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Briones AC, del Estal L, Villa-Gómez C, Bermejo V, Cervera I, Gutiérrez-Huerta P, Montes-Casado M, Ortega S, Barbacid M, Rojo JM, Portolés P. T Cell-Specific Inactivation of the PI3K p110α Catalytic Subunit: Effect in T Cell Differentiation and Antigen-Specific Responses. Int J Mol Sci 2025; 26:595. [PMID: 39859310 PMCID: PMC11765243 DOI: 10.3390/ijms26020595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Accepted: 01/09/2025] [Indexed: 01/27/2025] Open
Abstract
Class IA PI3K p110δ and p110α subunits participate in TCR and costimulatory receptor signals involved in T cell-mediated immunity, but the role of p110α is not completely understood. Here, we analyzed a mouse model of the Cre-dependent functional inactivation of p110α (kinase dead) in T lymphocytes (p110αKD-T, KD). KD mice showed increased cellularity in thymus and spleen and altered T cell differentiation with increased number of CD4+CD8+ DP thymocytes, enhanced proportion of CD4+ SP lymphocytes linked to altered apoptosis, lower Treg cells, and increased AKT and ERK phosphorylation in activated thymocytes. In the spleen, the percentages of CD4+ Treg cells and CD8+ naive lymphocytes were reduced. In vitro, the differentiation of CD4+ cells from p110αKD-T mice showed lower induced Treg (iTreg) cell yield or IL-10 secretion. Moreover, Tfh cell yield, IL-21 secretion, and PI3-K-dependent elongation were hampered, as was Erk and Akt activation. Th1 or Th17 differentiation in vitro was not altered. The immunization of p110α-KD-T mice with KLH protein antigen induced an enhanced proportion of CXCR5+ CD4+ cells and germinal center B cells, increased ICOS expression in CD4+ cells, or IFN-γ secretion upon antigen re-activation in vitro. However, anti-KLH antibody responses in serum was similar in WT or p110α KD mice. These data show that T cell-specific p110α inactivation alters T cell differentiation and function.
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Affiliation(s)
- Alejandro C. Briones
- Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain
- Department of Immunology, Complutense University School of Medicine, i+12 Research Institute, 28040 Madrid, Spain
| | - Laura del Estal
- Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain
| | - Cristina Villa-Gómez
- Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain
| | - Verónica Bermejo
- Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain
| | - Isabel Cervera
- Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain
| | - Pedro Gutiérrez-Huerta
- Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain
| | - María Montes-Casado
- Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain
| | - Sagrario Ortega
- Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain
| | - Mariano Barbacid
- Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain
| | - José María Rojo
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), 28040 Madrid, Spain
| | - Pilar Portolés
- Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain
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2
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Yang X, Bai H, Yuan X, Yang X, Liu Y, Guo M, Hu N, Jiang B, Lian Z, Ma Z, Wang J, Sun X, Zhang T, Su D, Wu Y, Li J, Wang F, Wang Z, Wang L, Liu X, Song X. A highly selective PI3Kδ inhibitor BGB-10188 shows superior preclinical anti-tumor activities and decreased on-target side effects on colon. Neoplasia 2024; 57:101053. [PMID: 39260132 PMCID: PMC11415975 DOI: 10.1016/j.neo.2024.101053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 09/05/2024] [Indexed: 09/13/2024]
Abstract
PI3Kδ is a key signal transduction molecule in normal and malignant B cells, as well as in T-regulatory cells, making it a promising target for treatment of hematologic malignancies through both direct killing and anti-tumor immunity regulation. BGB-10188 is a highly selective inhibitor of PI3Kδ, showing more than 3000 folds selectivity over other PI3K isoforms and no significant inhibition across tested kinases. BGB-10188 potently inhibited PI3Kδ with IC50s ranging from 1.7-16 nM through various in vitro assays and showed a long-lasting and strong target inhibition in mouse B cells in vivo. BGB-10188 showed significant antitumor effects in human B cell lymphoma xenograft models as single agent or in combination with the BTK inhibitor zanubrutinib. BGB-10188 showed significant Treg inhibition in blood but not in colon, along with less drug accumulation in colon compared with idelalisib, which is an approved PI3Kdelta inhibitor with high incidence of gastrointestinal side effects in clinic. In summary, BGB-10188 is a novel PI3Kδ inhibitor with high selectivity, potency and improved safety profile shown in preclinical studies, which is showing the potential as a best-in-class PI3Kδ inhibitor.
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Affiliation(s)
- Xiao Yang
- BeiGene Global Research, Beijing 102206, PR China
| | - Huichen Bai
- BeiGene Global Research, Beijing 102206, PR China
| | - Xi Yuan
- BeiGene Global Research, Beijing 102206, PR China
| | | | - Ye Liu
- BeiGene Global Research, Beijing 102206, PR China
| | - Mingming Guo
- BeiGene Global Research, Beijing 102206, PR China
| | - Nan Hu
- BeiGene Global Research, Beijing 102206, PR China
| | - Beibei Jiang
- BeiGene Global Research, Beijing 102206, PR China
| | - Zeqin Lian
- BeiGene Global Research, Beijing 102206, PR China
| | - Zhilong Ma
- BeiGene Global Research, Beijing 102206, PR China
| | | | - Xuebing Sun
- BeiGene Global Research, Beijing 102206, PR China
| | | | - Dan Su
- BeiGene Global Research, Beijing 102206, PR China
| | - Yue Wu
- BeiGene Global Research, Beijing 102206, PR China
| | - Jing Li
- BeiGene Global Research, Beijing 102206, PR China
| | - Fan Wang
- BeiGene Global Research, Beijing 102206, PR China
| | - Zhiwei Wang
- BeiGene Global Research, Beijing 102206, PR China
| | - Lai Wang
- BeiGene Global Research, Beijing 102206, PR China
| | - Xuesong Liu
- BeiGene Global Research, Beijing 102206, PR China
| | - Xiaomin Song
- BeiGene Global Research, Beijing 102206, PR China.
