The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Warren J Leonard - One of the best experts on this subject based on the ideXlab platform.
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Interleukin 21 signaling in b cells but not in t cells is indispensable for the development of collagen induced arthritis in mice
Arthritis Research & Therapy, 2016Co-Authors: Koji Sakuraba, Rosanne Spolski, Warren J Leonard, Akiko Oyamada, Kenjiro Fujimura, Yukihide Iwamoto, Yasunobu Yoshikai, Hisakata YamadaAbstract:Interleukin-21 (IL-21) is a T-cell-derived cytokine whose receptor is expressed on a variety of cells and therefore might have pleiotropic roles in the pathogenesis of rheumatoid arthritis (RA). In this study, we investigated the involvement of IL-21 signaling in the development of collagen-induced arthritis (CIA), an animal model of RA, using IL-21 receptor knockout (Il21r KO) mice. Il21r KO mice or wild-type (WT) C57BL/6 mice were immunized with chicken type II collagen (CII) emulsified in complete Freund adjuvant on day 0 and were given a boost injection on day 21. The production of anti-CII antibody, development of T-cell and B-cell subsets, and T-cell responses to CII were analyzed. CIA was induced in Rag2 KO mice to which combinations of WT or Il21r KO CD4 T cells and WT or Il21r KO B cells had been transferred, in order to examine the role of IL-21 signaling in each cell subset. Il21r KO mice were resistant to the development of CIA. CII-specific IgG but not IgM production was impaired in Il21r KO mice. This is consistent with a reduction of germinal center B cells in the draining lymph nodes. In contrast, CII-specific Th1 and Th17 responses were unaffected in Il21r KO mice. There was also no difference in the number of CII-specific follicular helper T cells between WT and Il21r KO mice. By analyzing the development of CIA in T-cell and B-cell mixed transfer experiments, we confirmed that IL-21 receptor expression on B cells, but not on T cells, was essential for the development of CIA. IL-21 signaling in B cells, but not in T cells, plays essential roles in the production of pathogenic autoantibodies that induce CIA development.
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Endothelial Interleukin-21 receptor up-regulation in peripheral artery disease.
Vascular Medicine, 2015Co-Authors: Tao Wang, Rosanne Spolski, Warren J Leonard, Alexis Cunningham, Kevin Houston, Aditya M. Sharma, Lingdan Chen, Ayotunde O. Dokun, R. John Lye, Brian H. AnnexAbstract:In most patients with symptomatic peripheral artery disease (PAD), severe stenosis in or occlusion of the major blood vessels that supply the legs make the amount of distal blood flow dependent on the capacity to induce angiogenesis and collateral vessel formation. Currently, there are no medications that improve perfusion to the ischemic limb, and thus directly treat the primary problem of PAD. A recent report from our group in a pre-clinical mouse PAD model showed that Interleukin-21 receptor (IL-21R) is up-regulated in the endothelial cells from ischemic hindlimb muscle. We further showed that loss of IL-21R resulted in impaired perfusion recovery in this model. In our study, we sought to determine whether IL-21R is present in the endothelium from ischemic muscle of patients with PAD. Using human gastrocnemius muscle biopsies, we found increased levels of IL-21R in the skeletal muscle endothelial cells of patients with PAD compared to control individuals. Interestingly, PAD patients had approximately 1.7-fold higher levels of circulating IL-21. These data provide direct evidence that the IL-21R pathway is indeed up-regulated in patients with PAD. This pathway may serve as a therapeutic target for modulation.
