The effect of graft-versus-host disease (GVHD) on transplant outcomes after unrelated cord blood transplantation (UCBT) has not been fully elucidated. We analyzed the impact of acute and chronic GVHD ...on outcomes in adult patients with acute leukemia or myelodysplastic syndrome who underwent their first UCBT (n=2558). The effect of GVHD on outcomes was analyzed after adjusting for other significant variables. The occurrence of GVHD was treated as a time-dependent covariate. The occurrence of grade 1-2 or 3-4 acute GVHD was significantly associated with a lower relapse rate. Grade 3-4 acute GVHD was associated with a higher risk of non-relapse and overall mortality than no acute GVHD, whereas grade 1-2 acute GVHD was associated with a lower risk of non-relapse and overall mortality than no acute GVHD. Limited or extensive chronic GVHD was significantly associated with a lower relapse rate. Limited chronic GVHD was associated with a lower overall and non-relapse mortality than no chronic GVHD. In conclusion, mild acute or chronic GVHD was associated not only with a low risk of relapse but also with a low risk of non-relapse mortality, and provides a survival benefit in UCBT.
Transition metals are required cofactors for many proteins that are critical for life, and their concentration within cells is carefully maintained to avoid both deficiency and toxicity. To defend ...against bacterial pathogens, vertebrate immune proteins sequester metals, in particular zinc, iron, and manganese, as a strategy to limit bacterial acquisition of these necessary nutrients in a process termed “nutritional immunity.” In response, bacteria have evolved elegant strategies to access metals and counteract this host defense. In mammals, metal abundance can drastically shift due to changes in dietary intake or absorption from the intestinal tract, disrupting the balance between host and pathogen in the fight for metals and altering susceptibility to disease. This review describes the current understanding of how dietary metals modulate host-microbe interactions and the subsequent impact on the outcome of disease.
Transition metals are necessary nutrients and key players at the host-pathogen interface. In their review, Lopez and Skaar describe the multi-faceted ways in which dietary metal availability influences bacterial virulence and the host response to infection.
Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for many patients with severe benign and malignant hematologic disorders. The success of allogeneic HSCT is limited by the ...development of transplant-related complications such as acute graft-versus-host disease (GvHD). Early pre-clinical studies suggested that intestinal microflora contribute to the pathogenesis of acute GvHD, and that growth suppression or eradication of intestinal bacteria prevented the development of acute GvHD even in MHC-mismatched transplants. These observations led to the practice of gut decontamination (GD) with oral non-absorbable antibiotics in patients undergoing allogeneic HSCT as a method of acute GvHD prophylaxis. Microbiome studies in the modern sequencing era are beginning to challenge the benefit of this practice. In this review, we provide a historical perspective on the practice of GD and highlight findings from the limited number of clinical trials evaluating the use of GD for acute GvHD prevention in allogeneic HSCT patients. In addition, we examine the role of the gut microbiota in allogeneic HSCT in the context of recent studies linking the microflora to regulation of intestinal immune homeostasis. We discuss the implications of these findings for future strategies to reduce acute GvHD risk by selective manipulation of the microbiota.
Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract is the principal determinant of lethality following allogeneic bone marrow transplantation (BMT). Here, we examined the mechanisms ...that initiate GVHD, including the relevant antigen-presenting cells. MHC class II was expressed on intestinal epithelial cells (IECs) within the ileum at steady state but was absent from the IECs of germ-free mice. IEC-specific deletion of MHC class II prevented the initiation of lethal GVHD in the GI tract. MHC class II expression on IECs was absent from mice deficient in the TLR adaptors MyD88 and TRIF and required IFNγ secretion by lamina propria lymphocytes. IFNγ responses are characteristically driven by IL-12 secretion from myeloid cells. Antibiotic-mediated depletion of the microbiota inhibited IL-12/23p40 production by ileal macrophages. IL-12/23p40 neutralization prevented MHC class II upregulation on IECs and initiation of lethal GVHD in the GI tract. Thus, MHC class II expression by IECs in the ileum initiates lethal GVHD, and blockade of IL-12/23p40 may represent a readily translatable therapeutic strategy.
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•The microbiota influences MHC class II expression on IECs in the ileum•MHC class II expression on IECs requires an IL-12-IFNγ cytokine axis•MHC class II+ IECs present antigen, activate CD4+ T cells, and initiate lethal gut GVHD•IL-12/23p40 neutralization pretransplant prevents the initiation of lethal GVHD
Graft-versus-host disease in the gastrointestinal tract is the principal determinant of lethality following allogeneic bone marrow transplantation. Koyama et al. find that MHC class II-dependent antigen presentation by ileal intestinal epithelial cells (IECs) is critical for the initiation of lethal GVHD in the gut, define the requirements for IEC MHC class II expression, and propose IL-12 neutralization as a therapeutic strategy for GVHD.
