GVHD-associated, inflammasome-mediated loss of function in adoptively transferred myeloid-derived suppressor cells

Koehn, Brent H.; Apostolova, Petya; Haverkamp, Jessica M.; Miller, Jeffrey S.; McCullar, Valarie; Tolar, Jakub; Munn, David H.; Murphy, William J.; Brickey, W. June; Serody, Jonathan S.; Gabrilovich, Dmitry I.; Bronte, Vincenzo; Murray, Peter J.; Ting, Jenny P.‐Y.; Zeiser, Robert; Blazar, Bruce R.

doi:10.1182/blood-2015-03-634691

Cited by 103 publications

(103 citation statements)

References 43 publications

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“…Preliminary investigations showed that neutrophilic MDSCs reach lungs of mice within 24 h after lateral tail vein injection (data not shown). It is further known from previous studies that adoptively transferred MDSCs can be recovered from splenocytes 5 days post-injection (Koehn et al, 2015), yet studies focusing on the kinetics and dynamics of adoptively transferred MDSCs in the pulmonary compartment are lacking to the best of our current knowledge; (vi) Our adoptive transfer study lacks further in-depth read-outs, such as lung inflammation parameters, amounts, and characteristics of parenchymal T-cells or kinetics on pathogen clearance. Since our MDSC adoptive transfer studies did not reveal any impact of MDSCs on morbidity, we did restrict our read-outs to the minimum.…”

Section: Discussionmentioning

confidence: 91%

“…The underlying mechanism requires further investigation, particularly given the complex role of Cftr deficiency in driving a hyper-inflammatory micromilieu (Corvol et al, 2003; Livraghi-Butrico et al, 2012) associated with MDSC induction (Rieber et al, 2013; Ballbach et al, 2016). A possible explanation for the diminished suppressive activity of Cftr −/− neutrophilic MDSCs could be a scenario where MDSCs may lose their suppressive function via inflammasome activity, as discussed by Koehn et al (2015). …”

Section: Discussionmentioning

confidence: 99%

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Pseudomonas aeruginosa Airway Infection Recruits and Modulates Neutrophilic Myeloid-Derived Suppressor Cells

Öz

Zhou

Voß

et al. 2016

Front. Cell. Infect. Microbiol.

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Pseudomonas aeruginosa is an opportunistic pathogen that causes infections mainly in patients with cystic fibrosis (CF) lung disease. Despite innate and adaptive immune responses upon infection, P. aeruginosa is capable of efficiently escaping host defenses, but the underlying immune mechanisms remain poorly understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells that are functionally characterized by their potential to suppress T- and natural killer (NK)-cell responses. Here we demonstrate, using an airway in vivo infection model, that P. aeruginosa recruits and activates neutrophilic MDSCs, which functionally suppress T-cell responses. We further show that the CF gene defect (CF transmembrane conductance regulator, CFTR) modulates the functionality, but not the recruitment or generation of neutrophilic MDSCs. Collectively, we define a mechanism by which P. aeruginosa airway infection undermines host immunity by modulating neutrophilic MDSCs in vivo.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa Airway Infection Recruits and Modulates Neutrophilic Myeloid-Derived Suppressor Cells

Öz

Zhou

Voß

et al. 2016

Front. Cell. Infect. Microbiol.

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“…Assembly of inflammasome complexes containing the adapter protein ASC (apoptosis-associated speck-like protein containing C-terminal caspase recruitment domain [CARD]) and Caspase I regulates antigen presentation and migratory capacity of DCs and lymphocytes respectively (64), causing loss of myeloid-derived suppressor cell function during acute GVHD induction (65, 66). Inflammasomes also catalyze production of active IL-1β and IL-18 from their pro-forms.…”

Section: A Three Phase Model For Chronic Gvhd Biologymentioning

confidence: 99%

The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease

Cooke

Luznik

Sarantopoulos

et al. 2017

Biology of Blood and Marrow Transplantation

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352

322

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Summary Chronic graft-versus-host disease (GVHD) is the leading cause of late, non-relapse, mortality and disability in allogeneic hematopoietic cell transplantation (HCT) patients and a major obstacle to improving outcomes. Chronic GVHD biology remains enigmatic, but understanding the underpinnings of the immunologic mechanisms responsible for the initiation and progression of disease is fundamental to developing effective prevention and treatment strategies. The goals of this task force review are as follows: Summarize the current “state-of-the-science” regarding pathogenic mechanisms of chronic GVHD and critical knowledge gaps.Develop working hypotheses/overriding concepts for chronic GVHD development.Define the usefulness of current preclinical models to test working hypotheses and ultimately discover and develop new therapeutic strategies.Identify shortcomings of preclinical models, and define criteria for the creation of additional models to address these limitations. This document is intended as a review of our understanding of chronic GVHD biology and therapies resulting from preclinical studies, and as a platform for developing innovative clinical strategies to prevent and treat chronic GVHD.

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“…Conditioning therapy leads to loss of ILC2s and diminished antiinflammatory properties in the GI tract with impaired barrier repair. Finally, all of these processes alter (161)(162)(163) Reduces number/function of proinflammatory donor T cells Ex vivo administration of MDSCs Donor/third-party Tregs (164)(165)(166)(167) Enhances number of Tregs in the GI tract Ex vivo administration of donor/third-party Tregs Donor/third-party MSCs (168,169) Induces APC production of IL-10 and prostaglandin E 2 and decreases proinflammatory T cells…”

Section: Discussionmentioning

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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GVHD-associated, inflammasome-mediated loss of function in adoptively transferred myeloid-derived suppressor cells

Abstract: Key Points MDSCs are potent suppressors of alloimmune responses; however, efficacy is limited in the context of acute GVHD due to inflammasome induction.

Cited by 103 publications

References 43 publications

Pseudomonas aeruginosa Airway Infection Recruits and Modulates Neutrophilic Myeloid-Derived Suppressor Cells

Pseudomonas aeruginosa Airway Infection Recruits and Modulates Neutrophilic Myeloid-Derived Suppressor Cells

The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease

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

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