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loss of Interleukin 21 receptor activation in hypoxic endothelial cells impairs perfusion recovery after hindlimb ischemia
Arteriosclerosis Thrombosis and Vascular Biology, 2015Co-Authors: Tao Wang, Rosanne Spolski, Warren J Leonard, Alexis Cunningham, Kevin Houston, Lingdan Chen, Ayotunde O. Dokun, Surovi Hazarika, John R Lye, Brian H. AnnexAbstract:Objective— Surgical hindlimb ischemia (HLI) in mice has become a valuable preclinical model to study peripheral arterial disease. We previously identified that the different phenotypic outcomes after HLI across inbred mouse strains is related to a region on the short arm of mouse chromosome 7. The gene coding the Interleukin-21 receptor (IL-21R) lies at the peak of association in this region. Approach and Results— With quantitative real-time polymerase chain reaction, we found that a mouse strain with a greater ability to upregulate IL-21R after HLI had better perfusion recovery than a strain with no upregulation after HLI. Immunofluorescent staining of ischemic hindlimb tissue showed IL-21R expression on endothelial cells (ECs) from C57BL/6 mice. An EC-enriched fraction isolated from ischemic hindlimb muscle showed higher Il-21R levels than an EC-enriched fraction from nonischemic limbs. In vitro, human umbilical vein ECs showed elevated IL-21R expression after hypoxia and serum starvation. Under these conditions, IL-21 treatment increased cell viability, decreased cell apoptosis, and augmented tube formation. In vivo, either knockout Il21r or blocking IL-21 signaling by treating with IL-21R-Fc (fusion protein that blocks IL-21 binding to its receptor) in C57BL/6 mice resulted in less perfusion recovery after HLI. Both in vitro and in vivo modulation of the IL-21/IL-21R axis under hypoxic conditions resulted in increased signal transducer and activator of transcription 3 phosphorylation and a subsequent increase in the B-cell lymphoma leukemia-2/BCL-2–associated X protein ratio. Conclusion— Our data indicate that IL-21R upregulation and ligand activation in hypoxic ECs may help perfusion recovery by limiting/preventing apoptosis and favoring cell survival and angiogenesis through the signal transducer and activator of transcription 3 pathway.
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Interleukin-21: a double-edged sword with therapeutic potential
Nature Reviews Drug Discovery, 2014Co-Authors: Rosanne Spolski, Warren J LeonardAbstract:Interleukin-21 is a cytokine with broad pleiotropic actions that affect the differentiation and function of lymphoid and myeloid cells. Since its discovery in 2000, a tremendous amount has been learned about its biological actions and the molecular mechanisms controlling IL-21-mediated cellular responses. IL-21 regulates both innate and adaptive immune responses, and it not only has key roles in antitumour and antiviral responses but also exerts major effects on inflammatory responses that promote the development of autoimmune diseases and inflammatory disorders. Numerous studies have shown that enhancing or inhibiting the action of IL-21 has therapeutic effects in animal models of a wide range of diseases, and various clinical trials are underway. The current challenge is to understand how to specifically modulate the actions of IL-21 in the context of each specific immune response or pathological situation. In this Review, we provide an overview of the basic biology of IL-21 and discuss how this information has been - and can be - exploited therapeutically.
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Interleukin-21: A Pleiotropic Mediator of Immunity and Inflammation with Broad Therapeutic Potential
Cytokine Frontiers, 2013Co-Authors: Rosanne Spolski, Warren J LeonardAbstract:Interleukin-21 (IL-21) is a member of the family of cytokines that share the common cytokine receptor γ-chain, γc. IL-21 plays critical roles in the differentiation and function of multiple lymphoid and myeloid lineages. In this chapter, we review the inflammatory and immunosuppressive activities of this cytokine and the specific mechanisms by which this cytokine regulates both the innate and adaptive immune responses. Despite the fact that IL-21 and its receptor were only identified in 2000, a tremendous amount has been learned already, leading to the development of potential therapeutic approaches to cancer as well as potentially allowing for the specific manipulation of IL-21 effects in a spectrum of autoimmune diseases, allergic responses, and viral infections.
Rosanne Spolski - One of the best experts on this subject based on the ideXlab platform.
