Journal Articles

Cytokine therapy

Treatment strategies based on cytokines, including cytokine gene therapy and immunocytokines

A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma

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BACKGROUND: Preclinical studies suggest that BRAF inhibitors enhance anti-tumor immunity and antigen presentation. Combination BRAF inhibition with immunotherapy is an appealing therapeutic approach. We sequenced vemurafenib with HD IL-2 in patients with BRAF-mutated metastatic melanoma to improve long term outcomes. METHODS: Eligible patients were HD IL-2 eligible with metastatic BRAF V600 mutated melanoma. Cohort 1 was treatment naive and received vemurafenib 960 mg BID for 6 weeks before HD IL-2. Cohort 2 received vemurafenib for 7-18 weeks before enrollment. Both cohorts received HD IL-2 at 600,000 IU/kg every 8 h days 1-5 and days 15-19. The primary objective was to assess complete responses (CR) at 10 weeks +/-3 (assessment 1) and 26 weeks +/-3 (assessment 2) from the start of HD IL-2. RESULTS: Fifty-three patients were enrolled, (cohort 1, n = 38; cohort 2, n = 15). Of these, 39 underwent assessment 1 and 15 assessment 2. The CR rate at assessment 1 was 10% (95% CI 3-24) for both cohorts combined, and 27% (95% CI 8-55) at assessment 2. Three-year survival was 30 and 27% for cohort 1 and cohort 2, respectively. No unexpected toxicities occurred. A shift in the melanoma treatment landscape during this trial adversely affected accrual, leading to early trial closure. CONCLUSIONS: Vemurafenib in sequence with HD IL-2 did not change the known toxicity profile for either agent. Lower than expected response rates to vemurafenib were observed. Overall response rates and durability of responses appear similar to that observed with HD IL-2 alone. TRIAL REGISTRATION: NCTN, NCT01683188. Registered 11 September 2012, http://www.clinicaltrials.gov/NCT01683188.

Author Info: (1) Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153, USA. jclark@lumc.edu. (2) Primary Biostatistical Solutions, Victoria, BC, Canada

Author Info: (1) Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153, USA. jclark@lumc.edu. (2) Primary Biostatistical Solutions, Victoria, BC, Canada. (3) Roswell Park Cancer Institute, Buffalo, NY, USA. (4) University of Michigan, Ann Arbor, MI, USA. (5) The Karmanos Cancer Institute, Detroit, MI, USA. (6) Indiana University, Indianapolis, IN, USA. (7) Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA. (8) St. Luke's Hospital and Health Network, Bethlehem, PA, USA. (9) Columbia University/Herbert Irving Comprehensive Cancer Center, New York, NY, USA. (10) Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA. (11) Mt. Sinai Comprehensive Cancer Center, Miami Beach, FL, USA. (12) Prometheus Laboratories Inc, San Diego, CA, USA. (13) Prometheus Laboratories Inc, San Diego, CA, USA. Nektar Inc, San Diego, CA, USA. (14) Emory Winship Cancer Institute at Emory University, Atlanta, GA, USA.

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Interferon gene therapy reprograms the leukemia microenvironment inducing protective immunity to multiple tumor antigens

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Immunotherapy is emerging as a new pillar of cancer treatment with potential to cure. However, many patients still fail to respond to these therapies. Among the underlying factors, an immunosuppressive tumor microenvironment (TME) plays a major role. Here we show that monocyte-mediated gene delivery of IFNalpha inhibits leukemia in a mouse model. IFN gene therapy counteracts leukemia-induced expansion of immunosuppressive myeloid cells and imposes an immunostimulatory program to the TME, as shown by bulk and single-cell transcriptome analyses. This reprogramming promotes T-cell priming and effector function against multiple surrogate tumor-specific antigens, inhibiting leukemia growth in our experimental model. Durable responses are observed in a fraction of mice and are further increased combining gene therapy with checkpoint blockers. Furthermore, IFN gene therapy strongly enhances anti-tumor activity of adoptively transferred T cells engineered with tumor-specific TCR or CAR, overcoming suppressive signals in the leukemia TME. These findings warrant further investigations on the potential development of our gene therapy strategy towards clinical testing.

