Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial

Kennedy, Glen; Varelias, Antiopi; Vučković, Slavica; Texier, Laëtitia Le; Gartlan, Kate H.; Zhang, Ping; Thomas, Gethin; Anderson, Lisa R.; Boyle, Glen M.; Cloonan, Nicole; Leach, Justine; Sturgeon, Elise; Avery, Judy; Olver, Stuart D.; Lor, Mary; Misra, Ashish; Hutchins, Cheryl; Morton, A. James; Durrant, Simon; Subramoniapillai, Elango; Butler, Jason; Curley, Cameron; MacDonald, Kelli P. A.; Tey, Siok-Keen; Hill, Geoffrey R.

doi:10.1016/s1470-2045(14)71017-4

Cited by 200 publications

(188 citation statements)

References 30 publications

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“…Initially identified with the use of G-CSF in stem cell mobilization of donors and prominent Th17 differentiation (43), IL-17 was shown more recently to result in CSF1-dependent macrophage accumulation in skin and lung, which drives tissue fibrosis (44). We demonstrated recently that, consistent with this, systemic IL-17 levels increase late after clinical BMT, at a time when cGVHD develops (45). It is also clear that T follicular helper (T FH ) cells and IL-21 play important roles in the development of cGVHD via the stimulation of germinal center B cells and alloantibody generation (46).…”

Section: Cytokines and Cgvhdmentioning

confidence: 60%

“…There is an increasing appreciation for the role that Th17 cells play in determining the severity of GVHD (65), with a particular role for IL-6 becoming apparent (66,67). Recently, our group demonstrated the importance of this effect in cohorts in which IL-6 inhibition represents a potentially effective therapeutic strategy to reduce the severity of aGVHD in clinical stem cell transplantation (45). IL-22 may be secreted by Th17 cells and, in this setting, it appears to be pathogenic (68); conversely, it may be secreted by innate lymphoid cells where, in the GI tract at least, it appears to be an important protective cytokine (69).…”

Section: Cytokines and T Cell-differentiation Programsmentioning

confidence: 99%

“…The Journal of Immunologyproduction by flow cytometry have allowed identification of, and will continue to define, the key cytokines in aGVHD (45,79), as well as facilitate clinical translation of findings. However, a number of factors must be considered when extrapolating laboratory observations into clinical cohorts.…”

Section: Translational Applicationmentioning

confidence: 99%

“…Therefore, effective translation will require validation of observations made in animal models with clinical cohorts, because standard immunesuppressing agents were shown to affect cytokine levels produced by T cells and NK cells, and profiles vary with stem cell source (80,81). Importantly, IFN-g, TNF, and IL-1 are not systemically dysregulated in clinical subjects after BMT who receive immune suppression in the same way as seen in rodent models (45). With this in mind, it should be noted that no cytokine-inhibition strategy or cytokine administration has proved efficacious in randomized studies.…”

Section: Translational Applicationmentioning

confidence: 99%

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Cytokines in Graft-versus-Host Disease

Henden

Hill

2015

The Journal of Immunology

153

117

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Graft-versus-host disease (GVHD) is a complication of allogeneic bone marrow transplantation whereby transplanted naive and marrow-derived T cells damage recipient tissue through similar mechanisms to those that allow destruction of malignant cells, the therapeutic intent of bone marrow transplantation. The manifestations and severity of GVHD are highly variable and are influenced by the proportions of naive cells maturing along regulatory T cell, Th1, Th2, or Th17 phenotypes. This maturation is largely influenced by local cytokines, which, in turn, activate transcription factors and drive development toward a dominant phenotype. In addition, proinflammatory cytokines exert direct effects on GVHD target tissues. Our knowledge of the role that cytokines play in orchestrating GVHD is expanding rapidly and parallels other infective and inflammatory conditions in which a predominant T cell signature is causative of pathology. Because a broad spectrum of cytokine therapies is now routinely used in clinical practice, they are increasingly relevant to transplant medicine.