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Interleukin 21 signaling in b cells but not in t cells is indispensable for the development of collagen induced arthritis in mice
Arthritis Research & Therapy, 2016Co-Authors: Koji Sakuraba, Rosanne Spolski, Warren J Leonard, Akiko Oyamada, Kenjiro Fujimura, Yukihide Iwamoto, Yasunobu Yoshikai, Hisakata YamadaAbstract:Interleukin-21 (IL-21) is a T-cell-derived cytokine whose receptor is expressed on a variety of cells and therefore might have pleiotropic roles in the pathogenesis of rheumatoid arthritis (RA). In this study, we investigated the involvement of IL-21 signaling in the development of collagen-induced arthritis (CIA), an animal model of RA, using IL-21 receptor knockout (Il21r KO) mice. Il21r KO mice or wild-type (WT) C57BL/6 mice were immunized with chicken type II collagen (CII) emulsified in complete Freund adjuvant on day 0 and were given a boost injection on day 21. The production of anti-CII antibody, development of T-cell and B-cell subsets, and T-cell responses to CII were analyzed. CIA was induced in Rag2 KO mice to which combinations of WT or Il21r KO CD4 T cells and WT or Il21r KO B cells had been transferred, in order to examine the role of IL-21 signaling in each cell subset. Il21r KO mice were resistant to the development of CIA. CII-specific IgG but not IgM production was impaired in Il21r KO mice. This is consistent with a reduction of germinal center B cells in the draining lymph nodes. In contrast, CII-specific Th1 and Th17 responses were unaffected in Il21r KO mice. There was also no difference in the number of CII-specific follicular helper T cells between WT and Il21r KO mice. By analyzing the development of CIA in T-cell and B-cell mixed transfer experiments, we confirmed that IL-21 receptor expression on B cells, but not on T cells, was essential for the development of CIA. IL-21 signaling in B cells, but not in T cells, plays essential roles in the production of pathogenic autoantibodies that induce CIA development.
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Endothelial Interleukin-21 receptor up-regulation in peripheral artery disease.
Vascular Medicine, 2015Co-Authors: Tao Wang, Rosanne Spolski, Warren J Leonard, Alexis Cunningham, Kevin Houston, Aditya M. Sharma, Lingdan Chen, Ayotunde O. Dokun, R. John Lye, Brian H. AnnexAbstract:In most patients with symptomatic peripheral artery disease (PAD), severe stenosis in or occlusion of the major blood vessels that supply the legs make the amount of distal blood flow dependent on the capacity to induce angiogenesis and collateral vessel formation. Currently, there are no medications that improve perfusion to the ischemic limb, and thus directly treat the primary problem of PAD. A recent report from our group in a pre-clinical mouse PAD model showed that Interleukin-21 receptor (IL-21R) is up-regulated in the endothelial cells from ischemic hindlimb muscle. We further showed that loss of IL-21R resulted in impaired perfusion recovery in this model. In our study, we sought to determine whether IL-21R is present in the endothelium from ischemic muscle of patients with PAD. Using human gastrocnemius muscle biopsies, we found increased levels of IL-21R in the skeletal muscle endothelial cells of patients with PAD compared to control individuals. Interestingly, PAD patients had approximately 1.7-fold higher levels of circulating IL-21. These data provide direct evidence that the IL-21R pathway is indeed up-regulated in patients with PAD. This pathway may serve as a therapeutic target for modulation.
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loss of Interleukin 21 receptor activation in hypoxic endothelial cells impairs perfusion recovery after hindlimb ischemia
Arteriosclerosis Thrombosis and Vascular Biology, 2015Co-Authors: Tao Wang, Rosanne Spolski, Warren J Leonard, Alexis Cunningham, Kevin Houston, Lingdan Chen, Ayotunde O. Dokun, Surovi Hazarika, John R Lye, Brian H. AnnexAbstract:Objective— Surgical hindlimb ischemia (HLI) in mice has become a valuable preclinical model to study peripheral arterial disease. We previously identified that the different phenotypic outcomes after HLI across inbred mouse strains is related to a region on the short arm of mouse chromosome 7. The gene coding the Interleukin-21 receptor (IL-21R) lies at the peak of association in this region. Approach and Results— With quantitative real-time polymerase chain reaction, we found that a mouse strain with a greater ability to upregulate IL-21R after HLI had better perfusion recovery than a strain with no upregulation after HLI. Immunofluorescent staining of ischemic hindlimb tissue showed IL-21R expression on endothelial cells (ECs) from C57BL/6 mice. An EC-enriched fraction isolated from ischemic hindlimb muscle showed higher Il-21R levels than an EC-enriched fraction from nonischemic limbs. In vitro, human umbilical vein ECs showed elevated IL-21R expression after hypoxia and serum starvation. Under these conditions, IL-21 treatment increased cell viability, decreased cell apoptosis, and augmented tube formation. In vivo, either knockout Il21r or blocking IL-21 signaling by treating with IL-21R-Fc (fusion protein that blocks IL-21 binding to its receptor) in C57BL/6 mice resulted in less perfusion recovery after HLI. Both in vitro and in vivo modulation of the IL-21/IL-21R axis under hypoxic conditions resulted in increased signal transducer and activator of transcription 3 phosphorylation and a subsequent increase in the B-cell lymphoma leukemia-2/BCL-2–associated X protein ratio. Conclusion— Our data indicate that IL-21R upregulation and ligand activation in hypoxic ECs may help perfusion recovery by limiting/preventing apoptosis and favoring cell survival and angiogenesis through the signal transducer and activator of transcription 3 pathway.