Author Info: (1) Vita-Salute San Raffaele University, 20132, Milan, Italy. Targeted Cancer Gene Therapy Unit, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. San Raffaele Telethon Institute

Author Info: (1) Vita-Salute San Raffaele University, 20132, Milan, Italy. Targeted Cancer Gene Therapy Unit, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. San Raffaele Telethon Institute for Gene Therapy, 20132, Milan, Italy. (2) Targeted Cancer Gene Therapy Unit, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. San Raffaele Telethon Institute for Gene Therapy, 20132, Milan, Italy. (3) San Raffaele Telethon Institute for Gene Therapy, 20132, Milan, Italy. (4) Vita-Salute San Raffaele University, 20132, Milan, Italy. Division of Immunology, Transplant and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. (5) San Raffaele Telethon Institute for Gene Therapy, 20132, Milan, Italy. (6) Targeted Cancer Gene Therapy Unit, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. (7) San Raffaele Telethon Institute for Gene Therapy, 20132, Milan, Italy. (8) Division of Immunology, Transplant and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. (9) CUSSB-University Center for Statistics in the Biomedical Sciences, Vita-Salute San Raffaele University, 20132, Milan, Italy. (10) San Raffaele Telethon Institute for Gene Therapy, 20132, Milan, Italy. Centre for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. (11) San Raffaele Telethon Institute for Gene Therapy, 20132, Milan, Italy. (12) Vita-Salute San Raffaele University, 20132, Milan, Italy. Division of Immunology, Transplant and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. (13) San Raffaele Telethon Institute for Gene Therapy, 20132, Milan, Italy. (14) San Raffaele Telethon Institute for Gene Therapy, 20132, Milan, Italy. gentner.bernhard@hsr.it. Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. gentner.bernhard@hsr.it. (15) Vita-Salute San Raffaele University, 20132, Milan, Italy. naldini.luigi@hsr.it. Targeted Cancer Gene Therapy Unit, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. naldini.luigi@hsr.it. San Raffaele Telethon Institute for Gene Therapy, 20132, Milan, Italy. naldini.luigi@hsr.it.

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Interleukin-1 Beta-A Friend or Foe in Malignancies

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Interleukin-1 beta (IL-1beta) is induced by inflammatory signals in a broad number of immune cell types. IL-1beta (and IL-18) are the only cytokines which are processed by caspase-1 after inflammasome-mediated activation. This review aims to summarize current knowledge about parameters of regulation of IL-1beta expression and its multi-facetted role in pathophysiological conditions. IL-1 signaling activates innate immune cells including antigen presenting cells, and drives polarization of CD4+ T cells towards T helper type (Th) 1 and Th17 cells. Therefore, IL-1beta has been attributed a largely beneficial role in resolving acute inflammations, and by initiating adaptive anti-tumor responses. However, IL-1beta generated in the course of chronic inflammation supports tumor development. Furthermore, IL-1beta generated within the tumor microenvironment predominantly by tumor-infiltrating macrophages promotes tumor growth and metastasis via different mechanisms. These include the expression of IL-1 targets which promote neoangiogenesis and of soluble mediators in cancer-associated fibroblasts that evoke antiapoptotic signaling in tumor cells. Moreover, IL-1 promotes the propagation of myeloid-derived suppressor cells. Using genetic mouse models as well as agents for pharmacological inhibition of IL-1 signaling therapeutically applied for treatment of IL-1 associated autoimmune diseases indicate that IL-1beta is a driver of tumor induction and development.

Author Info: (1) Department of Dermatology, University Medical Center, 55131 Mainz, Germany. Rebekka.Bent@unimedizin-mainz.de. (2) Department of Dermatology, University Medical Center, 55131 Mainz, Germany. Lorna.Moll@unimedizin-mainz.de. (3) Department of

Author Info: (1) Department of Dermatology, University Medical Center, 55131 Mainz, Germany. Rebekka.Bent@unimedizin-mainz.de. (2) Department of Dermatology, University Medical Center, 55131 Mainz, Germany. Lorna.Moll@unimedizin-mainz.de. (3) Department of Dermatology, University Medical Center, 55131 Mainz, Germany. Stephan.Grabbe@unimedizin-mainz.de. (4) Department of Dermatology, University Medical Center, 55131 Mainz, Germany. mbros@uni-mainz.de.

