Altered Effector CD4+ T Cell Function in IL-21R−/− CD4+ T Cell-Mediated Graft-Versus-Host Disease

Oh, Iekuni; Ozaki, Katsutoshi; Meguro, Akiko; Hatanaka, Keiko; Kadowaki, Masanori; Matsu, Haruko; Tatara, Raine; Sato, Kazuya; Iwakura, Yoichiro; Nakae, Susumu; Sudo, Katsuko; Teshima, Takanori; Ozawa, Keiya

doi:10.4049/jimmunol.0902217

Cited by 18 publications

(22 citation statements)

References 43 publications

(42 reference statements)

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“…Blocking IL-21 significantly ameliorates pathology in the small intestine and colon in multiple murine models. 22,23,26 However, although IL-21-secreting cells are present in the small intestine and colon of animals in the xenogeneic GVHD model, the pathology observed in animals electively killed on day 10 or 20 was not severe enough to assess the actions of anti-IL-21 (not shown). Blocking IL-21 also decreases liver pathology in some, 23,26 but not all, 22,23 murine GVHD models, and had some beneficial effects in the xenogeneic model.…”

Section: Discussionmentioning

confidence: 99%

“…Recent reports by us and others show that inhibiting IL-21 also decreases disease severity in murine models of GVHD. [22][23][24][25][26] Specifically, disruption of IL-21 signaling, either genetically or via neutralizing mAbs, reduces transplant-related weight loss, tissue pathology, and mortality. Disease amelioration correlated with decreased numbers of CD4 ϩ T cells secreting IFN-␥ and a concomitant increase in the proportion of CD4 ϩ T cells expressing Foxp3.…”

Section: Introductionmentioning

confidence: 99%

“…22,23,26 However, although IL-21-secreting cells are present in the small intestine and colon of animals in the xenogeneic GVHD model, the pathology observed in animals electively killed on day 10 or 20 was not severe enough to assess the actions of anti-IL-21 (not shown). Blocking IL-21 also decreases liver pathology in some, 23,26 but not all, 22,23 murine GVHD models, and had some beneficial effects in the xenogeneic model.Results in murine GVHD models have not always translated to human disease and, similar to our findings with IL-21, discrepancies between serum and in situ cytokine levels have previously been reported. 34 In the xenogeneic GVHD model, human IL-21 levels correlated with disease severity, although mice were analyzed at a time when they were moribund, in contrast to the samples obtained from patients who, for the most part, were assayed at GVHD diagnosis or shortly thereafter (not shown).…”

mentioning

confidence: 99%

“…Increased numbers of Foxp3 ϩ cells were also observed in a recent study by the Ozawa group using IL-21R Ϫ/Ϫ mice, although they postulated that attenuated GVHD might be caused by an impairment of effector T-cell differentiation itself, rather than by an increase in Tregs. 26 These 2 possibilities are not mutually exclusive, as T cells do not differentiate into effector cells if activated in the presence of Treg. 39 However, our current data show that effector T-cell differentiation on day 10 is not significantly influenced by anti-IL-21 mAb treatment.…”

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Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes