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Interleukin-21: a double-edged sword with therapeutic potential
Nature Reviews Drug Discovery, 2014Co-Authors: Rosanne Spolski, Warren J LeonardAbstract:Interleukin-21 is a cytokine with broad pleiotropic actions that affect the differentiation and function of lymphoid and myeloid cells. Since its discovery in 2000, a tremendous amount has been learned about its biological actions and the molecular mechanisms controlling IL-21-mediated cellular responses. IL-21 regulates both innate and adaptive immune responses, and it not only has key roles in antitumour and antiviral responses but also exerts major effects on inflammatory responses that promote the development of autoimmune diseases and inflammatory disorders. Numerous studies have shown that enhancing or inhibiting the action of IL-21 has therapeutic effects in animal models of a wide range of diseases, and various clinical trials are underway. The current challenge is to understand how to specifically modulate the actions of IL-21 in the context of each specific immune response or pathological situation. In this Review, we provide an overview of the basic biology of IL-21 and discuss how this information has been - and can be - exploited therapeutically.
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Interleukin-21: A Pleiotropic Mediator of Immunity and Inflammation with Broad Therapeutic Potential
Cytokine Frontiers, 2013Co-Authors: Rosanne Spolski, Warren J LeonardAbstract:Interleukin-21 (IL-21) is a member of the family of cytokines that share the common cytokine receptor γ-chain, γc. IL-21 plays critical roles in the differentiation and function of multiple lymphoid and myeloid lineages. In this chapter, we review the inflammatory and immunosuppressive activities of this cytokine and the specific mechanisms by which this cytokine regulates both the innate and adaptive immune responses. Despite the fact that IL-21 and its receptor were only identified in 2000, a tremendous amount has been learned already, leading to the development of potential therapeutic approaches to cancer as well as potentially allowing for the specific manipulation of IL-21 effects in a spectrum of autoimmune diseases, allergic responses, and viral infections.
Kresten Skak - One of the best experts on this subject based on the ideXlab platform.
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clinical and biological efficacy of recombinant human Interleukin 21 in patients with stage iv malignant melanoma without prior treatment a phase iia trial
Clinical Cancer Research, 2009Co-Authors: Ian D. Davis, Kresten Skak, Birte K Skrumsager, Jonathan Cebon, Ben Brady, Richard F Kefford, Michael Millward, Ulrik Mouritzen, Lasse Hansen, Dorthe LundsgaardAbstract:Purpose: Human Interleukin-21 (IL-21) is a class I cytokine that mediates activation of CD8 + T cells, natural killer (NK) cells, and other cell types. We report final clinical and biological results of a phase II study of recombinant human IL-21 (rIL-21) in patients with metastatic melanoma. Experimental Design: Open-label, single-arm, two-stage trial. Eligibility criteria: unresectable metastatic melanoma, measurable disease by Response Evaluation Criteria in Solid Tumors, no prior systemic therapy (adjuvant IFN permitted), adequate major organ function, good performance status, no significant autoimmune disease, and life expectancy at least 4 months. Primary objective: antitumor efficacy (response rate). Secondary objectives: safety, blood biomarkers, and generation of anti-rIL-21 antibodies. rIL-21 (30 μg/kg/dose) was administered by intravenous bolus injection in 8-week cycles (5 dosing days followed by 9 days of rest for 6 weeks and then 2 weeks off treatment). Results: Stage I of the study comprised 14 patients. One confirmed complete response (CR) was observed, and as per protocol, 10 more patients were accrued to stage II (total n = 24: 10 female and 14 male). Best tumor response included one confirmed CR and one confirmed partial response, both with lung metastases. Treatment was overall well tolerated. Biomarker analyses showed increases in serum soluble CD25, frequencies of CD25 + NK and CD8 + T cells, and mRNA for IFN-γ, perforin, and granzyme B in CD8 + T and NK cells. Conclusions: rIL-21 administered at 30 μg/kg/d in 5-day cycles every second week is biologically active and well tolerated in patients with metastatic melanoma. Confirmed responses, including one CR, were observed.
