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Intestinal glucocorticoid-refractory (SR) acute (a) graft-versus-host disease (GVHD) causes high non-relapse mortality (NRM) in patients after allogeneic hematopoietic cell transplantation (allo-HCT). Recent preclinical data indicate that acute GVHD causes a loss of intestinal neuroendocrine L-cells leading to reduced levels of glucagon-like peptide-2 (GLP-2). GLP-2 substitution improved GVHD severity and increased Paneth cells and intestinal stem cells in mice. This motivated us to treat patients with refractory intestinal aGHVD using the GLP-2-analogon teduglutide. In this retrospective multicenter survey, 17 patients received teduglutide as salvage-therapy for SR-intestinal aGVHD. The best response (CR or PR) at any time point during and after treatment was 64.7% (11/17) including 41.2% (7/17) CR and 23.5% (4/17) PR. At a median follow-up of 28 weeks after teduglutide 10/17 patients are alive. Most patients experienced an increase of the albumin serum level within 2 months after the first teduglutide dose, including patients who clinically did not respond to teduglutide treatment. No specific teduglutide-related toxicity was observed. Our retrospective analysis suggests that teduglutide is safe and has activity in a fraction of patients with intestinal SR-aGVHD, which needs validation in a prospective trial.

When acute GVHD is refractory to glucocorticoids, no consensus exists on the best therapy. In a phase 3, randomized trial, ruxolitinib led to a response in 62% of patients at day 28 and in 40% at day 56, as compared with 39% at day 28 and 22% at day 56 with the investigator’s choice of therapy.

In the past 65 years, over 25 000 referenced articles have been published on graft-versus-host disease (GVHD). Although this included clinically orientated papers or publications on chronic GVHD, the conservative estimate of scientific publications still contains several thousands of documents on the pathophysiology of acute GVHD. Thus, summarizing what we believe are prominent publications that can be considered milestones in our knowledge of this disease is a challenging and inherently biased task. Here we review from a historical perspective what can be regarded as publications that have made the field move forward. We also included several references of reviews on aspects we could not cover in detail.

Charles Chiu and colleagues analyze the gut viromes of recipients of hematopoietic stem cell transplantation and identify characteristics associated with the severity of graft-versus-host disease in the gut. Much attention has been focused on the role of the bacterial microbiome in human health, but the virome is understudied. Although previously investigated in individuals with inflammatory bowel diseases or solid-organ transplants 1 , 2 , virome dynamics in allogeneic hematopoietic stem cell transplantation (HSCT) and enteric graft-versus-host disease (GVHD) remain unexplored. Here we characterize the longitudinal gut virome in 44 recipients of HSCT using metagenomics. A viral 'bloom' was identified, and significant increases were demonstrated in the overall proportion of vertebrate viral sequences following transplantation ( P = 0.02). Increases in both the rates of detection ( P < 0.0001) and number of sequences ( P = 0.047) of persistent DNA viruses (anelloviruses, herpesviruses, papillomaviruses and polyomaviruses) over time were observed in individuals with enteric GVHD relative to those without, a finding accompanied by a reduced phage richness ( P = 0.01). Picobirnaviruses were detected in 18 individuals (40.9%), more frequently before or within a week after transplant than at later time points ( P = 0.008). In a time-dependent Cox proportional-hazards model, picobirnaviruses were predictive of the occurrence of severe enteric GVHD (hazard ratio, 2.66; 95% confidence interval (CI) = 1.46–4.86; P = 0.001), and correlated with higher fecal levels of two GVHD severity markers, calprotectin and α1-antitrypsin. These results reveal a progressive expansion of vertebrate viral infections over time following HSCT, and they suggest an unexpected association of picobirnaviruses with early post-transplant GVHD.

As a result of impressive increases in our knowledge of rodent and human immunology, the understanding of the pathophysiologic mechanisms underlying graft-versus-host disease (GVHD) has dramatically improved in the past 15 years. Despite improved knowledge, translation to clinical care has not proceeded rapidly, and results from experimental models have been inconsistent in their ability to predict the clinical utility of new therapeutic agents. In parallel, new tools in immunology have allowed in-depth analyses of the human system and have recently been applied in the field of clinical GVHD. Notwithstanding these advances, there is a relative paucity of mechanistic insights into human translational research, and this remains an area of high unmet need. Here we review selected recent advances in both preclinical experimental transplantation and translational human studies, including new insights into human immunology, the microbiome, and regenerative medicine. We focus on the fact that both approaches can interactively improve our understanding of both acute and chronic GVHD biology and open the door to improved therapeutics and successes.

This collaborative initiative aimed to provide recommendations on the use of polyclonal antithymocyte globulin (ATG) or anti-T lymphocyte globulin (ATLG) for the prevention of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). A comprehensive review of articles released up to October, 2018 was performed as a source of scientific evidence. Fourteen clinically relevant key questions to the domains indication, administration, and post-transplant management were developed and recommendations were produced using the Delphi technique involving a Panel of 14 experts. ATG/ATLG was strongly recommended as part of myeloablative conditioning regimen prior to matched or mismatched unrelated bone marrow or peripheral blood allogeneic HSCT in malignant diseases to prevent severe acute and chronic GvHD. ATG/ATLG was also recommended prior to HLA-identical sibling peripheral HSCT with good but lesser bulk of evidence. In reduced intensity or nonmyeloablative conditioning regimens, ATG/ATLG was deemed appropriate to reduce the incidence of acute and chronic GvHD, but a higher risk of relapse should be taken into account. Recommendations regarding dose, application, and premedication were also provided as well as post-transplant infectious prophylaxis and vaccination. Overall, these recommendations can be used for a proper and safe application of polyclonal ATG/ATLG to prevent GvHD after allogeneic HSCT.