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Phase I Trial of ALT-803, a Novel Recombinant Interleukin-15 Complex, in Patients with Advanced Solid Tumors

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BACKGROUND: IL-15 induces the activation and proliferation of NK and memory CD8+ T cells and has preclinical antitumor activity. Given the superior activity and favorable kinetics of ALT-803 (IL-15N72D:IL-15RalphaSu/IgG1 Fc complex) over recombinant human IL-15 (rhIL-15) in animal models, we performed this first-in-human Phase I trial of ALT-803 in patients with advanced solid tumors. METHODS: Patients with incurable advanced melanoma, renal cell, non-small cell lung, and head and neck cancer were treated with ALT-803 0.3-6 mg/kg weekly i.v. or 6-20 mg/kg weekly s.c. for 4 consecutive weeks, every 6 weeks. Immune correlates included pharmacokinetics, immunogenicity, lymphocyte expansion and function. Clinical endpoints were toxicity and antitumor activity. RESULTS: Twenty-four patients were enrolled; eleven received i.v. and 13 received s.c. ALT-803. Of these patients, 9 had melanoma, 6 renal, 3 head and neck, and 6 lung cancer. Although total lymphocyte and CD8+ T cell expansion were modest, NK cell numbers rose significantly. Neither anti-ALT-803 antibodies nor clinical activity were observed. Overall, ALT-803 was well-tolerated, with adverse effects including fatigue and nausea most commonly with i.v. administration, while painful injection site wheal was reported most commonly with s.c. ALT-803. CONCLUSIONS: Subcutaneous ALT-803 produced the expected NK cell expansion and was well-tolerated with minimal cytokine toxicities and a strong local inflammatory reaction at injection sites in advanced cancer patients. These data, together with compelling evidence of synergy in preclinical and clinical studies, provide the rationale for combining ALT-803 with other anti-cancer agents.

Author Info: (1) Medical Oncology, City of Hope kmargolin@coh.org. (2) Laboratory Medicine, University of Washington. (3) Solid Tumor Oncology, Cleveland Clinic. (4) Department of Medicine, University of

Author Info: (1) Medical Oncology, City of Hope kmargolin@coh.org. (2) Laboratory Medicine, University of Washington. (3) Solid Tumor Oncology, Cleveland Clinic. (4) Department of Medicine, University of Minnesota. (5) Medicine, University of Washington. (6) Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School. (7) Medicine, University of Minnesota. (8) Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center. (9) VIDD, Fred Hutchinson Cancer Research Ctr. (10) Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center. (11) Preclinical-Translational, Altor Bioscience Corporation. (12) Research and Development, Altor BioScience Corporation. (13) Research and Development, Altor Bioscience Corp. (14) Research and Development, Altor Bioscience, a NantWorks Company. (15) Clinical Research Division, FHCRC/ CITN. (16) Research and Development, Altor Bioscience Corp. (17) Department of Medicine, Roswell Park Comprhensive Cancer Center.

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IL-27 regulates the number, function and cytotoxic program of antiviral CD4 T cells and promotes cytomegalovirus persistence

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The role of IL-27 in antiviral immunity is still incompletely understood, especially in the context of chronic viruses that induce a unique environment in their infected host. Cytomegalovirus (CMV) establishes a persistent, tissue localized infection followed by lifelong latency. CMV infects the majority of people and although asymptomatic in healthy individuals, can cause serious disease or death in those with naive or compromised immune systems. Therefore, there is an urgent need to develop a protective CMV vaccine for people at-risk and identifying key regulators of the protective immune response towards CMV will be crucial. Here we studied mouse CMV (MCMV) in IL-27 receptor deficient animals (Il27ra-/-) to assess the role of IL-27 in regulating CMV immunity. We found that IL-27 enhanced the number of antiviral CD4 T cells upon infection. However, in contrast to a well-established role for CD4 T cells in controlling persistent replication and a positive effect of IL-27 on their numbers, IL-27 promoted MCMV persistence in the salivary gland. This coincided with IL-27 mediated induction of IL-10 production in CD4 T cells. Moreover, IL-27 reduced expression of the transcription factor T-bet and restricted a cytotoxic phenotype in antiviral CD4 T cells. This is a highly intriguing result given the profound cytotoxic phenotype of CMV-specific CD4 T cells seen in humans and we established that dendritic cell derived IL-27 was responsible for this effect. Together, these data show that IL-27 regulates the number and effector functions of MCMV-specific CD4 T cells and could be targeted to enhance control of persistent/latent infection.