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Interleukin 21 activates human natural killer cells and modulates their surface receptor expression
Immunology, 2008Co-Authors: Kresten Skak, Klaus Stensgaard Frederiksen, Dorthe LundsgaardAbstract:Interleukin (IL)-21 is a novel cytokine that has been shown to enhance proliferation and activation of CD8+ T cells, enhance natural killer (NK) cell activity and costimulate anti-CD40-driven B-cell proliferation in mice. Several studies have furthermore demonstrated antitumour effects of IL-21 administration in mouse models. In this study we have investigated how IL-21 affects the survival and cytotoxicity of human NK cells and modulates their expression of surface receptors and of the effector molecules granzyme B and perforin. In contrast to murine NK cells, where IL-21 alone cannot sustain survival, IL-21 and IL-2 were equally efficient in sustaining survival of human NK cells. In the absence of other cytokines, IL-21 had little effect on expression of a panel of surface receptors on human NK cells. However, IL-21 synergized with IL-2 to up-regulate several surface receptors, including NKG2A, CD25, CD86 and CD69. The CD25+ CD86+ NK cells were CD56(bright) and were large and granular. Expression of the effector molecules perforin and granzyme A and B was up-regulated by IL-21 at both mRNA and protein levels. Furthermore, IL-21 increased the cytotoxicity of NK cells against K562 target cells. These findings suggest that IL-21 modulates NK cell activity through induction of intracellular effector molecules as well as modulation of surface receptor expression.
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Interleukin 21: combination strategies for cancer therapy.
Nature Reviews Drug Discovery, 2008Co-Authors: Kresten Skak, Mark J. Smyth, Michael Kragh, Diana F. Hausman, Pallavur V. SivakumarAbstract:In the past 20 years researchers have attempted to activate the host immune defence system to kill tumour cells and eradicate cancer. In some cases, the response of patients to immunotherapy has been extremely successful; however, other trials have shown disappointing results, and so there is a clear need for more effective therapies that can effectively adjunct conventional approaches. Interleukin 21 (IL21) is a new immune-stimulating cytokine that has demonstrated antitumour activity in several preclinical models, and has recently undergone Phase I trials in metastatic melanoma and renal cell carcinoma. Here, we provide an overview of the antitumour effects of IL21 and describe strategies to combine IL21 with other drugs for future cancer therapies.
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Interleukin-21 signaling: functions in cancer and autoimmunity.