Intestinal microbiota disruption is associated with acute gastrointestinal (GI) Graft-versus-Host Disease (GvHD) and poor outcome after allogeneic stem cell transplantation (ASCT). Here, in a ...retrospective analysis of 200 patients undergoing ASCT at the Regensburg University Medical Center, we assessed the relative expression of Paneth cell antimicrobial peptides (AMPs), Human Defensins (HD) 5 and 6 and regenerating islet-derived 3α (Reg3α), in 292 human intestinal biopsies as well as Reg3α serum levels in relation to acute GI GvHD. In the absence of GI GvHD, the relative expression of Paneth cell AMPs was significantly higher in the small intestine (duodenum to ileum) than in the stomach and large intestine (cecum to rectum) for Reg3α (p≤0.001), HD5 (p≤0.002) and HD6 (p≤0.02). Acute stage 2-4 GI GvHD was associated with reduced expression of AMPs in the small intestine (p≤0.01) in comparison to stage 0-1 disease, accompanied by a decrease in Paneth cell count in case of severe acute GI GvHD (p<0.001). The opposite held true for the large intestine as we found stage 2-4 GI GvHD correlated with significantly higher expression of HD5, HD6, and Reg3α compared to mild or no acute GI GvHD (p≤0.002). Severe GI GvHD in both the lower and the upper GI tract also correlated with higher serum concentrations of Reg3α (p = 0.002). As indirect markers of intestinal microbiome diversity low levels of urinary 3-indoxyl sulfate levels were associated with severe stages of acute GI GvHD compared to mild stage or no acute GI GvHD (p = 0.05). In conclusion, acute GI GvHD correlates with intestinal expression of HD5, HD6 and Reg3α as well as Reg3α serum levels and is associated with intestinal dysbiosis.
Fleas are one of the most interesting and fascinating taxa of ectoparasites. All species in this relatively small order are obligatory haematophagous (blood-feeding) parasites of higher vertebrates. ...This book examines how functional, ecological and evolutionary patterns and processes of host-parasite relationships are realized in this particular system. As such it provides an in-depth case study of a host-parasite system, demonstrating how fleas can be used as a model taxon for testing ecological and evolutionary hypotheses. The book moves from basic descriptive aspects, to functional issues and finally to evolutionary explanations. It extracts several general principles that apply equally well to other host-parasite systems, so it appeals not only to flea biologists but also to 'mainstream' parasitologists and ecologists.
Acute graft-versus-host disease (aGVHD) is a common complication of allogeneic hematopoietic stem cell transplantation (alloHCT) and is a major cause of morbidity and mortality. Systemic steroid ...therapy is the first-line treatment for aGVHD, although about half of patients will become refractory to treatment. As the number of patients undergoing alloHCT increases, developing safe and effective treatments for aGVHD will become increasingly important, especially for those whose disease becomes refractory to systemic steroid therapy. This paper reviews current treatment options for patients with steroid-refractory aGVHD and discusses data from recently published clinical studies to outline emerging therapeutic strategies.
Researchers studying animal phenotypes often overlook the potential influence of parasites hiding inside their study organisms. Yet, most wild animals host parasites, which can alter individual ...phenotypes (e.g. morphology, physiology, behaviour).
Infection‐induced phenotypes stem from several nonmutually exclusive mechanisms (i.e. adaptive host defences, infection‐induced debilitation and host manipulation by parasites), driven by parasites and/or hosts.
Changes in host phenotype can impact all levels of biological organization, from cells to communities. The nature and magnitude of these effects can vary depending on the biotic and abiotic environmental factors experienced by hosts and parasites.
This special feature highlights recent insights into the ways parasites alter host phenotypes across a range of systems. Here, we contextualize how each contribution expands our knowledge of the role of parasites in driving individual variation in animal phenotypes.
Looking to the future, we need to better understand how infection‐induced phenotypes fluctuate with natural variation in infection (e.g. infection intensity, coinfection) and whether studies in laboratory‐based environments provide strong proxies for host–parasite interactions in the wild. The time is ripe to acknowledge, critique and discuss the implications of infection on host phenotypes across taxonomic boundaries and biological levels of organization.
Read the free Plain Language Summary for this article on the Journal blog.
Les recherches en biologie animale négligent souvent l'influence potentielle des parasites. Pourtant, la plupart des animaux sauvages ont des parasites qui peuvent modifier les phénotypes dont la morphologie, la physiologie et le comportement.
Les phénotypes induits par l'infection découlent de plusieurs mécanismes non mutuellement exclusifs tels les défenses adaptatives de l'hôte, l'affaiblissement induit par l'infection et la manipulation de l'hôte par les parasites.