Author Info: (1) Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America. (2) Division of Biological Sciences, University of California

Author Info: (1) Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America. (2) Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America. (3) Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America. (4) Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America. (5) Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America. (6) Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America.

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Lentiviral delivery of novel fusion protein IL12/FasTI for cancer immune/gene therapy

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Many of the cytokine-based cancer immunotherapies are hindered by the devastating side effects of systemic delivery of the cytokines. To address this problem, we previously described a novel approach to locally achieve high doses of interleukin-12 (IL-12) in tumors and demonstrated that bi-functional fusion protein mIL-12/FasTI expressed by stable clones of TC-1 cells efficiently suppressed tumor proliferation by activating natural killer (NK) cells and other cytolytic killer cells and sending apoptotic signals into tumor cells. In the present study, we employed a lentiviral vector-based gene delivery system to deliver this fusion construct directly into tumor cells. We show that lentiviral vector efficiently delivers the fusion constructs into Hela cells in vitro as assayed by RT-PCR and immunohistochemistry (IHC). We also confirm that fusion protein mIL-12/FasTI delivered by the viral vector significantly enhanced killer cell activation, increased caspase-3 activity and decreased tumor growth in vitro. This study offers a further step for fusion protein cancer therapy for cancer patients.

Author Info: (1) Department of Biological Sciences, Clemson University, Clemson, SC, United States of America. (2) Department of Biological Sciences, Clemson University, Clemson, SC, United States of

Author Info: (1) Department of Biological Sciences, Clemson University, Clemson, SC, United States of America. (2) Department of Biological Sciences, Clemson University, Clemson, SC, United States of America. (3) Department of Biological Sciences, Clemson University, Clemson, SC, United States of America.

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Targeting CCR8 induces protective antitumor immunity and enhances vaccine-induced responses in colon cancer

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CCR8 is a chemokine receptor expressed principally on regulatory T cells (Tregs) and is known to be critical for CCR8+ Treg-mediated immunosuppression. Recent studies have demonstrated that CCR8 is uniquely upregulated in human tumor-resident Tregs of breast, colon, and lung cancer patients when compared to normal tissue-resident Tregs. Therefore, CCR8+ tumor-resident Tregs are rational targets for cancer immunotherapy. Here we demonstrate that monoclonal antibody (mAb) therapy targeting CCR8 significantly suppresses tumor growth and improves long-term survival in colorectal tumor mouse models. This antitumor activity correlated with increased tumor-specific T cells, enhanced infiltration of CD4+ and CD8+ T cells, and a significant decrease in the frequency of tumor-resident CD4+CCR8+ Tregs. Tumor-specific CD8+ T cells displayed lower expression of exhaustion markers as well as increased functionality upon restimulation. Treatment with anti-CCR8 mAb prevented de novo induction and suppressive function of Tregs without affecting CD8+ T cells. Initial studies explored a combinatorial regimen using anti-CCR8 mAb therapy and a Listeria monocytogenes (Lm)-based immunotherapy. Anti-CCR8 mAb therapy synergized with Lm-based immunotherapy to significantly delay growth of established tumors and prolong survival. Collectively, these findings identify CCR8 as a promising new target for tumor immunotherapy and provide a strong rationale for further development of this approach, either as a monotherapy or in combination with other immunotherapies.

Author Info: (1) ImmunoOncology - Research, Advaxis (United States) dovill33@gmail.com. (2) ImmunoOncology - Research, Advaxis (United States). (3) ImmunoOncology - Research, Advaxis (United States). (4) ImmunoOncology -

Author Info: (1) ImmunoOncology - Research, Advaxis (United States) dovill33@gmail.com. (2) ImmunoOncology - Research, Advaxis (United States). (3) ImmunoOncology - Research, Advaxis (United States). (4) ImmunoOncology - Research, Advaxis (United States). (5) ImmunoOncology - Research, Advaxis (United States). (6) ImmunoOncology - Research, Advaxis (United States). (7) ImmunoOncology - Research, Advaxis (United States). (8) ImmunoOncology - Research, Advaxis (United States).

