived MSC (BMSC) as comparative controls to determine differences in immunomodulatory functions depending on the MSC origin. Administration of AMSC significantly prolonged survival, and reduced human tumor necrosis factor-α (TNF-α) concentration and percentage of programmed cell death protein-1 receptor (PD-1) + CD8 + T cell populations compared with in GVHD control mice. Furthermore, colonic inflammation score and percentage of human CD8 + T cell populations in AMSC-treated mice were significantly lower than in GVHD control and BMSC-treated mice. Interestingly, gene expression and protein secretion of the PD-1 ligands were higher in AMSC than in BMSC. These findings are the first to demonstrate that AMSC exhibit marked immunosuppression and delay acute GVHD progression by preventing T cell activation and proliferation via the PD-1 pathway.

Pathogenic CD4 + memory T cells (Tm) sustain chronic inflammation, but mechanisms remain undefined. Here, we identify four donor-type CD4 + Tm subsets in the target tissues of autoimmune-like chronic graft-versus-host disease in mice: Ly108 + CD69 − stem-like memory T cells (Tsm), Ly108 + CD69 + resident memory progenitor T cells (Trmp), Ly108 − CD69 + terminally differentiated tissue-resident T cells (Trm), and Ly108 − CD69 − intermediate T cells (Tint). Trm are terminally differentiated but not exhausted and show highly biased clonotypes with high proinflammatory cytokine expression. Tsm cells require TCR-MHCII interactions for their maintenance and expansion and show greater capacity than Trmp cells in self-renewal/expansion, generation of Trm, and pathogenicity in adoptive recipients. The transcription factors TCF1/BCL6 and BHLHE40 differentially regulate the stemness and differentiation of Tsm into Trm, respectively, and their selective targeting reduces the number of Trm in tissues and ameliorates inflammation. Thus, our findings indicate that targeting the Tsm subset, involved in the maintenance of the pathogenic Tm pool, offers an attractive approach to treat T cell-mediated chronic inflammation. Tissue resident donor CD4 T cells contribute to chronic graft-versus-host disease (GVHD). To date, how these cells are maintained and the mechanism of pathogenesis remain undefined. Here, the authors perform transcriptomics and epigenomic analyses, they analyze memory CD4 T cell heterogeneity and differentiation pathways in tissues of mice with chronic GVHD and propose the selective targeting of stem-like memory T cell stemness or differentiation as a strategy to alleviate chronic tissue inflammation

Graft-versus-host disease (GvHD) remains one of the major complications following allogeneic haematopoietic stem cell transplantation (allo-HSCT). GvHD can occur in almost every tissue, with the skin, liver, and intestines being the mainly affected organs. T cells are implicated in initiating GvHD. T cells identify a broad range of antigens and mediate the immune response through receptors on their surfaces (T cell receptors, TCRs). The composition of TCRs within a T cell population defines the TCR repertoire of an individual, and this repertoire represents exposure to self and non-self proteins. Monitoring the changes in the TCR repertoire using TCR sequencing can provide an indication of the dynamics of a T cell population. Monitoring the frequency and specificities of specific TCR clonotypes longitudinally in different conditions and specimens (peripheral blood, GvHD-affected tissue samples) can provide insights into factors modulating immune reactions following allogeneic transplantation and will help to understand the underlying mechanisms mediating GvHD. This review provides insights into current studies of the TCR repertoire in GvHD and potential future clinical implications of TCR sequencing.