Clinical Cancer Research, 2007Co-Authors: Ian D. Davis, Kresten Skak, Mark J. Smyth, Paul E.g. Kristjansen, Dennis M. Miller, Pallavur V. SivakumarAbstract:Interleukin-21 (IL-21) is a cytokine with structural and sequence homology to IL-2 and IL-15, yet possesses several biological properties distinct from these cytokines. IL-21 is produced mainly by activated CD4(+) T cells and natural killer T cells and mediates its activity by binding to the IL-21 receptor (IL-21R), consisting of an IL-21-specific alpha chain (IL-21Ralpha; JAK/STAT) that heterodimerizes with the common gamma chain (CD132). Intracellular signaling occurs through the Janus-activated kinase/signal transducer and activator of transcription pathways. Physiologic expression of IL-21R is restricted to lymphoid tissues and peripheral blood mononuclear cells; however, other tissues such as epithelium, synovium, or transformed cells can acquire expression of both components of IL-21R heterodimer. IL-21 has complex activities on a wide variety of cell types, leading to enhancement of adaptive T-cell immunity, antibody production, activation of natural killer cell subtypes, and opposition to suppressive effects mediated by regulatory T cells. Functionally, these activities promote immune responses and point to a physiologic role of IL-21 in autoimmunity and immune enhancement. Therapeutic manipulation of IL-21 activity may allow improved immunotherapy for cancer as well as insights into autoimmune disease. Recently conducted phase 1 trials in metastatic melanoma and renal cell carcinoma have shown that recombinant IL-21 has a favorable safety profile and support its continued investigation as a potential anticancer drug.
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an open label two arm phase i trial of recombinant human Interleukin 21 in patients with metastatic melanoma
Clinical Cancer Research, 2007Co-Authors: Ian D. Davis, Kresten Skak, Birte K Skrumsager, Jonathan Cebon, Theo Nicholaou, John W Barlow, Niels Peter Hundahl Moller, Dorthe Lundsgaard, Klaus Stensgaard Frederiksen, Peter ThygesenAbstract:Purpose: Human Interleukin-21 (IL-21) is a pleiotropic class I cytokine that activates CD8 + T cells and natural killer cells. We report a phase 1 study of recombinant human IL-21 in patients with surgically incurable metastatic melanoma. The primary objective was to investigate safety and tolerability by determining dose-limiting toxicity (DLT). The secondary objectives were to identify a dose response for various biomarkers in the peripheral blood, estimate the minimum biologically effective dose, determine the pharmacokinetics of IL-21, determine if anti-IL-21 antibodies were induced during therapy, and measure effects on tumor size according to Response Evaluation Criteria in Solid Tumors. Experimental Design: Open-label, two-arm, dose escalation trial of IL-21 administered by i.v. bolus injection at dose levels from 1 to 100 μg/kg using two parallel treatment regimens: thrice weekly for 6 weeks (3/wk) or three cycles of daily dosing for 5 days followed by 9 days of rest (5+9). Results: Twenty-nine patients entered the study. IL-21 was generally well tolerated and no DLTs were observed at the 1, 3, and 10 μg/kg dose levels. In the 3/wk regimen, DLTs were increased in alanine aminotransferase, neutropenia, and lightheadedness with fever and rigors. DLTs in the 5+9 regimen were increased in aspartate aminotransferase and alanine aminotransferase, neutropenia, fatigue, and thrombocytopenia. The maximum tolerated dose was declared to be 30 μg/kg for both regimens. Effects on biomarkers were observed at all dose levels, including increased levels of soluble CD25 and up-regulation of perforin and granzyme B mRNA in CD8 + cells. One partial tumor response observed after treatment with IL-21 for 2 × 6 weeks (3/wk) became complete 3 months later. Conclusions: IL-21 is biologically active at all dose levels administered and is generally well tolerated, and phase 2 studies have commenced using 30 μg/kg in the 5+9 regimen.
Thomas T. Macdonald - One of the best experts on this subject based on the ideXlab platform.