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The PD-L1- and IL6-mediated dampening of the IL27/STAT1 anticancer responses are prevented by alpha-PD-L1 or alpha-IL6 antibodies

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Interleukin-27 (IL27) is a type-I cytokine of the IL6/IL12 family and is predominantly secreted by activated macrophages and dendritic cells. We show that IL27 induces STAT factor phosphorylation in cancerous cell lines of different tissue origin. IL27 leads to STAT1 phosphorylation and recapitulates an IFN-gamma-like response in the microarray analyses, with up-regulation of genes involved in antiviral defense, antigen presentation, and immune suppression. Like IFN-gamma, IL27 leads to an up-regulation of TAP2 and MHC-I proteins, which mediate increased tumor immune clearance. However, both cytokines also upregulate proteins such as PD-L1 (CD274) and IDO-1, which are associated with immune escape of cancer. Interestingly, differential expression of these genes was observed within the different cell lines and when comparing IL27 to IFN-gamma. In coculture experiments of hepatocellular carcinoma (HCC) cells with peripheral blood mononuclear cells, pre-treatment of the HCC cells with IL27 resulted in lowered IL2 production by anti-CD3/-CD28 activated T-lymphocytes. Addition of anti-PD-L1 antibody, however, restored IL2 secretion. The levels of other TH 1 cytokines were also enhanced or restored upon administration of anti-PD-L1. In addition, we show that the suppression of IL27 signaling by IL6-type cytokine pre-stimulation-mimicking a situation occurring, for example, in IL6-secreting tumors or in tumor inflammation-induced cachexia-can be antagonized by antibodies against IL6-type cytokines or their receptors. Therapeutically, the antitumor effects of IL27 (mediated, e.g., by increased antigen presentation) might thus be increased by combining IL27 with blocking antibodies against PD-L1 or/and IL6-type cytokines.

Author Info: (1) University of Luxembourg, Life Sciences Research Unit-Signal Transduction Laboratory, Belvaux, Luxembourg. (2) University of Luxembourg, Life Sciences Research Unit-Signal Transduction Laboratory, Belvaux, Luxembourg. (3)

Author Info: (1) University of Luxembourg, Life Sciences Research Unit-Signal Transduction Laboratory, Belvaux, Luxembourg. (2) University of Luxembourg, Life Sciences Research Unit-Signal Transduction Laboratory, Belvaux, Luxembourg. (3) University of Luxembourg, Life Sciences Research Unit-Bioinformatics Core Facility, Belvaux, Luxembourg. (4) University of Luxembourg, Life Sciences Research Unit-Signal Transduction Laboratory, Belvaux, Luxembourg. (5) University of Luxembourg, Life Sciences Research Unit-Signal Transduction Laboratory, Belvaux, Luxembourg. (6) University of Luxembourg, Life Sciences Research Unit-Signal Transduction Laboratory, Belvaux, Luxembourg. (7) University Hospital Wurzburg, Medical Clinic II, Division of Hepatology, Wurzburg, Germany. (8) University Hospital Wurzburg, Medical Clinic II, Division of Hepatology, Wurzburg, Germany. (9) Proteome and Genome Research Unit, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg. (10) Proteome and Genome Research Unit, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg. (11) University of Luxembourg, Life Sciences Research Unit-Signal Transduction Laboratory, Belvaux, Luxembourg. (12) University of Luxembourg, Life Sciences Research Unit-Molecular Disease Mechanisms Laboratory, Belvaux, Luxembourg. (13) University of Luxembourg, Life Sciences Research Unit-Signal Transduction Laboratory, Belvaux, Luxembourg. (14) University of Luxembourg, Life Sciences Research Unit-Signal Transduction Laboratory, Belvaux, Luxembourg.