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Zogorean R, Wirtz S. The yin and yang of B cells in a constant state of battle: intestinal inflammation and inflammatory bowel disease. Front Immunol 2023; 14:1260266. [PMID: 37849749 PMCID: PMC10577428 DOI: 10.3389/fimmu.2023.1260266] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 09/18/2023] [Indexed: 10/19/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, defined by a clinical relapse-remitting course. Affecting people worldwide, the origin of IBD is still undefined, arising as a consequence of the interaction between genes, environment, and microbiota. Although the root cause is difficult to identify, data clearly indicate that dysbiosis and pathogenic microbial taxa are connected with the establishment and clinical course of IBD. The composition of the microbiota is shaped by plasma cell IgA secretion and binding, while cytokines such as IL10 or IFN-γ are important fine-tuners of the immune response in the gastrointestinal environment. B cells may also influence the course of inflammation by promoting either an anti-inflammatory or a pro-inflammatory milieu. Here, we discuss IgA-producing B regulatory cells as an anti-inflammatory factor in intestinal inflammation. Moreover, we specify the context of IgA and IgG as players that can potentially participate in mucosal inflammation. Finally, we discuss the role of B cells in mouse infection models where IL10, IgA, or IgG contribute to the outcome of the infection.
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Affiliation(s)
- Roxana Zogorean
- Medizinische Klinik 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Stefan Wirtz
- Medizinische Klinik 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, Erlangen, Bavaria, Germany
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Yang Y, Xiao G, Cheng P, Zeng J, Liu Y. Protective Application of Chinese Herbal Compounds and Formulae in Intestinal Inflammation in Humans and Animals. Molecules 2023; 28:6811. [PMID: 37836654 PMCID: PMC10574200 DOI: 10.3390/molecules28196811] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/16/2023] [Accepted: 09/19/2023] [Indexed: 10/15/2023] Open
Abstract
Intestinal inflammation is a chronic gastrointestinal disorder with uncertain pathophysiology and causation that has significantly impacted both the physical and mental health of both people and animals. An increasing body of research has demonstrated the critical role of cellular signaling pathways in initiating and managing intestinal inflammation. This review focuses on the interactions of three cellular signaling pathways (TLR4/NF-κB, PI3K-AKT, MAPKs) with immunity and gut microbiota to explain the possible pathogenesis of intestinal inflammation. Traditional medicinal drugs frequently have drawbacks and negative side effects. This paper also summarizes the pharmacological mechanism and application of Chinese herbal compounds (Berberine, Sanguinarine, Astragalus polysaccharide, Curcumin, and Cannabinoids) and formulae (Wumei Wan, Gegen-Qinlian decoction, Banxia xiexin decoction) against intestinal inflammation. We show that the herbal compounds and formulae may influence the interactions among cell signaling pathways, immune function, and gut microbiota in humans and animals, exerting their immunomodulatory capacity and anti-inflammatory and antimicrobial effects. This demonstrates their strong potential to improve gut inflammation. We aim to promote herbal medicine and apply it to multispecies animals to achieve better health.
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Affiliation(s)
- Yang Yang
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410125, China; (Y.Y.); (G.X.); (P.C.)
- Hunan Key Laboratory, Chinese Veterinary Medicine, Changsha 410125, China
| | - Gang Xiao
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410125, China; (Y.Y.); (G.X.); (P.C.)
| | - Pi Cheng
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410125, China; (Y.Y.); (G.X.); (P.C.)
- Hunan Key Laboratory, Chinese Veterinary Medicine, Changsha 410125, China
| | - Jianguo Zeng
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410125, China; (Y.Y.); (G.X.); (P.C.)
- Hunan Key Laboratory, Chinese Veterinary Medicine, Changsha 410125, China
| | - Yisong Liu
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410125, China; (Y.Y.); (G.X.); (P.C.)
- Hunan Key Laboratory, Chinese Veterinary Medicine, Changsha 410125, China
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Zhang X, Dai Q, Shan J, Zhang S, Zhang B, Liu S, Zhang Y, Wang Y, Li X, Jin X, Liang D, Ding J, Wang Y, Wen Y. Inhibition of phosphoinositide‑3 kinases γ/δ ameliorates pulmonary granuloma by rescuing Treg function in a sarcoidosis model. Exp Ther Med 2023; 25:225. [PMID: 37123205 PMCID: PMC10133787 DOI: 10.3892/etm.2023.11923] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 02/17/2023] [Indexed: 05/02/2023] Open
Abstract
Sarcoidosis is a multisystem inflammatory disease characterized by the development of Th1/Th17/regulatory T cells (Tregs)-related non-caseating granulomas. Phosphoinositide-3 kinases δ/γ (PI3Kδ/γ) play an important role in the maintenance of effective immunity, especially for Tregs homeostasis and stability. In the present study, superoxide dismutase A (SodA) stimulation was used to establish the sarcoidosis mouse model. The second immune stimulus was accompanied by CAL-101 (PI3Kδ inhibitor) or AS-605240 (PI3Kδ/γ inhibitor) treatment. To detect the effect of the PI3Kδ/γ inhibitor on the morphology of pulmonary granuloma and the activation of the PI3K signaling pathway, hematoxylin and eosin staining and immunofluorescence and western blotting was used, respectively. Fluorescence-activated cell sorting analysis and reverse transcription-quantitative PCR were adopted to detect the effect of the PI3Kδ/γ inhibitor on the SodA-induced sarcoidosis mouse model in respect to immune cell disorder and the function of Treg cells, with CD4+CD25- T cells and CD4+CD25+ T cells sorted by magnetic cell sorting. The results demonstrated that the inhibition of PI3Kδ/γ by transtracheal CAL-101/AS-605240 administration facilitated pulmonary granuloma formation. These therapeutic effects were associated with certain mechanisms, including suppressing the aberrantly activated PI3K/Akt signaling in both pulmonary granuloma and Tregs, particularly rescuing the suppressive function of Tregs. Notably, CAL-101 was more effective in immune modulation compared with AS-605240 and could overcome the aberrantly activated Akt in the lung and Tregs. These results suggest that PI3K/Akt signaling, especially the PI3Kδ subunit, can play a key role in optimal Tregs-mediated protection against pulmonary sarcoidosis. Therefore, transtracheal usage of PI3Kδ/γ inhibitors is an attractive therapy that may be developed into a new immune-therapeutic principle for sarcoidosis in the future.
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Affiliation(s)
- Xian Zhang
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Qianqian Dai
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Jiajia Shan
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Shiyun Zhang
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Bin Zhang
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Siyang Liu
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Yixue Zhang
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Ying Wang
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Xiaojie Li
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Xuguang Jin
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Dongmei Liang
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Jingjing Ding
- Department of Respiratory Medicine and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210003, P.R. China
| | - Yong Wang
- State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
- Correspondence to: Dr Yanting Wen, State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, P.R. China.
| | - Yanting Wen
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
- Correspondence to: Dr Yanting Wen, State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, P.R. China.
