IL-6 dysregulation originates in dendritic cells and mediates graft-versus-host disease via classical signaling

Wilkinson, A; Chang, Karshing; Kuns, Rachel D.; Henden, Andrea S.; Minnie, Simone A.; Ensbey, Kathleen S.; Clouston, Andrew D.; Zhang, Ping; Koyama, Motoko; Hidalgo, Juan; Rose–John, Stefan; Varelias, Antiopi; Vučković, Slavica; Gartlan, Kate H.; Hill, Geoffrey R.

doi:10.1182/blood.2019000396

Cited by 35 publications

(28 citation statements)

References 73 publications

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“…IL-10, for example, has been shown to mitigate GvHD, 54,70,71 while IL1-β and IL-6 have been shown to enhance GvHD. 56,72 Interestingly, in a purely in vitro study, BEN has been shown to increase IL-10 production by a B-cell cancer line. 73 This makes the cytokine profile following BEN administration an interesting candidate for further investigation of the mechanism by which BEN is reducing GvHD.…”

Section: Discussionmentioning

confidence: 99%

“…Given the critical roles of cytokine milieu 54,55 and host antigen presenting cells [56][57][58] in the pathophysiology of GvHD, we evaluated the effect of each on T-cell phenotype. On day 0, we collected plasma (Supplemental Figure 6a) and isolated splenic pan-DCs (Supplemental Figure 6b-D) from BEN-TBI and CY-TBI conditioned mice.…”

Section: Ben-tbi Conditioning Improves Gvhd Independently Of Donor Tregsmentioning

confidence: 99%

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Bendamustine with total body irradiation conditioning yields tolerant T-cells while preserving T-cell-dependent graft-versus-leukemia

et al. 2020

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Graft-versus-host disease (GvHD) remains a significant impediment to allogeneic hematopoietic cell transplantation (HCT) success, necessitating studies focused on alleviating GvHD, while preserving the graft-versus-leukemia (GvL) effect. Based on our previous studies showing bendamustine with total body irradiation (BEN-TBI) conditioning reduces GvHD compared to the current clinical standard of care cyclophosphamide (CY)-TBI in a murine MHC-mismatched bone marrow transplantation (BMT) model, this study aimed to evaluate the role and fate of donor T-cells following BEN-TBI conditioning. We demonstrate that BEN-TBI reduces GvHD compared to CY-TBI independently of T regulatory cells (Tregs). BEN-TBI conditioned mice have a smaller proportion and less activated donor T-cells, with lower CD47 expression, early post-transplant, but no sustained phenotypic differences in T-cells. In BEN-TBI conditioned mice, donor T-cells gain tolerance specific to host MHC antigens. Though these T-cells are tolerant to host antigens, we demonstrate that BEN-TBI preserves a T-cell-dependent GvL effect. These findings indicate that BEN-TBI conditioning reduces GvHD without compromising GvL, warranting its further investigation as a potentially safer and more efficacious clinical alternative to CY-TBI.

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Section: Discussionmentioning

confidence: 99%

Section: Ben-tbi Conditioning Improves Gvhd Independently Of Donor Tregsmentioning

confidence: 99%

Bendamustine with total body irradiation conditioning yields tolerant T-cells while preserving T-cell-dependent graft-versus-leukemia

et al. 2020

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“…Meanwhile, IL-6Rα can be proteolytically shed and bind to IL-6 as a soluble receptor (sIL-6Rα) and associate with gp130 on target cells in the transsignaling [18]. However, in IL-6 cluster signaling, the IL-6/IL-6Rα complex forms internally in dendritic cells (DCs) and interacts with gp130 expressed on antigen-specific T cells, a pathway which may be relevant to multiple T lymphocyteassociated autoimmune diseases (see Figure 2) [19]. After [22].…”

