Danger Signals and Graft-versus-host Disease: Current Understanding and Future Perspectives

Toubai, Tomomi; Mathewson, Nathan D.; Magenau, John; Reddy, Pavan

doi:10.3389/fimmu.2016.00539

Cited by 77 publications

(76 citation statements)

References 185 publications

(183 reference statements)

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“…Elimination of this species from the mouse flora before allo‐HSCT aggravates GVHD whereas its reintroduction has the opposite effect . Also, under certain conditions, TLR4 activation seems to have a benefic role against the disease . Together, these data show that environmental factors can both positively and negatively influence HSCT outcome.…”

Section: Introductionmentioning

confidence: 87%

Mouse nidovirus LDV infection alleviates graft versus host disease and induces type I IFN-dependent inhibition of dendritic cells and allo-responsive T cells

Gaignage

Marillier

Uyttenhove

et al. 2017

Immunity, Inflammation and Disease

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IntroductionViruses have developed multiple mechanisms to alter immune reactions. In 1969, it was reported that lactate dehydrogenase‐elevating virus (LDV), a single stranded positive sense mouse nidovirus, delays skin allograft rejection and inhibits spleen alterations in graft versus host disease (GVHD). As the underlying mechanisms have remained unresolved and given the need for new therapies of this disease, we reassessed the effects of the virus on GVHD and tried to uncover its mode of action.MethodsGVHD was induced by transfer of parent (B6) spleen cells to non‐infected or LDV‐infected B6D2F1 recipients. In vitro mixed‐lymhocyte culture (MLC) reactions were used to test the effects of the virus on antigen‐presenting cells (APC) and responder T cells.ResultsLDV infection resulted in a threefold increase in survival rate with reduced weight loss and liver inflammation but with the establishment of permanent chimerism that correlated with decreased interleukine (IL)‐27 and interferon (IFN)γ plasma levels. Infected mice showed a transient elimination of splenic CD11b+ and CD8α+ conventional dendritic cells (cDCs) required for allogeneic CD4 and CD8 T cell responses in vitro. This drop of APC numbers was not observed with APCs derived from toll‐like receptor (TLR)7‐deficient mice. A second effect of the virus was a decreased T cell proliferation and IFNγ production during MLC without detectable changes in Foxp3+ regulatory T cell (Tregs) numbers. Both cDC and responder T cell inhibition were type I IFN dependent. Although the suppressive effects were very transient, the GVHD inhibition was long‐lasting.ConclusionA type I IFN‐dependent suppression of DC and T cells just after donor spleen cell transplantation induces permanent chimerism and donor cell implantation in a parent to F1 spleen cell transplantation model. If this procedure can be extended to full allogeneic bone marrow transplantation, it could open new therapeutic perspectives for hematopoietic stem cell transplantation (HSCT).

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Section: Introductionmentioning

confidence: 87%

Mouse nidovirus LDV infection alleviates graft versus host disease and induces type I IFN-dependent inhibition of dendritic cells and allo-responsive T cells

Gaignage

Marillier

Uyttenhove

et al. 2017

Immunity, Inflammation and Disease

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“…However, the effectiveness of allo‐HCT is limited by acute graft versus host disease (GVHD) which is the principal cause of non‐relapse mortality . Conditioning regimens used in allo‐HCT cause host tissue injuries which release “danger signals” that activate host or donor antigen presenting cells (APCs) which in turn present allo‐antigens via major histocompatibility complex (MHC) class I or class II to donor T cells . In addition, activated APCs produce T‐cell stimulating cytokines which further escalate the inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

Microbial metabolites and graft versus host disease

Riwes

Reddy

2018

American Journal of Transplantation

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The health of mammals is a reflection of the diversity and composition of the intestinal microbiota. Alterations in the composition and functions of the intestinal microbiota have been implicated in multiple disease processes. The impact of the microbiota in health and disease is in part a function of the nutrient processing and release of metabolites. Recent studies have uncovered a major role for microbial metabolites in the function of the host immune system by which they influence disease processes such as acute graft versus host disease (GVHD), which is the main complication of allogeneic hematopoietic cell transplantation (allo-HCT). The mechanisms of acute GVHD regulation by the complex microbial community and the metabolites released by them are unclear. In this review we summarize major findings of how microbial metabolites interact with the immune system and discuss how these interactions could impact acute GVHD.