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Gadi D, Martindale SP, Chiu PY, Khalsa J, Chen PH, Fernandes SM, Wang Z, Tyekucheva S, Machado JH, Fisher DC, Armand P, Davids MS, Rodig S, Sherry B, Brown JR. Circulating Th17 T cells at treatment onset predict autoimmune toxicity of PI3Kδ inhibitors. Blood Cancer J 2023; 13:22. [PMID: 36732326 PMCID: PMC9895075 DOI: 10.1038/s41408-023-00788-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 12/29/2022] [Accepted: 01/09/2023] [Indexed: 02/04/2023] Open
Abstract
PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity, despite promising efficacy and evidence that toxicity is associated with improved clinical outcomes. Prior phenotypic evaluation by CyTOF has identified increases in activated CD8 T cells with activation of Th17 T cells, as well as decreases in Tregs, particularly in patients with toxicity. Here we sought to further understand the effects of idelalisib and duvelisib in vitro, and demonstrate that both idelalisib and duvelisib can inhibit T cell proliferation as well as Th1 and Treg differentiation in vitro, while promoting Th2 and Th17 differentiation. We further demonstrate directly using intracellular flow cytometry that autoimmune toxicity in patients is associated with higher absolute numbers of CD4 and CD8 T cells with Th17 differentiation in peripheral blood prior to therapy, and that gastrointestinal tissues from patients with active autoimmune complications of PI3Kδ inhibitors show infiltration with Th17+ T cells. These same tissues show depletion of Tregs as compared to CLL patients without toxicity, suggesting that loss of Tregs may be permissive for Th17 activation to lead to autoimmune toxicity. Clinical trials to restore this balance are warranted.
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Affiliation(s)
- Deepti Gadi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Stephen P Martindale
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Pui Yan Chiu
- Center for Immunology & Inflammation, Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Jasneet Khalsa
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Pei-Hsuan Chen
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Stacey M Fernandes
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Zixu Wang
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - John-Hanson Machado
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - David C Fisher
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Philippe Armand
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Matthew S Davids
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Scott Rodig
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Barbara Sherry
- Center for Immunology & Inflammation, Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Jennifer R Brown
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
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Hoffner O’Connor M, Berglind A, Kennedy Ng MM, Keith BP, Lynch ZJ, Schaner MR, Steinbach EC, Herzog J, Trad OK, Jeck WR, Arthur JC, Simon JM, Sartor RB, Furey TS, Sheikh SZ. BET Protein Inhibition Regulates Macrophage Chromatin Accessibility and Microbiota-Dependent Colitis. Front Immunol 2022; 13:856966. [PMID: 35401533 PMCID: PMC8988134 DOI: 10.3389/fimmu.2022.856966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 02/16/2022] [Indexed: 01/14/2023] Open
Abstract
Introduction In colitis, macrophage functionality is altered compared to normal homeostatic conditions. Loss of IL-10 signaling results in an inappropriate chronic inflammatory response to bacterial stimulation. It remains unknown if inhibition of bromodomain and extra-terminal domain (BET) proteins alters usage of DNA regulatory elements responsible for driving inflammatory gene expression. We determined if the BET inhibitor, (+)-JQ1, could suppress inflammatory activation of macrophages in Il10-/- mice. Methods We performed ATAC-seq and RNA-seq on Il10-/- bone marrow-derived macrophages (BMDMs) cultured in the presence and absence of lipopolysaccharide (LPS) with and without treatment with (+)-JQ1 and evaluated changes in chromatin accessibility and gene expression. Germ-free Il10-/- mice were treated with (+)-JQ1, colonized with fecal slurries and underwent histological and molecular evaluation 14-days post colonization. Results Treatment with (+)-JQ1 suppressed LPS-induced changes in chromatin at distal regulatory elements associated with inflammatory genes, particularly in regions that contain motifs for AP-1 and IRF transcription factors. This resulted in attenuation of inflammatory gene expression. Treatment with (+)-JQ1 in vivo resulted in a mild reduction in colitis severity as compared with vehicle-treated mice. Conclusion We identified the mechanism of action associated with a new class of compounds that may mitigate aberrant macrophage responses to bacteria in colitis.
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Affiliation(s)
- Michelle Hoffner O’Connor
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Ana Berglind
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Meaghan M. Kennedy Ng
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Genetics, Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Benjamin P. Keith
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Genetics, Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Zachary J. Lynch
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Matthew R. Schaner
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Erin C. Steinbach
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Medicine, Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Jeremy Herzog
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Omar K. Trad
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - William R. Jeck
- Department of Pathology, Duke University, Durham, NC, United States
| | - Janelle C. Arthur
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Jeremy M. Simon
- Department of Genetics, Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Carolina Institute for Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - R. Balfour Sartor
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Terrence S. Furey
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Genetics, Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Shehzad Z. Sheikh
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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Effects of Herb-Partitioned Moxibustion on Autophagy and Immune Activity in the Colon Tissue of Rats with Crohn’s Disease. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:3534874. [PMID: 35126598 PMCID: PMC8816589 DOI: 10.1155/2022/3534874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 01/11/2022] [Indexed: 11/18/2022]
Abstract
Objective To investigate the mechanism of action of herb-partitioned moxibustion on CD from the perspective of autophagy and immunity. Methods The expression of microtubule-associated protein LC3II and SQSTM1/p62 in the colon tissues was detected by immunohistochemistry. Western blot was used to detect the expression of autophagic and immune-related proteins in the colon, such as LC3II, SQSTM1/p62, Beclin1, ATG16L1, NOD2, IRGM, IL-1β, IL-17, and TNF-β. mRNA levels of immune factors, such as IL-1β, IL-17, and TNF-β, and autophagy signaling molecules, such as PI3KC, AKT1, LKB1, and mTOR, were detected by RT-qPCR. Results Herb-partitioned moxibustion reduced the protein levels of ATG16L1, NOD2, IRGM, LC3II, and Beclin1 (P < 0.01) and both the protein and mRNA levels of IL-1β, IL-17, and TNF-β in CD rats (P < 0.01 or P < 0.05), and it also increased the expression of SQSTM1/p62 protein (P < 0.01). The modulatory effects of herb-partitioned moxibustion on ATG16L1, NOD2, IRGM, LC3II, TNF-β, and IL-17 protein and IL-1β protein and mRNA were better than those of mesalazine (P < 0.01 or P < 0.05). Herb-partitioned moxibustion also reduced colon PI3KC, AKT1, and LKB1 mRNA expressions in CD rats (P < 0.01 or P < 0.05) and increased mTOR protein expression (P < 0.05). And the modulatory effect of herb-partitioned moxibustion on AKT1 mRNA was better than that of mesalazine (P < 0.05). Conclusion Herb-partitioned moxibustion may inhibit excessively activated autophagy and modulate the expression of immune-related factors by regulating the LKB1-mTOR-PI3KC signal transduction networks, thereby alleviating intestinal inflammation in CD rats.