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interferon gamma expressing cells are a major source of Interleukin 21 in inflammatory bowel diseases
Inflammatory Bowel Diseases, 2010Co-Authors: Massimiliano Sarra, Thomas T. Macdonald, Carmine Stolfi, F Pallone, Massimo C Fantini, Pierpaolo Sileri, I Monteleone, G Sica, R Tersigni, Giovanni MonteleoneAbstract:Background: We previously demonstrated that in inflammatory bowel disease (IBD) there is enhanced production of Interleukin (IL)-21, a cytokine that activates multiple pathways that sustain mucosal inflammation. However, the phenotype of IL-21-producing cells in IBD, and the cytokine(s) they coproduce, is not known. We here characterized the cell source of IL-21 and determined which factors regulate IL-21 in the human gut. Methods: Cytokines were analyzed in CD4+ T intestinal lamina propria lymphocytes (T-LPL) isolated from IBD patients and controls by flow cytometry. Moreover, IL-21 was evaluated in mucosal T follicular cells (TFH). To assess the involvement of IL-12 and IL-23 in the production of IL-21, T-LPL were activated in the presence or absence of IL-12 or IL-23. Results: The proportion of IL-21-producing CD4+ T-LPL was increased in IBD compared to controls. The majority of IL-21-producing T-LPL coexpressed interferon (IFN)-γ, and to a lesser extent IL-4 or IL-17A. Activation of CD4+ T-LPL with IL-12 but not IL-23 enhanced the fraction of cells coexpressing IL-21 and IFN-γ. TFH cells in LPL were identified by CXCR5 expression and expressed IL-21 both in IBD and controls; however, the fraction of IL-21-positive TFH cells was higher in Crohn's disease than in ulcerative colitis and controls. Treatment of CD4+ T-LPL with IL-12 enhanced the frequency of CXCR5+ IL-21-producing TFH cells. Conclusions: These findings indicate that in IBD IL-21 is mostly produced by CD4+ T-LPL coexpressing IFN-γ, reinforcing the concept that distinct subsets of T cells can produce IL-21. Inflamm Bowel Dis 2010
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Interleukin 21 as a new therapeutic target for immune mediated diseases
Trends in Pharmacological Sciences, 2009Co-Authors: Giovanni Monteleone, F Pallone, Thomas T. MacdonaldAbstract:Cytokines have a decisive role in initiating and shaping pathologic responses in patients with various immune-inflammatory diseases. Recent studies indicate that Interleukin (IL)-21, a cytokine produced mostly by activated CD4+ T cells, participates in the tissue damage in various tissues, owing to its ability to regulate the function of immune and non-immune cells. For instance, IL-21 controls the differentiation and functional activity of T cells, B cells and NK cells, limits the differentiation of inducible regulatory T cells (Tregs), and makes T cells resistant to the Treg-mediated immunesuppression. It also stimulates epithelial cells and fibroblasts to produce inflammatory mediators. Here, we focus on data supporting the pathogenic role of IL-21 in human inflammatory diseases and discuss pre-clinical studies that suggest that neutralization of IL-21 in vivo could be a new biological therapy to combat immune-mediated pathologies, such as inflammatory bowel diseases, diabetes, rheumatoid arthritis and systemic lupus erythematosus.
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Interleukin-21 (IL-21)-mediated pathways in T cell-mediated disease.
Cytokine & Growth Factor Reviews, 2009Co-Authors: Giovanni Monteleone, Francesco Pallone, Thomas T. MacdonaldAbstract:Interleukin-21 (IL-21) is produced mostly by activated CD4+ T cells and controls the differentiation and functional activity of effector T helper cells, counteracts the suppressive effects of regulatory T cells, and stimulates non-immune cells to make inflammatory mediators. IL-21-driven tissue damage has been demonstrated in a number of organs, such as the gut, pancreas, and brain. Therefore new treatment modalities to neutralise IL-21 in vivo would be a valuable addition to the therapeutic armamentarium to combat immune-mediated inflammation. Here we describe the emerging role of IL-21 in the initiation and progress of the tissue-damaging inflammatory response in immune-mediated pathologies.