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“…Initial studies of antibiotics to decontaminate the GI tract suggested promising results (91,92), but other studies demonstrated no benefit with broad-spectrum antibiotics. By contrast, a recent analysis demonstrated that broad-spectrum antibiotic use, specifically agents with activity against anaerobes such as imipein intestinal epithelial cells (IECs) and regulates epithelial homeostasis and the gut microbiome (69,76). NLRP6 deficiency improved GVHD, but exacerbated experimental inflammatory bowel disease (76,77).…”

Section: Microbiome and Gi Gvhdmentioning

confidence: 99%

“…Receptors with immunoreceptor tyrosine-based inhibitory motifs (ITIMs) or ITIM-like regions in their intracellular domains regulate DAMP-mediated innate inflammatory responses (65)(66)(67)(68) and belong to the family of sialic acid-binding immunoglobulinlike lectins (Siglecs) (68). Siglec-G expression in host APCs plays an important role in protecting against DAMP-mediated GVHD due to tissue damage following conditioning (69,70). Siglec-G interacts with its ligand CD24, a glycosylphosphatidylinositol-anchored glycoprotein expressed by T cells.…”

Section: R E V I E W S E R I E S : T R a N S P L A N Tat I O Nmentioning

confidence: 99%

Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis

Ferrara¹,

Smith²,

Sheets³

et al. 2017

Journal of Clinical Investigation

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Acute graft-versus-host disease (aGVHD) was noted as a complication of allogeneic bone marrow (BM) transplantation in animal models more than six decades ago (1, 2). The initial descriptions of aGVHD differentiated it from the complications of BM aplasia and focused on the severe consequences of GVHD for lower gastrointestinal (GI) tract function, as manifested by weight loss and profound diarrhea. Subsequent studies clearly identified donor T cells as the critical cells required for the induction of aGVHD (3)(4)(5). aGVHD was shown to predominantly involve the skin, liver, and lower GI tract and, later, the upper GI tract (6). In the absence of approaches to prevent aGVHD, this complication occurs in close to 100% of recipients of allogeneic BM/stem cell transplants (allogeneic hematopoietic cell transplantation, allo-HCT), greatly limiting the survival of the first cohort of patients who underwent allo-HCT. Lower GI tract GVHD: clinical findingsDespite the use of prophylaxis to prevent aGVHD, without rigorous T cell depletion this complication occurs in 30%-70% of patients undergoing allo-HCT (7-9). Standard treatment of aGVHD is the administration of systemic corticosteroids and additional immunosuppressive agents, which, as primary therapy, do not substantially improve patient outcomes (10). Thirty to seventyfive percent of patients who develop aGVHD will have a complete response to corticosteroid therapy (11).The outcome for patients with severe aGVHD (grades III-IV) of the lower GI tract is poor, with 25% overall survival (12). Four risk factors (corticosteroid resistance, age under 18 years at time of transplant, GI tract bleeding, and total bilirubin greater than 3 mg/dl) were found on multivariate analysis to be statistically associated with poor survival; no patients with all 4 factors survived, highlighting the critical need to improve survival for these patients. This Review will focus on recent findings regarding the homeostatic mechanisms of the lower GI tract that relate to the pathophysiology of aGVHD involving the distal small intestine and colon. Immune homeostasis in the GI tractThe immune balance of the human small intestine and colon is complex. There are over 100 trillion bacteria that are critical to the function of the GI tract, and individuals are exposed to a huge number of food-borne antigens on a daily basis. Thus, there must exist dynamic and robust mechanisms that mediate immune responses to pathogenic organisms but that prevent immune responses to normal flora and dietary antigens.Antigen-presenting cells in the GI tract. Specialized hematopoietic antigen-presenting cells (APCs) in the GI tract include multiple subpopulations of dendritic cells (DCs) and macrophages ( Figure 1). DCs in the lamina propria (LP) and Peyer's patch sample luminal antigens and migrate to regional lymph nodes (LNs) to activate immune responses (13,14). Macrophages are sessile and are the most abundant innate immune cells in the intestine; they maintain homeostasis by phagocytosing microorganisms and apop...

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Danger Signals and Graft-versus-host Disease: Current Understanding and Future Perspectives

Cited by 77 publications

References 185 publications

Mouse nidovirus LDV infection alleviates graft versus host disease and induces type I IFN-dependent inhibition of dendritic cells and allo-responsive T cells

Mouse nidovirus LDV infection alleviates graft versus host disease and induces type I IFN-dependent inhibition of dendritic cells and allo-responsive T cells

Microbial metabolites and graft versus host disease

Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis

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