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Vanhaesebroeck B, Perry MWD, Brown JR, André F, Okkenhaug K. PI3K inhibitors are finally coming of age. Nat Rev Drug Discov 2021; 20:741-769. [PMID: 34127844 PMCID: PMC9297732 DOI: 10.1038/s41573-021-00209-1] [Citation(s) in RCA: 269] [Impact Index Per Article: 67.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/08/2021] [Indexed: 01/08/2023]
Abstract
Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval - the PI3Kα isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3Kδ in B cell malignancies. In addition to targeting cancer cell-intrinsic PI3K activity, emerging evidence highlights the potential of PI3K inhibitors in cancer immunotherapy. This Review summarizes key discoveries that aid the clinical translation of PI3Kα and PI3Kδ inhibitors, highlighting lessons learnt and future opportunities.
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Affiliation(s)
| | - Matthew W D Perry
- Medicinal Chemistry, Research and Early Development, Respiratory & Immunology BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Jennifer R Brown
- CLL Center, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Fabrice André
- Institut Gustave Roussy, INSERM U981, Université Paris Saclay, Paris, France
| | - Klaus Okkenhaug
- Department of Pathology, University of Cambridge, Cambridge, UK
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10
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Rojo JM, Montes-Casado M, Aragoneses-Fenoll L, Ojeda G, Dianzani U, Portolés P. PI3-Kinase p110α Deficiency Modulates T Cell Homeostasis and Function and Attenuates Experimental Allergic Encephalitis in Mature Mice. Int J Mol Sci 2021; 22:ijms22168698. [PMID: 34445401 PMCID: PMC8395417 DOI: 10.3390/ijms22168698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/09/2021] [Accepted: 08/11/2021] [Indexed: 11/16/2022] Open
Abstract
Class I phosphoinositide 3-kinases (PI3K) are involved in the development of normal and autoimmune responses, including Experimental Autoimmune Encephalomyelitis (EAE), a mouse model for human multiple sclerosis (MS). Here, the role of the ubiquitously expressed class IA PI3K p110α catalytic subunits in EAE has been analyzed using a model of Cre/flox mediated T cell specific deletion of p110α catalytic chain (p110αΔT). Comparison of two month-old (young) and six month-old (mature) p110αΔT mice and their wild type (WT) counterparts indicated loss of spleen CD4+ T cells that increased with age, indicating a role of p110α in their homeostasis. In contrast, CD4+ T regulatory (Treg) cells were enhanced in mature p110αΔT mice when compared to WT mice. Since Myelin Oligodendrocyte Glycoprotein (MOG) peptide-induced EAE is dependent on, or mediated by CD4+ T cells and CD4+ T cell-derived cytokines and controlled by Treg cells, development of EAE in young and mature WT or p110αΔT mice was analyzed. EAE clinical symptoms and disease scores in six month p110αΔT mice were significantly lower than those of mature WT, or young WT and p110αΔT mice. Furthermore, ex vivo antigen activation of lymph node cells from MOG immunized mature p110αΔT mice induced significantly lower levels of IFN-γ and IL-17A than young p110αΔT or young and mature WT mice. Other cytokines including IL-2, IL-10 or TNF-α showed no significant differences between p110αΔT and WT mature mice. Our data show a lower incidence of MOG-induced EAE in mature p110αΔT mice linked to altered T cell homeostasis and lower secretion of inflammatory cytokines.
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Affiliation(s)
- José M. Rojo
- Departamento de Biomedicina Molecular, Centro de Investigaciones Biológicas Margarita Salas, CSIC, 28040 Madrid, Spain
- Correspondence: (J.M.R.); (P.P.)
| | - María Montes-Casado
- Unidad de Inmunología Celular, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain; (M.M.-C.); (L.A.-F.); (G.O.)
| | - Laura Aragoneses-Fenoll
- Unidad de Inmunología Celular, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain; (M.M.-C.); (L.A.-F.); (G.O.)
| | - Gloria Ojeda
- Unidad de Inmunología Celular, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain; (M.M.-C.); (L.A.-F.); (G.O.)
| | - Umberto Dianzani
- Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Department of Health Sciences, University of Piemonte Orientale (UPO), 28100 Novara, Italy;
| | - Pilar Portolés
- Unidad de Inmunología Celular, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain; (M.M.-C.); (L.A.-F.); (G.O.)
- Presidencia, Consejo Superior de Investigaciones Científicas (CSIC), 28006 Madrid, Spain
- Correspondence: (J.M.R.); (P.P.)
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11
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Juarez M, Diaz N, Johnston GI, Nayar S, Payne A, Helmer E, Cain D, Williams P, Devauchelle-Pensec V, Fisher BA, Giacomelli R, Gottenberg JE, Guggino G, Kvarnström M, Mariette X, Ng WF, Rosas J, Sánchez Bursón J, Triolo G, Barone F, Bowman SJ. A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren's syndrome. Rheumatology (Oxford) 2021; 60:1364-1375. [PMID: 32949140 DOI: 10.1093/rheumatology/keaa410] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/08/2020] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVES This phase 2 proof-of-concept study (NCT02610543) assessed efficacy, safety and effects on salivary gland inflammation of seletalisib, a potent and selective PI3Kδ inhibitor, in patients with moderate-to-severe primary Sjögren's syndrome (PSS). METHODS Adults with PSS were randomized 1:1 to seletalisib 45 mg/day or placebo, in addition to current PSS therapy. Primary end points were safety and tolerability and change from baseline in EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score at week 12. Secondary end points included change from baseline at week 12 in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score and histological features in salivary gland biopsies. RESULTS Twenty-seven patients were randomized (seletalisib n = 13, placebo n = 14); 20 completed the study. Enrolment challenges led to early study termination with loss of statistical power (36% vs 80% planned). Nonetheless, a trend for improvement in ESSDAI and ESSPRI [difference vs placebo: -2.59 (95% CI: -7.30, 2.11; P=0.266) and -1.55 (95% CI: -3.39, 0.28), respectively] was observed at week 12. No significant changes were seen in saliva and tear flow. Serious adverse events (AEs) were reported in 3/13 of patients receiving seletalisib vs 1/14 for placebo and 5/13 vs 1/14 discontinued due to AEs, respectively. Serum IgM and IgG concentrations decreased in the seletalisib group vs placebo. Seletalisib demonstrated efficacy in reducing size and organisation of salivary gland inflammatory foci and in target engagement, thus reducing PI3K-mTOR signalling compared with placebo. CONCLUSION Despite enrolment challenges, seletalisib demonstrated a trend towards clinical improvement in patients with PSS. Histological analyses demonstrated encouraging effects of seletalisib on salivary gland inflammation and organisation. TRIAL REGISTRATION https://clinicaltrials.gov, NCT02610543.