Hippen

Bucher

Schirm

et al. 2012

Blood

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In rodent graft-versus-host disease (GVHD) models, anti-IL-21 neutralizing mAb treatment ameliorates lethality and is associated with decreases in Th1 cytokine production and gastrointestinal tract injury. GVHD prevention was dependent on the in vivo generation of donor-inducible regulatory T cells (Tregs). To determine whether the IL-21 pathway might be targeted for GVHD prevention, skin and colon samples obtained from patients with no GVHD or grade 2 to 4 GVHD were analyzed for IL-21 protein expression. By immunohistochemistry staining, IL-21 protein-producing cells were present in all gastrointestinal tract samples and 54% of skin samples obtained from GVHD patients but not GVHDfree controls. In a human xenogeneic GVHD model, human IL-21-secreting cells were present in the colon of GVHD recipients and were associated with elevated serum IL-21 levels. A neutralizing anti-human IL-21 mAb given prophylactically significantly reduced GVHD-associated weight loss and mortality, resulting in a concomitant increase in Tregs and a decrease in T cells secreting IFN-␥ or granzyme B. Based on these findings, anti-IL-21 mAb could be considered for GVHD prevention in the clinic. (Blood. 2012;119(2): 619-628) IntroductionGraft-versus-host disease (GVHD) is a severe complication and major cause of morbidity and mortality after HSCT. 1 Although pro-inflammatory cytokine production has been associated with GVHD induction, the relative contribution of specific cytokines to GVHD has been difficult to establish because of seemingly paradoxical results. For example, whereas secretion of the Th1 inflammatory cytokine IFN-␥ increases GVHD-related colon damage, 2,3 CD4 ϩ T cells from IFN-␥ Ϫ/Ϫ mice cause even more severe GVHD. 4 Similarly, although early experiments inferred a role for Th2 responses in GVHD, 3 donor T cells from IL-4 Ϫ/Ϫ mice cause severe disease in some, 5 but not all, 4 studies, and the cotransfer of Th2-skewed cells can mitigate GVHD pathology. 6,7 Like Th1 and Th2 cells, the role of Th17 cells in GVHD is controversial. Whereas cotransfer of highly purified ex vivo polarized Th17 cells with naive T cells results in a more aggressive disease that is dependent on 8 CD4 ϩ T cells from IL-17 Ϫ/Ϫ or ROR␥t (Th17-deficient) donors attenuate, exacerbate, or had no effect on GVHD, depending on the model and knockout strain. [9][10][11][12] IL-21 is produced by CD4 ϩ T cells (especially Th17 cells 13 ) and natural killer T cells 14 and signals through the IL-2R␥ c and IL-21R complex. The receptor for IL-21 is expressed on hematopoietic and epithelial cells and promotes the activation, differentiation, maturation, and expansion of NK cells, B cells, CD8 ϩ and CD4 ϩ T cells, dendritic cells, and macrophages. 15,16 IL-21 contributes to autoimmunity in some, [17][18][19] but not all, 20,21 experimental models. Recent reports by us and others show that inhibiting IL-21 also decreases disease severity in murine models of GVHD. [22][23][24][25][26] Specifically, disruption of IL-21 signaling, either genetically or via neutralizing...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes

Hippen

Bucher

Schirm

et al. 2012

Blood

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“…Lu et al found that phosphorylation of STAT3, a transcriptional factor involved in Th17 cell differentiation 15 Transplantation with IL-21R-/-donor T cells resulted in less severe aGVHD, while sparing the GVL effect [71][72][73][74] . Furthermore, IL-21 blockade using a monoclonal antibody also decreased aGVHD 75 .…”

Section: Studies In Mouse Models Of Agvhdmentioning

confidence: 99%

Translational opportunities for targeting the Th17 axis in acute graft-vs.-host disease

et al. 2016

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Allogeneic stem cell transplantation (allo-SCT) is a curative therapy for different life-threatening malignant and non-malignant hematologic disorders. Acute graft-versus-host disease (aGVHD) and particularly gastro-intestinal aGVHD remains a major source of morbidity and mortality following allo-SCT, which limits the use of this treatment in a broader spectrum of patients. Better understanding of aGVHD pathophysiology is indispensable to identify new therapeutic targets for aGVHD prevention and therapy. Growing amount of data suggest a role for Th17 cells in aGVHD pathophysiology. In this review, we will discuss the current knowledge in this area in animal models and in humans.Based on it, we will then describe new potential treatments for aGVHD along the Th17 axis.

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Interleukin‐21 in chronic inflammatory diseases

Sarra

Pallone²,

Monteleone³

2013

BioFactors

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Interleukin-21 (IL-21), a cytokine produced by various subsets of activated CD4+ T cells, regulates multiple innate and adaptive immune responses. Indeed, IL-21 controls the proliferation and function of CD4+ and CD8+ T lymphocytes, drives the differentiation of B cells into memory cells and Ig-secreting plasma cells, enhances the activity of natural killer cells and negatively regulates the differentiation and activity of regulatory T cells. Moroever, IL-21 can stimulate nonimmune cells to synthesize various inflammatory molecules. Excessive production of IL-21 has been described in many human chronic inflammatory disorders and there is evidence that blockade of IL-21 helps attenuate detrimental responses in mouse models of immune-mediated diseases. In this article we briefly review data supporting the pathogenic role of IL-21 in immune-inflammatory pathologies and discuss the benefits and risks of IL-21 neutralization in patients with such diseases.

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Altered Effector CD4+ T Cell Function in IL-21R−/− CD4+ T Cell-Mediated Graft-Versus-Host Disease

Cited by 18 publications

References 43 publications

Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes

Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes

Translational opportunities for targeting the Th17 axis in acute graft-vs.-host disease

Interleukin‐21 in chronic inflammatory diseases

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