Section: Interleukin -6mentioning

confidence: 99%

Cytokines that Modulate the Differentiation of Th17 Cells in Autoimmune Uveitis

Guo

Zhang

2021

Journal of Immunology Research

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Increasing evidence has suggested that T helper 17 (Th17) cells play a central role in the pathogenesis of ocular immune disease. The association between pathogenic Th17 cells and the development of uveitis has been confirmed in experimental and clinical studies. Several cytokines affect the initiation and stabilization of the differentiation of Th17 cells. Therefore, understanding the mechanism of related cytokines in the differentiation of Th17 cells is important for exploring the pathogenesis and the potential therapeutic targets of uveitis. This article briefly describes the structures, mechanisms, and targeted drugs of cytokines—including interleukin (IL)-6, transforming growth factor-β1 (TGF-β1), IL-1β, IL-23, IL-27, IL-35, IL-2, IL-4, IL-21, and interferon (IFN)-γ—which have an important influence on the differentiation of Th17 cells and discusses their potential as therapeutic targets for treating autoimmune uveitis.

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“…NK cells were shown to mediate tumor regression in AML patients, eliminate graft rejection and protect patients against GvHD (51,52). The presence of mature antigen-presenting dendritic cells (DCs) has been correlated with improved survival (53)(54)(55)(56). T regulatory (Treg) cells down-modulate T-cell activation through the production of immunosuppressive cytokines (TGFβ, IL-10), as well as through surface receptors (CTLA4), and can drastically impact both the anti-tumor immune response as well as the control of GvHD (57)(58)(59).…”

Section: Monitoring Immune Cell Reconstitutionmentioning

confidence: 99%

Immune Monitoring After Allogeneic Hematopoietic Cell Transplantation: Toward Practical Guidelines and Standardization

2020

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Hematopoietic cell transplantation (HCT) is often a last resort, but potentially curative treatment option for children suffering from hematological malignancies and a variety of non-malignant disorders, such as bone marrow failure, inborn metabolic disease or immune deficiencies. Although efficacy and safety of the HCT procedure has increased significantly over the last decades, the majority of the patients still suffer from severe acute toxicity, viral reactivation, acute or chronic graft-versus-host disease (GvHD) and/or, in case of malignant disease, relapses. Factors influencing HCT outcomes are numerous and versatile. For example, there is variation in the selected graft sources, type of infused cell subsets, cell doses, and the protocols used for conditioning, as well as immune suppression and treatment of adverse events. Moreover, recent pharmacokinetic studies show that medications used in the conditioning regimen (e.g., busulphan, fludarabine, anti-thymocyte globulin) should be dosed patient-specific to achieve optimal exposure in every individual patient. Due to this multitude of variables and site-specific policies/preferences, harmonization between HCT centers is still difficult to achieve. Literature shows that adequate immune recovery post-HCT limits both relapse and non-relapse mortality (death due to viral reactivations and GvHD). Monitoring immune parameters post-HCT may facilitate a timely prediction of outcome. The use of standardized assays to measure immune parameters would facilitate a fast comparison between different strategies tested in different centers or between different clinical trials. We here discuss immune cell markers that may contribute to clinical decision making and may be worth to standardize in multicenter collaborations for future trials.

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IL-6 dysregulation originates in dendritic cells and mediates graft-versus-host disease via classical signaling

Abstract: Key Points DCs are the principal source of IL-6 dysregulation after alloSCT. IL-6–dependent GVHD is driven by classical signaling of IL-6R on donor T cells but is regulated by trans signaling.

Cited by 35 publications

References 73 publications

Bendamustine with total body irradiation conditioning yields tolerant T-cells while preserving T-cell-dependent graft-versus-leukemia

Bendamustine with total body irradiation conditioning yields tolerant T-cells while preserving T-cell-dependent graft-versus-leukemia

Cytokines that Modulate the Differentiation of Th17 Cells in Autoimmune Uveitis

Immune Monitoring After Allogeneic Hematopoietic Cell Transplantation: Toward Practical Guidelines and Standardization

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