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Affiliation(s)
| | - Nieves Diaz
- Translational Medicine, UCB Pharma, Slough, UK
| | | | - Saba Nayar
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | | | - Eric Helmer
- Quantitative Clinical Pharmacology, Slough, UK
| | - Dionne Cain
- Global Clinical Sciences and Operations, UCB Pharma, Slough, UK
| | | | | | - Benjamin A Fisher
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.,Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Roberto Giacomelli
- Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Jacques-Eric Gottenberg
- Department of Rheumatology, National Reference Centre For Rare Systemic Auto-Immune Diseases, Strasbourg University Hospital, University of Strasbourg, IBMC, CNRS UPR 3572, Strasbourg, France
| | - Giuliana Guggino
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology Section, University of Palermo, Palermo, Italy
| | - Marika Kvarnström
- Department of Medicine, Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden
| | - Xavier Mariette
- Université Paris-Saclay, INSERM, CEA, Centre de recherche en Immunologie des Infections Virales et des Maladies auto-Immunes, AP-HP.Université Paris-Saclay, Hôpital Bicêtre, Rheumatology Department, Le Kremlin Bicêtre, France
| | - Wan Fai Ng
- Translational and Clinical Research Institute, Newcastle University & NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne, UK
| | - José Rosas
- Department of Rheumatology, Hospital Marina Baixa, Villajoyosa, Spain
| | | | - Giovanni Triolo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology Section, University of Palermo, Palermo, Italy
| | - Francesca Barone
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Simon J Bowman
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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12
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Ishida K, Werner JA, Lafleur M, Wisler J, Wannberg S, Kalanzi J, Bussiere JL, Monticello TM. Phosphatidylinositol 3-Kinase δ-Specific Inhibitor-Induced Changes in the Ovary and Testis in the Sprague Dawley Rat and Cynomolgus Monkey. Int J Toxicol 2021; 40:344-354. [PMID: 33866838 DOI: 10.1177/10915818211008175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Phosphatidylinositol 3-kinase (PI3K) δ is a lipid kinase primarily found in leukocytes, which regulates important cell functions. AMG2519493 was a PI3K δ-specific inhibitor in development for treatment of various inflammatory diseases. AMG2519493-related changes in the male and/or female reproductive organs were observed in the 1- and 3-month oral repeat dose toxicology studies in the rat and cynomolgus monkey. Hemorrhagic corpora lutea cysts and increased incidence of corpora lutea cysts without hemorrhage were observed in the ovaries at supra pharmacological doses in the rat. A decrease in seminiferous germ cells in the testis, indicative of spermatogenesis maturation arrest, was observed in both the rat and cynomolgus monkey. Although the characteristics were comparable, the drug systemic exposures associated with the testicular changes were very different between the 2 species. In the rat, the testicular change was only observed at supra pharmacologic exposure. Isotype assessment of PI3K signaling in rat spermatogonia in vitro indicated a role for PI3K β, but not δ, in the c Kit/PI3K/protein kinase B signaling pathway. Therefore, changes in both the ovary and testis of the rat were considered due to off target effect as they only occurred at suprapharmacologic exposure. In contrast, the testicular changes in the cynomolgus monkey (decrease in seminiferous germ cells) occurred at very low doses associated with PI3K δ-specific inhibition, indicating that the PI3K δ isoform may be important in spermatogenesis maturation in the cynomolgus monkey. Our results suggest species-related differences in PI3K isoform-specific control on reproductive organs.
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Affiliation(s)
| | | | | | - John Wisler
- 7129Amgen Inc, Thousand Oaks, CA, USA
- 328878AnaptysBio Inc, San Diego, CA, USA
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13
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Guarente V, Sportoletti P. Lessons, Challenges and Future Therapeutic Opportunities for PI3K Inhibition in CLL. Cancers (Basel) 2021; 13:cancers13061280. [PMID: 33805745 PMCID: PMC7999552 DOI: 10.3390/cancers13061280] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/08/2021] [Accepted: 03/09/2021] [Indexed: 01/04/2023] Open
Abstract
Simple Summary The phosphoinositide 3-kinase (PI3K) is a family of kinases that play a key role in the biology of chronic lymphocytic leukemia (CLL). Inhibitors of PI3K demonstrated efficacy in the treatment of CLL, associated with significant adverse events that limited the clinical use of this drugs. In this review, we underlined the relevance of PI3K inhibitors in CLL, we collected recent data about the use of these molecules in clinical practice and in clinical trial discussing strategies for the management of adverse events, which could help to improve the use of these therapies in the treatment of CLL. Abstract Chronic lymphocytic leukemia (CLL) shows constitutive phosphatidylinositol 3-kinase (PI3K) activation resulting from aberrant regulation of the B-cell receptor (BCR) signaling. PI3K inhibitors have been evaluated in CLL therapy, bringing a new treatment opportunity for patients with this disease. Despite the proven therapeutic efficacy, the use of approved PI3K inhibitors is limited by severe immune-mediated toxicities and given the availability of other more tolerable agents. This article reviews the relevance of PI3K signaling and pharmacologic inhibition in CLL. Data on efficacy and toxicity of PI3K inhibitors are also presented, as well as strategies for overcoming barriers for their clinical use in CLL treatment.
