Regeneration After Radiation- and Immune-Mediated Tissue Injury Is Not Enhanced by Type III Interferon Signaling

Fischer, Julius; Lin, Chung-Saint; Heidegger, Simon; Wintges, Alexander; Schlapschy, Martin; Beudert, Matthias; Combs, Stephanie E.; Bassermann, Florian; Skerra, Arne; Haas, Tobias; Poeck, Hendrik

doi:10.1016/j.ijrobp.2018.11.038

Cited by 6 publications

(7 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several independent studies have recently found that type I interferon (IFN-I) signaling but not type III interferon (IFN-III) activation can modulate GVHD in mice 4–7 . IFN-I receptor deficient (IFNaR1 −/− ) recipient mice developed more severe GVHD, while treatment of allo-HSCT recipients with recombinant IFN-I ameliorated the course of GVHD 5,6 .…”

Section: Introductionmentioning

confidence: 99%

Type I interferon signaling before hematopoietic stem cell transplantation lowers donor T cell activation via reduced allogenicity of recipient cells

Fischer

Bscheider

Göttert

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

Recent studies highlight immunoregulatory functions of type I interferons (IFN-I) during the pathogenesis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that selective activation of IFN-I pathways including RIG-I/MAVS and cGAS/STING prior to allo-HSCT conditioning therapy can ameliorate the course of GVHD. However, direct effects of IFN-Is on immune cells remain ill characterized. We applied RIG-I agonists (3pRNA) to stimulate IFN-I production in murine models of conditioning therapy with total body irradiation (TBI) and GVHD. Using IFN-I receptor-deficient donor T cells and hematopoietic cells, we found that endogenous and RIG-I-induced IFN-Is do not reduce GVHD by acting on these cell types. However, 3pRNA applied before conditioning therapy reduced the ability of CD11c+ recipient cells to stimulate proliferation and interferon gamma expression of allogeneic T cells. Consistently, RIG-I activation before TBI reduced the proliferation of transplanted allogeneic T-cells. The reduced allogenicity of CD11c+ recipient cells was dependent on IFN-I signaling. Notably, this immunosuppressive function of DCs was restricted to a scenario where tissue damage occurs. Our findings uncover a context (damage by TBI) and IFN-I dependent modulation of T cells by DCs and extend the understanding about the cellular targets of IFN-I during allo-HSCT and GVHD.

show abstract

Section: Introductionmentioning

confidence: 99%

Type I interferon signaling before hematopoietic stem cell transplantation lowers donor T cell activation via reduced allogenicity of recipient cells

Fischer

Bscheider

Göttert

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, our knowledge of IFN-l in GVHD is limited. An initial study found that IFN-l2 did not significantly modulate GVHD mortality in a murine model upon deleting its receptor (Ifnlr1 -/-) or administration of recombinant IFN-l2 (82). Intriguingly, a most recent study revealed that Ifnlr1 deletion led to exaggerated damages in the GI tract and recombinant IFN-l treatment reduced GVHD lethality (83).…”

Section: Type III Ifnsmentioning

confidence: 99%

The Effects of Interferons on Allogeneic T Cell Response in GVHD: The Multifaced Biology and Epigenetic Regulations

2021

View full text Add to dashboard Cite

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. This beneficial effect is derived mainly from graft-versus-leukemia (GVL) effects mediated by alloreactive T cells. However, these alloreactive T cells can also induce graft-versus-host disease (GVHD), a life-threatening complication after allo-HSCT. Significant progress has been made in the dissociation of GVL effects from GVHD by modulating alloreactive T cell immunity. However, many factors may influence alloreactive T cell responses in the host undergoing allo-HSCT, including the interaction of alloreactive T cells with both donor and recipient hematopoietic cells and host non-hematopoietic tissues, cytokines, chemokines and inflammatory mediators. Interferons (IFNs), including type I IFNs and IFN-γ, primarily produced by monocytes, dendritic cells and T cells, play essential roles in regulating alloreactive T cell differentiation and function. Many studies have shown pleiotropic effects of IFNs on allogeneic T cell responses during GVH reaction. Epigenetic mechanisms, such as DNA methylation and histone modifications, are important to regulate IFNs’ production and function during GVHD. In this review, we discuss recent findings from preclinical models and clinical studies that characterize T cell responses regulated by IFNs and epigenetic mechanisms, and further discuss pharmacological approaches that modulate epigenetic effects in the setting of allo-HSCT.

show abstract

“…Both human and murine IECs show a high responsiveness to treatment with type III IFNs. Recently, mice deficient for the IFN type III receptor (IL-28 receptor alpha subunit, IL-28Rα) showed comparable thymic regeneration potential and GVHD development as wildtype mice ( 145 ). In line with these data, IL-28A protein administration did not support recovery from irradiation-induced thymus damage ( 145 ).…”

Section: Role Of Ifns In Gvhdmentioning

confidence: 99%

“…Recently, mice deficient for the IFN type III receptor (IL-28 receptor alpha subunit, IL-28Rα) showed comparable thymic regeneration potential and GVHD development as wildtype mice ( 145 ). In line with these data, IL-28A protein administration did not support recovery from irradiation-induced thymus damage ( 145 ). Nevertheless, single nucleotide polymorphisms in the IFNL4 gene in donors was associated with increased risk of non-relapse mortality in humans ( 146 ).…”

Section: Role Of Ifns In Gvhdmentioning

confidence: 99%

Interfering With Inflammation: Heterogeneous Effects of Interferons in Graft-Versus-Host Disease of the Gastrointestinal Tract and Inflammatory Bowel Disease

2021

View full text Add to dashboard Cite

The intestine can be the target of several immunologically mediated diseases, including graft-versus-host disease (GVHD) and inflammatory bowel disease (IBD). GVHD is a life-threatening complication that occurs after allogeneic hematopoietic stem cell transplantation. Involvement of the gastrointestinal tract is associated with a particularly high mortality. GVHD development starts with the recognition of allo-antigens in the recipient by the donor immune system, which elicits immune-mediated damage of otherwise healthy tissues. IBD describes a group of immunologically mediated chronic inflammatory diseases of the intestine. Several aspects, including genetic predisposition and immune dysregulation, are responsible for the development of IBD, with Crohn’s disease and ulcerative colitis being the two most common variants. GVHD and IBD share multiple key features of their onset and development, including intestinal tissue damage and loss of intestinal barrier function. A further common feature in the pathophysiology of both diseases is the involvement of cytokines such as type I and II interferons (IFNs), amongst others. IFNs are a family of protein mediators produced as a part of the inflammatory response, typically to pathogens or malignant cells. Diverse, and partially paradoxical, effects have been described for IFNs in GVHD and IBD. This review summarizes current knowledge on the role of type I, II and III IFNs, including basic concepts and controversies about their functions in the context of GVHD and IBD. In addition, therapeutic options, research developments and remaining open questions are addressed.

show abstract

Regeneration After Radiation- and Immune-Mediated Tissue Injury Is Not Enhanced by Type III Interferon Signaling

Cited by 6 publications

References 28 publications

Type I interferon signaling before hematopoietic stem cell transplantation lowers donor T cell activation via reduced allogenicity of recipient cells

Type I interferon signaling before hematopoietic stem cell transplantation lowers donor T cell activation via reduced allogenicity of recipient cells

The Effects of Interferons on Allogeneic T Cell Response in GVHD: The Multifaced Biology and Epigenetic Regulations

Interfering With Inflammation: Heterogeneous Effects of Interferons in Graft-Versus-Host Disease of the Gastrointestinal Tract and Inflammatory Bowel Disease

Contact Info

Product

Resources

About