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Section: Cytokines and Cgvhdmentioning

confidence: 60%

Section: Cytokines and T Cell-differentiation Programsmentioning

confidence: 99%

Section: Translational Applicationmentioning

confidence: 99%

Section: Translational Applicationmentioning

confidence: 99%

See 2 more Smart Citations

Cytokines in Graft-versus-Host Disease

Henden

Hill

2015

The Journal of Immunology

153

117

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“…[116] Based on these data, IL-6 inhibition with tocilizumab, an anti-IL-6 receptor monoclonal antibody, has recently been assessed in a phase I-II clinical trial. [96] Adding tocilizumab to standard GVHD prophylaxis after HLA-matched donor alloHSCT resulted in low rate of grade II-IV aGVHD (12%) compared to historical controls.…”

Section: Gene Expression Modulation In T Cells and Other Immune Cellsmentioning

confidence: 97%

Novel approaches for preventing acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Servais

Béguin

Delens

et al. 2016

Expert Opinion on Investigational Drugs

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Introduction: Allogeneic hematopoietic stem cell transplantation (alloHSCT) offers potential curative treatment for a wide range of malignant and nonmalignant hematological disorders. However, its success may be limited by post-transplant acute graft-versus-host disease (aGVHD), a systemic syndrome in which donor's immune cells attack healthy tissues in the immunocompromised host. aGVHD is one of the main causes of morbidity and mortality after alloHSCT. Despite standard GVHD prophylaxis regimens, aGVHD still develops in approximately 40-60% of alloHSCT recipients. Areas covered: In this review, after a brief summary of current knowledge on the pathogenesis of aGVHD, the authors review the current combination of a calcineurin inhibitor with an antimetabolite with or without added anti-thymocyte globulin (ATG) and emerging strategies for GVHD prevention. Expert opinion: A new understanding of the involvement of cytokines, intracellular signaling pathways, epigenetics and immunoregulatory cells in GVHD pathogenesis will lead to new standards for aGVHD prophylaxis allowing better prevention of severe aGVHD without affecting graft-versus-tumor effects.ARTICLE HISTORY

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Multiomics Analysis Identifies SOCS1 as Restraining T Cell Activation and Preventing Graft‐Versus‐Host Disease

Guo

Wang

et al. 2022

Advanced Science

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Graft-versus-host disease (GVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Inflammatory signaling pathways promote T-cell activation and are involved in the pathogenesis of GVHD. Suppressor of cytokine signaling 1 (SOCS1) is a critical negative regulator for several inflammatory cytokines. However, its regulatory role in T-cell activation and GVHD has not been elucidated. Multiomics analysis of the transcriptome and chromatin structure of granulocyte-colony-stimulating-factor (G-CSF)-administered hyporesponsive T cells from healthy donors reveal that G-CSF upregulates SOCS1 by reorganizing the chromatin structure around the SOCS1 locus. Parallel in vitro and in vivo analyses demonstrate that SOCS1 is critical for restraining T cell activation. Loss of Socs1 in T cells exacerbates GVHD pathogenesis and diminishes the protective role of G-CSF in GVHD mouse models. Further analysis shows that SOCS1 inhibits T cell activation not only by inhibiting the colony-stimulating-factor 3 receptor (CSF3R)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, but also by restraining activation of the inflammasome signaling pathway. Moreover, high expression of SOCS1 in T cells from patients correlates with low acute GVHD occurrence after HSCT. Overall, these findings identify that SOCS1 is critical for inhibiting T cell activation and represents a potential target for the attenuation of GVHD.

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Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial

Cited by 200 publications

References 30 publications

Cytokines in Graft-versus-Host Disease

Cytokines in Graft-versus-Host Disease

Novel approaches for preventing acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Multiomics Analysis Identifies SOCS1 as Restraining T Cell Activation and Preventing Graft‐Versus‐Host Disease

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