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Interferon gamma in cancer immunotherapy

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Immune system can recognize self vs transformed self. That is why cancer immunotherapy achieves notable benefits in a wide variety of cancers. Recently, several papers reported that immune checkpoint blockade therapy led to upregulation of IFNgamma and in turn clearance of tumor cells. In this review, we conducted an extensive literature search of recent 5-year studies about the roles of IFNgamma signaling in both tumor immune surveillance and immune evasion. In addition to well-known functions, IFNgamma signaling also induces tumor ischemia and homeostasis program, resulting in tumor clearance and tumor escape, respectively. The yin and the yang of IFNgamma signaling are summarized. Thus, this review helps us to comprehensively understand the roles of IFNgamma in tumor immunity, which contributes to better design and management of clinical immunotherapy approaches.

Author Info: (1) Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China. (2) Department of Urology, Peking University Third Hospital, Beijing, China.

Author Info: (1) Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China. (2) Department of Urology, Peking University Third Hospital, Beijing, China.

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In drug-induced, immune-mediated hepatitis, interleukin-33 reduces hepatitis and improves survival independently and as a consequence of FoxP3+ T-cell activity

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Immune-mediated, drug-induced hepatitis is a rare complication of halogenated volatile anesthetic administration. IL-4-regulated Th2-polarized reactions initiate this type and other types of hepatitis, while the mechanisms that regulate the severity remain elusive. IL-33 is an innate, IL-4-inducing, Th2-polarizing cytokine that has been detected in patients with liver failure and has been associated with upregulated ST2+Foxp3+CD4+CD25+ T cells; however, roles for IL-33 in drug-induced hepatitis are unclear. We investigated IL-33 in an anesthetic, immune-mediated hepatitis modeled in BALB/c, IL-33-/- and ST2-/- mice, as well as in patients with anesthetic hepatitis. The hepatic IL-33 and ST2 levels were elevated in BALB/c mice (p < 0.05) with hepatitis, and anti-IL-33 diminished hepatitis (p < 0.05) without reducing IL-33 levels. The complete absence of IL-33 reduced IL-10 (p < 0.05) and ST2+Foxp3+CD4+CD25+ T cells (p < 0.05), as well as reduced the overall survival (p < 0.05), suggesting suppressive roles for IL-33 in anesthetic, immune-mediated hepatitis. All of the mice demonstrated similar levels of CD4+ T-cell proliferation following direct T-cell receptor stimulation, but we detected splenic IL-33 and ST2-negative Foxp3+CD4+CD25+ T cells in ST2-/- mice that developed less hepatitis than BALB/c mice (p < 0.05), suggesting that ST2-negative Foxp3+CD4+CD25+ T cells reduced hepatitis. In patients, serum IL-33 and IPEX levels were correlated in controls (r(2) = 0.5, p < 0.05), similar to the levels in mice, but not in anesthetic hepatitis patients (r(2) = 0.01), who had elevated IL-33 (p < 0.001) and decreased IPEX (p < 0.01). Our results suggest that, in anesthetic, immune-mediated hepatitis, IL-33 does not regulate the CD4+ T-cell proliferation that initiates hepatitis, but IL-33, likely independent of ST2, reduces hepatitis via upregulation of Foxp3+CD4+CD25+ T cells. Further studies are needed to translate the role of IL-33 to human liver disease.

Author Info: (1) Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 1800 Orleans Street, Suite 6349, Baltimore, MD, 21287, USA. (2) Department of Anesthesiology and

Author Info: (1) Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 1800 Orleans Street, Suite 6349, Baltimore, MD, 21287, USA. (2) Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 1800 Orleans Street, Suite 6349, Baltimore, MD, 21287, USA. (3) Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 1800 Orleans Street, Suite 6349, Baltimore, MD, 21287, USA. (4) Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 1800 Orleans Street, Suite 6349, Baltimore, MD, 21287, USA. (5) RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minamimachi, Chuo-ku, Kobe, Japan, 650-0047. (6) Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Melbourne, Australia. (7) Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA, 02115, USA. (8) Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 1800 Orleans Street, Suite 6349, Baltimore, MD, 21287, USA. dnjoku@jhmi.edu. Department of Pathology, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD, 21205, USA. dnjoku@jhmi.edu.

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