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Interleukin 21 contributes to the mucosal t helper cell type 1 response in coeliac disease
Gut, 2008Co-Authors: Daniele Fina, Roberta Caruso, Massimiliano Sarra, Thomas T. Macdonald, G Del Vecchio Blanco, F Pallone, G MonteleoneAbstract:Background: In coeliac disease (CD), the upper bowel lesion is associated with a marked infiltration of the mucosa with Th1 cells secreting interferon γ (IFNγ) and expressing the Th1-associated transcription factor, T-bet. However, the molecular mechanisms which regulate T-bet and promote the Th1 cell response are unknown. Objective: To examine whether Interleukin 21 (IL21), a cytokine that regulates T cell activation, has a role in CD. Methods: Duodenal mucosal samples were taken from CD patients and normal controls. IL21 and T-bet were examined by real-time PCR and western blotting, and IFNγ was assessed by real-time PCR and ELISA. The effect of blockade of endogenous IL21 on the expression of T-bet was examined in an ex vivo culture of biopsies taken from untreated CD patients. Finally, the role of IL21 in controlling T-bet and IFNγ was also evaluated in cultures of biopsies taken from treated CD patients and cultured with a peptic–tryptic digest of gliadin (PT) in the presence or absence of a neutralising IL21 antibody. Results: Enhanced IL21 RNA and protein expression was seen in duodenal samples from untreated CD patients. Blockade of IL21 activity in biopsies of untreated CD patients reduced T-bet and IFNγ secretion. Stimulation of treated CD biopsies with PT enhanced IL21 expression, and neutralisation of IL21 largely prevented PT-driven T-bet and IFNγ induction. Conclusions: IL21 is overproduced in the mucosa of CD patients, where it helps sustain T-bet expression and IFNγ production.
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Interleukin-21: a critical regulator of the balance between effector and regulatory T-cell responses.
Trends in Immunology, 2008Co-Authors: Giovanni Monteleone, Francesco Pallone, Thomas T. MacdonaldAbstract:Naive T cells can commit to effector [T helper 1 (Th1), Th2 and Th17] or regulatory lineages. Skewing of responses toward inflammatory Th1, Th2 or Th17 pathways and away from regulatory T-cell pathways might be responsible for the initiation and progress of immune-mediated diseases. Based on recent data, we propose that Interleukin-21 (IL-21), a cytokine produced by activated CD4 + T cells, induces the development of Th17 cells, blocks the differentiation of transforming growth factor-β1–induced regulatory T cells and renders CD4 + T cells resistant to the suppressive effects of regulatory T cells, thereby playing a major role in pathogenic T-cell responses.
Diana F. Hausman - One of the best experts on this subject based on the ideXlab platform.
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phase i study of recombinant Interleukin 21 in patients with metastatic melanoma and renal cell carcinoma
Journal of Clinical Oncology, 2008Co-Authors: John A Thompson, Shailender Bhatia, Brendan D Curti, Bruce G Redman, Jeffrey S Weber, Sanjiv S Agarwala, Eric L Sievers, Steven D Hughes, Todd Devries, Diana F. HausmanAbstract:Purpose A phase I study of patients with metastatic malignant melanoma (MM) and renal cell carcinoma (RCC) evaluated the safety and maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of recombinant human Interleukin-21 (rIL-21). Patients and Methods Patients who had one or fewer prior systemic treatments for metastatic MM or RCC were treated with rIL-21 administered for two 5-day cycles on days 1 through 5 and 15 through 19 of a treatment course; rIL-21 was administered by rapid intravenous infusion in an outpatient setting. Cohorts of patients received doses ranging from 3 to 100 μg/kg/dose, and an expanded cohort was treated at the MTD. Patients with stable disease (SD) or better could receive additional treatment cycles. Results Forty-three patients were treated (24 MM; 19 RCC), including 28 in the expanded cohort. Dose-limiting toxicities consisted primarily of transient grade 3 laboratory abnormalities. The MTD was estimated to be 30 μg/kg. The most c...
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Interleukin 21: combination strategies for cancer therapy.
Nature Reviews Drug Discovery, 2008Co-Authors: Kresten Skak, Mark J. Smyth, Michael Kragh, Diana F. Hausman, Pallavur V. SivakumarAbstract:In the past 20 years researchers have attempted to activate the host immune defence system to kill tumour cells and eradicate cancer. In some cases, the response of patients to immunotherapy has been extremely successful; however, other trials have shown disappointing results, and so there is a clear need for more effective therapies that can effectively adjunct conventional approaches. Interleukin 21 (IL21) is a new immune-stimulating cytokine that has demonstrated antitumour activity in several preclinical models, and has recently undergone Phase I trials in metastatic melanoma and renal cell carcinoma. Here, we provide an overview of the antitumour effects of IL21 and describe strategies to combine IL21 with other drugs for future cancer therapies.