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14
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Aydin E, Faehling S, Saleh M, Llaó Cid L, Seiffert M, Roessner PM. Phosphoinositide 3-Kinase Signaling in the Tumor Microenvironment: What Do We Need to Consider When Treating Chronic Lymphocytic Leukemia With PI3K Inhibitors? Front Immunol 2021; 11:595818. [PMID: 33552053 PMCID: PMC7857022 DOI: 10.3389/fimmu.2020.595818] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 12/07/2020] [Indexed: 12/12/2022] Open
Abstract
Phosphoinositide 3-kinases (PI3Ks) and their downstream proteins constitute a signaling pathway that is involved in both normal cell growth and malignant transformation of cells. Under physiological conditions, PI3K signaling regulates various cellular functions such as apoptosis, survival, proliferation, and growth, depending on the extracellular signals. A deterioration of these extracellular signals caused by mutational damage in oncogenes or growth factor receptors may result in hyperactivation of this signaling cascade, which is recognized as a hallmark of cancer. Although higher activation of PI3K pathway is common in many types of cancer, it has been therapeutically targeted for the first time in chronic lymphocytic leukemia (CLL), demonstrating its significance in B-cell receptor (BCR) signaling and malignant B-cell expansion. The biological activity of the PI3K pathway is not only limited to cancer cells but is also crucial for many components of the tumor microenvironment, as PI3K signaling regulates cytokine responses, and ensures the development and function of immune cells. Therefore, the success or failure of the PI3K inhibition is strongly related to microenvironmental stimuli. In this review, we outline the impacts of PI3K inhibition on the tumor microenvironment with a specific focus on CLL. Acknowledging the effects of PI3K inhibitor-based therapies on the tumor microenvironment in CLL can serve as a rationale for improved drug development, explain treatment-associated adverse events, and suggest novel combinatory treatment strategies in CLL.
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Affiliation(s)
- Ebru Aydin
- Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden
| | - Sebastian Faehling
- Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Medical Faculty, University of Heidelberg, Heidelberg, Germany
| | - Mariam Saleh
- Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Molecular Medicine, Ulm University, Ulm, Germany
| | - Laura Llaó Cid
- Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Bioscience, University of Heidelberg, Heidelberg, Germany
| | - Martina Seiffert
- Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Philipp M Roessner
- Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
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15
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Methot JL, Achab A, Christopher M, Zhou H, McGowan MA, Trotter BW, Fradera X, Lesburg CA, Goldenblatt P, Hill A, Chen D, Otte KM, Augustin M, Shah S, Katz JD. Optimization of Versatile Oxindoles as Selective PI3Kδ Inhibitors. ACS Med Chem Lett 2020; 11:2461-2469. [PMID: 33335668 PMCID: PMC7734802 DOI: 10.1021/acsmedchemlett.0c00441] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 11/17/2020] [Indexed: 12/11/2022] Open
Abstract
The 3,3-disubstituted oxindole moiety is a versatile and rigid three-dimensionally shaped scaffold. When engineered with a purine hinge-binding core, exceptionally selective PI3Kδ kinase inhibitors were discovered by exploiting small differences in isoform selectivity pockets. Crystal structures of early lead 2f bound to PI3Kδ and PI3Kα helped rationalize the high selectivity observed with 2f. By attenuating the lypophilicity and metabolic liabilities of an oxindole moiety, we improved the preclinical species PK and solubility and reduced adenosine uptake activity. The excellent potency and kinome selectivity of 7-azaoxindole 4d and spirooxindole 5d, together with a low plasma clearance and good half-life in rat and dog, supported a low once-daily predicted human dose.
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Affiliation(s)
- Joey L. Methot
- Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics,
Pharmacodynamics and Drug Metabolism, Merck
& Co., Inc., Boston, Massachusetts 02115, United States
| | - Abdelghani Achab
- Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics,
Pharmacodynamics and Drug Metabolism, Merck
& Co., Inc., Boston, Massachusetts 02115, United States
| | - Matthew Christopher
- Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics,
Pharmacodynamics and Drug Metabolism, Merck
& Co., Inc., Boston, Massachusetts 02115, United States
| | - Hua Zhou
- Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics,
Pharmacodynamics and Drug Metabolism, Merck
& Co., Inc., Boston, Massachusetts 02115, United States
| | - Meredeth A. McGowan
- Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics,
Pharmacodynamics and Drug Metabolism, Merck
& Co., Inc., Boston, Massachusetts 02115, United States
| | - B. Wesley Trotter
- Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics,
Pharmacodynamics and Drug Metabolism, Merck
& Co., Inc., Boston, Massachusetts 02115, United States
| | - Xavier Fradera
- Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics,
Pharmacodynamics and Drug Metabolism, Merck
& Co., Inc., Boston, Massachusetts 02115, United States
| | - Charles A. Lesburg
- Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics,
Pharmacodynamics and Drug Metabolism, Merck
& Co., Inc., Boston, Massachusetts 02115, United States
| | - Peter Goldenblatt
- Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics,
Pharmacodynamics and Drug Metabolism, Merck
& Co., Inc., Boston, Massachusetts 02115, United States
| | - Armetta Hill
- Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics,
Pharmacodynamics and Drug Metabolism, Merck
& Co., Inc., Boston, Massachusetts 02115, United States
| | - Dapeng Chen
- Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics,
Pharmacodynamics and Drug Metabolism, Merck
& Co., Inc., Boston, Massachusetts 02115, United States
| | - Karin M. Otte
- Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics,
Pharmacodynamics and Drug Metabolism, Merck
& Co., Inc., Boston, Massachusetts 02115, United States
| | | | - Sanjiv Shah
- Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics,
Pharmacodynamics and Drug Metabolism, Merck
& Co., Inc., Boston, Massachusetts 02115, United States
| | - Jason D. Katz
- Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics,
Pharmacodynamics and Drug Metabolism, Merck
& Co., Inc., Boston, Massachusetts 02115, United States
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16
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Shin N, Stubbs M, Koblish H, Yue EW, Soloviev M, Douty B, Wang KH, Wang Q, Gao M, Feldman P, Yang G, Hall L, Hansbury M, O'Connor S, Leffet L, Collins R, Katiyar K, He X, Waeltz P, Collier P, Lu J, Li YL, Li Y, Liu PCC, Burn T, Covington M, Diamond S, Shuey D, Roberts A, Yeleswaram S, Hollis G, Metcalf B, Yao W, Huber R, Combs A, Newton R, Scherle P. Parsaclisib Is a Next-Generation Phosphoinositide 3-Kinase δ Inhibitor with Reduced Hepatotoxicity and Potent Antitumor and Immunomodulatory Activities in Models of B-Cell Malignancy. J Pharmacol Exp Ther 2020; 374:211-222. [PMID: 32345620 DOI: 10.1124/jpet.120.265538] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 04/20/2020] [Indexed: 12/18/2022] Open
Abstract
The clinical use of first-generation phosphoinositide 3-kinase (PI3K)δ inhibitors in B-cell malignancies is hampered by hepatotoxicity, requiring dose reduction, treatment interruption, and/or discontinuation of therapy. In addition, potential molecular mechanisms by which resistance to this class of drugs occurs have not been investigated. Parsaclisib (INCB050465) is a potent and selective next-generation PI3Kδ inhibitor that differs in structure from first-generation PI3Kδ inhibitors and has shown encouraging anti-B-cell tumor activity and reduced hepatotoxicity in phase 1/2 clinical studies. Here, we present preclinical data demonstrating parsaclisib as a potent inhibitor of PI3Kδ with over 1000-fold selectivity against other class 1 PI3K isozymes. Parsaclisib directly blocks PI3K signaling-mediated cell proliferation in B-cell lines in vitro and in vivo and indirectly controls tumor growth by lessening immunosuppression through regulatory T-cell inhibition in a syngeneic lymphoma model. Diffuse large B-cell lymphoma cell lines overexpressing MYC were insensitive to proliferation blockade via PI3Kδ signaling inhibition by parsaclisib, but their proliferative activities were reduced by suppression of MYC gene transcription. Molecular structure analysis of the first- and next-generation PI3Kδ inhibitors combined with clinical observation suggests that hepatotoxicity seen with the first-generation inhibitors could result from a structure-related off-target effect. Parsaclisib is currently being evaluated in multiple phase 2 clinical trials as a therapy against various hematologic malignancies of B-cell origin (NCT03126019, NCT02998476, NCT03235544, NCT03144674, and NCT02018861). SIGNIFICANCE STATEMENT: The preclinical properties described here provide the mechanism of action and support clinical investigations of parsaclisib as a therapy for B-cell malignancies. MYC overexpression was identified as a resistance mechanism to parsaclisib in DLBCL cells, which may be useful in guiding further translational studies for the selection of patients with DLBCL who might benefit from PI3Kδ inhibitor treatment in future trials. Hepatotoxicity associated with first-generation PI3Kδ inhibitors may be an off-target effect of that class of compounds.