Les modifications du phénotype de l'hôte peuvent avoir un impact à tous les niveaux d'organisation biologique. L'ampleur de ces effets peut varier en fonction des facteurs biotiques et abiotiques subis par les hôtes et les parasites dans leur habitat naturel.
Cette édition spéciale met en lumière les connaissances récentes sur la manière dont les parasites modifient les phénotypes de l'hôte dans une gamme de systèmes. Ici, nous contextualisons comment chaque contribution élargit nos connaissances sur le rôle des parasites dans la variation individuelle des phénotypes animaux.
Les études futures devraient viser à mieux comprendre comment les phénotypes induits par l'infection fluctuent avec la variation naturelle de l'infection (par exemple, l'intensité de l'infection et la co‐infection) et si les connaissances acquises lors des études en laboratoire peuvent être transposées dans les systèmes naturels. Nous considérons qu'il est essentiel de discuter des implications de l'infection parasitaire sur les phénotypes de l'hôte à travers les frontières taxonomiques et les niveaux d'organisation biologique.
Read the free Plain Language Summary for this article on the Journal blog.
Graft-versus-host disease (GVHD) is a major barrier to successful allogeneic hematopoietic stem-cell transplantation (HSCT). The chemokine receptor CCR5 appears to play a role in alloreactivity. We ...tested whether CCR5 blockade would be safe and limit GVHD in humans.
We tested the in vitro effect of the CCR5 antagonist maraviroc on lymphocyte function and chemotaxis. We then enrolled 38 high-risk patients in a single-group phase 1 and 2 study of reduced-intensity allogeneic HSCT that combined maraviroc with standard GVHD prophylaxis.
Maraviroc inhibited CCR5 internalization and lymphocyte chemotaxis in vitro without impairing T-cell function or formation of hematopoietic-cell colonies. In 35 patients who could be evaluated, the cumulative incidence rate (±SE) of grade II to IV acute GVHD was low at 14.7±6.2% on day 100 and 23.6±7.4% on day 180. Acute liver and gut GVHD were not observed before day 100 and remained uncommon before day 180, resulting in a low cumulative incidence of grade III or IV GVHD on day 180 (5.9±4.1%). The 1-year rate of death that was not preceded by disease relapse was 11.7±5.6% without excessive rates of relapse or infection. Serum from patients receiving maraviroc prevented CCR5 internalization by CCL5 and blocked T-cell chemotaxis in vitro, providing evidence of antichemotactic activity.
In this study, inhibition of lymphocyte trafficking was a specific and potentially effective new strategy to prevent visceral acute GVHD. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00948753.).
Significance
Hematopoietic cell transplantation is the gold standard treatment for many blood disorders, including blood cancers. Nonetheless, frequent post-transplant complications limit the ...long-term benefit of HCT. Here, we find that circulating cell-free DNA is a highly versatile analyte for monitoring of the most important complications of HCT: Graft-Versus-Host Disease, infection, graft failure and disease relapse. We show that these different therapeutic complications can be informed from a single cell-free DNA sequencing assay followed by disease-specific bioinformatic analyses. This test requires only low coverage DNA sequencing and is compatible with small volumes of blood. Cell-free DNA may improve the care of allogeneic HCT recipients by enabling earlier detection and better prediction of the complex array of complications that occur after HCT.
Allogeneic hematopoietic cell transplantation (HCT) provides effective treatment for hematologic malignancies and immune disorders. Monitoring of posttransplant complications is critical, yet current diagnostic options are limited. Here, we show that cell-free DNA (cfDNA) in blood is a versatile analyte for monitoring of the most important complications that occur after HCT: graft-versus-host disease (GVHD), a frequent immune complication of HCT, infection, relapse of underlying disease, and graft failure. We demonstrate that these therapeutic complications are informed from a single assay, low-coverage bisulfite sequencing of cfDNA, followed by disease-specific bioinformatic analyses. To inform GVHD, we profile cfDNA methylation marks to trace the cfDNA tissues-of-origin and to quantify tissue-specific injury. To inform infection, we implement metagenomic cfDNA profiling. To inform cancer relapse, we implement analyses of tumor-specific genomic aberrations. Finally, to detect graft failure, we quantify the proportion of donor- and recipient-specific cfDNA. We applied this assay to 170 plasma samples collected from 27 HCT recipients at predetermined timepoints before and after allogeneic HCT. We found that the abundance of solid-organ–derived cfDNA in the blood at 1 mo after HCT is predictive of acute GVHD (area under the curve, 0.88). Metagenomic profiling of cfDNA revealed the frequent occurrence of viral reactivation in this patient population. The fraction of donor-specific cfDNA was indicative of relapse and remission, and the fraction of tumor-specific cfDNA was informative of cancer relapse. This proof-of-principle study shows that cfDNA has the potential to improve the care of allogeneic HCT recipients by enabling earlier detection and better prediction of the complex array of complications that occur after HCT.
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