Type 2 innate lymphoid cells treat and prevent acute gastrointestinal graft-versus-host disease

Bruce, Danny; Stefanski, Heather E.; Vincent, Benjamin G.; Dant, Trisha A.; Reisdorf, Shannon; Bommiasamy, Hemamalini; Serody, David A.; Wilson, Justin E.; McKinnon, Karen P.; Shlomchik, Warren D.; Armistead, Paul M.; Ting, Jenny P.‐Y.; Woosley, John T.; Blazar, Bruce R.; Zaiss, Dietmar M.; McKenzie, Andrew N. J.; Coghill, James M.; Serody, Jonathan S.

doi:10.1172/jci91816

Cited by 89 publications

(125 citation statements)

References 57 publications

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“…In contrast to the persistence of host ILC3s after conditioning therapy, recent work demonstrated that ILC2s in the LP were markedly depleted by both irradiation and cytotoxic chemotherapy and did not recover significantly from donor BM cells (138). Interestingly, ILC2s in the lung were not depleted by either treatment.…”

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: 95%

“…Interestingly, ILC2s in the lung were not depleted by either treatment. The administration of ex vivo-expanded ILC2s markedly diminished aGVHD in the lower GI tract with improvement in survival with infusion on day 0 (preventative) or day 7 (treatment) (138). Infusion of donor ILC2s significantly decreased the generation of proinflammatory donor T cells in the colon and small bowel, which was associated with enhanced numbers of donor myeloid-derived suppressor cells in the lower GI tract.…”

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: 96%

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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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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: 95%

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: 96%

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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“…Therapeutically, restoring the balance of ILCs may alleviate ACD. In a murine model, donor ILC2 infusions reduced the severity of acute graft versus host disease, also a Th1-driven disease (Bruce et al, 2017).…”

Section: Innate Lymphoid Cellsmentioning

confidence: 98%

Shifting Paradigms in Allergic Contact Dermatitis: The Role of Innate Immunity

Brys

Rodriguez-Homs

Suwanpradid

et al. 2020

Journal of Investigative Dermatology

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The role of the innate immune system in allergic contact dermatitis (ACD) has traditionally been confined to the initial antigen sensitization phase. However, more recent findings have shown the role of innate immunity in additional aspects of ACD, including the effector phase of the classic type IV hypersensitivity reaction. As a result, the precise immunologic mechanisms mediating ACD are more complex than previously believed. The aim of this review is to provide insight into recent advances in understanding the role of the innate immune system in the pathogenesis of ACD, including novel mechanistic roles for macrophages, innate lymphoid cells, natural killer cells, innate gd T cells, and other signaling molecules. These insights provide new opportunities for therapeutic intervention in ACD.

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“…The adoptive transfer of mST2 + cells such as Tregs, IL-9expressing T cells, and innate lymphoid cells showed the same effect. This is currently being evaluated in clinical trials (111,112).…”

Section: Pathogenic and Druggable Biomarkersmentioning

confidence: 99%

Biomarkers for Allogeneic HCT Outcomes

et al. 2020

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Allogeneic hematopoietic cell transplantation (HCT) remains the only curative therapy for many hematological malignant and non-malignant disorders. However, key obstacles to the success of HCT include graft-versus-host disease (GVHD) and disease relapse due to absence of graft-versus-tumor (GVT) effect. Over the last decade, advances in "omics" technologies and systems biology analysis, have allowed for the discovery and validation of blood biomarkers that can be used as diagnostic test and prognostic test (that risk-stratify patients before disease occurrence) for acute and chronic GVHD and recently GVT. There are also predictive biomarkers that categorize patients based on their likely to respond to therapy. Newer mathematical analysis such as machine learning is able to identify different predictors of GVHD using clinical characteristics pre-transplant and possibly in the future combined with other biomarkers. Biomarkers are not only useful to identify patients with higher risk of disease progression, but also help guide treatment decisions and/or provide a basis for specific therapeutic interventions. This review summarizes biomarkers definition, omics technologies, acute, chronic GVHD and GVT biomarkers currently used in clinic or with potential as targets for existing or new drugs focusing on novel published work.

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Type 2 innate lymphoid cells treat and prevent acute gastrointestinal graft-versus-host disease

Cited by 89 publications

References 57 publications

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

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

Shifting Paradigms in Allergic Contact Dermatitis: The Role of Innate Immunity

Biomarkers for Allogeneic HCT Outcomes

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