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Affiliation(s)
- Niu Shin
- Incyte Research Institute, Wilmington, Delaware
| | | | | | - Eddy W Yue
- Incyte Research Institute, Wilmington, Delaware
| | | | - Brent Douty
- Incyte Research Institute, Wilmington, Delaware
| | | | - Qian Wang
- Incyte Research Institute, Wilmington, Delaware
| | | | | | | | - Leslie Hall
- Incyte Research Institute, Wilmington, Delaware
| | | | | | - Lynn Leffet
- Incyte Research Institute, Wilmington, Delaware
| | | | | | - Xin He
- Incyte Research Institute, Wilmington, Delaware
| | - Paul Waeltz
- Incyte Research Institute, Wilmington, Delaware
| | | | - Jin Lu
- Incyte Research Institute, Wilmington, Delaware
| | - Yun-Long Li
- Incyte Research Institute, Wilmington, Delaware
| | - Yanlong Li
- Incyte Research Institute, Wilmington, Delaware
| | | | | | | | | | - Dana Shuey
- Incyte Research Institute, Wilmington, Delaware
| | | | | | - Greg Hollis
- Incyte Research Institute, Wilmington, Delaware
| | | | - Wenqing Yao
- Incyte Research Institute, Wilmington, Delaware
| | - Reid Huber
- Incyte Research Institute, Wilmington, Delaware
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17
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Profile of Dennis L. Kasper. Proc Natl Acad Sci U S A 2019; 116:26144-26146. [DOI: 10.1073/pnas.1920088116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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18
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Nawab A, An L, Wu J, Li G, Liu W, Zhao Y, Wu Q, Xiao M. Chicken toll-like receptors and their significance in immune response and disease resistance. Int Rev Immunol 2019; 38:284-306. [PMID: 31662000 DOI: 10.1080/08830185.2019.1659258] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Infectious diseases are a major challenge for the poultry industry that causes widespread production losses. Thus, management and control of poultry health and diseases are essential for the viability of the industry. Toll-like receptors are best characterized as membrane-bound receptors that perform a central role in immune homeostasis and disease resistance by recognition of pathogen-associated molecular patterns. In response to pathogen recognition, TLRs initiate both innate and adaptive immune responses which may help to develop immunomodulatory therapeutics for TLR associated diseases. Vaccination produces specific immunity in the animal's body towards pathogens. However, due to certain disadvantages of vaccines, (inactivation of attenuated pathogens into the virulent strains and weak immunogenicity of inactivated vaccines) there is a crucial need to develop the safe and effective therapeutic intervention. TLR ligands have been classified as a potential adjuvant against the infectious diseases in farm animals. TLR adjuvants induce both specific and nonspecific immune responses in chickens to combat several bacterial, viral and parasitic diseases. Therefore, the aim of this review was to explore the chicken TLR4 and their role in immune responses and disease resistance to develop disease resistance poultry breeds in future.
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Affiliation(s)
- Aamir Nawab
- Department of Animal Science, Guangdong Ocean University, Zhanjiang, Guangdong, China.,Faculty of Veterinary Medicine, PMAS- Arid Agriculture University Rawalpindi, Rawalpindi, Pakistan
| | - Lilong An
- Department of Animal Science, Guangdong Ocean University, Zhanjiang, Guangdong, China
| | - Jiang Wu
- Department of Animal Science, Guangdong Ocean University, Zhanjiang, Guangdong, China
| | - Guanghui Li
- Department of Animal Science, Guangdong Ocean University, Zhanjiang, Guangdong, China
| | - Wenchao Liu
- Department of Animal Science, Guangdong Ocean University, Zhanjiang, Guangdong, China
| | - Yi Zhao
- Department of Animal Science, Guangdong Ocean University, Zhanjiang, Guangdong, China
| | - Qimin Wu
- Mechanical and Power Engineering College, Guangdong Ocean University, Zhanjiang, Guangdong, China
| | - Mei Xiao
- Department of Animal Science, Guangdong Ocean University, Zhanjiang, Guangdong, China
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19
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Oka A, Mishima Y, Liu B, Herzog JW, Steinbach EC, Kobayashi T, Plevy SE, Sartor RB. Phosphoinositide 3-Kinase P110δ-Signaling Is Critical for Microbiota-Activated IL-10 Production by B Cells that Regulate Intestinal Inflammation. Cells 2019; 8:1121. [PMID: 31546615 PMCID: PMC6829312 DOI: 10.3390/cells8101121] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/18/2019] [Accepted: 09/20/2019] [Indexed: 12/15/2022] Open
Abstract
The phosphoinositide 3-kinase catalytic subunit p110δ (PI3Kδ) gene maps to a human inflammatory bowel diseases (IBD) susceptibility locus, and genetic deletion of PI3Kδ signaling causes spontaneous colitis in mice. However, little is known regarding the role of PI3Kδ on IL-10-producing B cells that help regulate mucosal inflammation in IBD. We investigated the role of PI3Kδ signaling in B cell production of IL-10, following stimulation by resident bacteria and B cell regulatory function against colitis. In vitro, B cells from PI3KδD910A/D910A mice or wild-type B cells treated with PI3K specific inhibitors secreted significantly less IL-10 with greater IL-12p40 following bacterial stimulation. These B cells failed to suppress inflammatory cytokines by co-cultured microbiota-activated macrophages or CD4+ T cells. In vivo, co-transferred wild-type B cells ameliorated T cell-mediated colitis, while PI3KδD910A/D910A B cells did not confer protection from mucosal inflammation. These results indicate that PI3Kδ-signaling mediates regulatory B cell immune differentiation when stimulated with resident microbiota or their components, and is critical for induction and regulatory function of IL-10-producing B cells in intestinal homeostasis and inflammation.
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Affiliation(s)
- Akihiko Oka
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- Department of Internal Medicine II, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan.
| | - Yoshiyuki Mishima
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- Department of Internal Medicine II, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan.
| | - Bo Liu
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Jeremy W Herzog
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Erin C Steinbach
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
| | - Taku Kobayashi
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Minato-ku, Tokyo 108-8642, Japan.
| | - Scott E Plevy
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- Synlogic Therapeutics, Boston, MA 02139, USA.
| | - R Balfour Sartor
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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20
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Buchanan CM, Lee KL, Shepherd PR. For Better or Worse: The Potential for Dose Limiting the On-Target Toxicity of PI 3-Kinase Inhibitors. Biomolecules 2019; 9:biom9090402. [PMID: 31443495 PMCID: PMC6770514 DOI: 10.3390/biom9090402] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/15/2019] [Accepted: 08/21/2019] [Indexed: 02/07/2023] Open
Abstract
The hyper-activation of the phosphoinositide (PI) 3-kinase signaling pathway is a hallmark of many cancers and overgrowth syndromes, and as a result, there has been intense interest in the development of drugs that target the various isoforms of PI 3-kinase. Given the key role PI 3-kinases play in many normal cell functions, there is significant potential for the disruption of essential cellular functions by PI 3-kinase inhibitors in normal tissues; so-called on-target drug toxicity. It is, therefore, no surprise that progress within the clinical development of PI 3-kinase inhibitors as single-agent anti-cancer therapies has been slowed by the difficulty of identifying a therapeutic window. The aim of this review is to place the cellular, tissue and whole-body effects of PI 3-kinase inhibition in the context of understanding the potential for dose limiting on-target toxicities and to introduce possible strategies to overcome these.
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Affiliation(s)
- Christina M Buchanan
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Kate L Lee
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Peter R Shepherd
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
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21
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Jeong JS, Kim JS, Kim SR, Lee YC. Defining Bronchial Asthma with Phosphoinositide 3-Kinase Delta Activation: Towards Endotype-Driven Management. Int J Mol Sci 2019; 20:ijms20143525. [PMID: 31323822 PMCID: PMC6679152 DOI: 10.3390/ijms20143525] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/15/2019] [Accepted: 07/16/2019] [Indexed: 12/15/2022] Open
Abstract
Phosphoinositide 3-kinase (PI3K) pathways play a critical role in orchestrating the chronic inflammation and the structural changes of the airways in patients with asthma. Recently, a great deal of progress has been made in developing selective and effective PI3K-targeted therapies on the basis of a vast amount of studies on the roles of specific PI3K isoforms and fine-tuned modulators of PI3Ks in a particular disease context. In particular, the pivotal roles of delta isoform of class I PI3Ks (PI3K-δ) in CD4-positive type 2 helper T cells-dominant disorders such as asthma have been consistently reported since the early investigations. Furthermore, there has been great advancement in our knowledge of the implications of PI3K-δ in various facets of allergic inflammation. This has involved the airway epithelial interface, adaptive T and B cells, potent effector cells (eosinophils and neutrophils), and, more recently, subcellular organelles (endoplasmic reticulum and mitochondria) and cytoplasmic innate immune receptors such as NLRP3 inflammasome, all of which make this PI3K isoform an important druggable target for treating asthma. Defining subpopulations of asthma patients with PI3K-δ activation, namely PI3K-δ-driven asthma endotype, may therefore provide us with a novel framework for the treatment of the disease, particularly for corticosteroid-resistant severe form, an important unresolved aspect of the current asthma management. In this review, we specifically summarize the recent advancement of our knowledge on the critical roles of PI3K-δ in the pathogenesis of bronchial asthma.
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Affiliation(s)
- Jae Seok Jeong
- Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju 54907, Korea
- Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 54907, Korea
| | - Jong Seung Kim
- Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 54907, Korea
- Department of Otorhinolaryngology-Head and Neck Surgery, Chonbuk National University Medical School, Jeonju 54907, Korea
| | - So Ri Kim
- Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju 54907, Korea
- Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 54907, Korea
| | - Yong Chul Lee
- Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju 54907, Korea.
- Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 54907, Korea.
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22
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Mishima Y, Oka A, Liu B, Herzog JW, Eun CS, Fan TJ, Bulik-Sullivan E, Carroll IM, Hansen JJ, Chen L, Wilson JE, Fisher NC, Ting JP, Nochi T, Wahl A, Garcia JV, Karp CL, Sartor RB. Microbiota maintain colonic homeostasis by activating TLR2/MyD88/PI3K signaling in IL-10-producing regulatory B cells. J Clin Invest 2019; 129:3702-3716. [PMID: 31211700 PMCID: PMC6715367 DOI: 10.1172/jci93820] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 06/06/2019] [Indexed: 12/15/2022] Open
Abstract
Resident microbiota activate regulatory cells that modulate intestinal inflammation and promote and maintain intestinal homeostasis. IL-10 is a key mediator of immune regulatory function. Our studies described the functional importance and mechanisms by which gut microbiota and specific microbial components influenced the development of intestinal IL-10-producing B cells. We used fecal transplant to germ-free (GF) Il10+/EGFP reporter and Il10-/- mice to demonstrate that microbiota from specific pathogen-free mice primarily stimulated IL-10-producing colon-specific B cells and T regulatory-1 cells in ex-GF mice. IL-10 in turn down-regulated microbiota-activated mucosal inflammatory cytokines. TLR2/9 ligands and enteric bacterial lysates preferentially induced IL-10 production and regulatory capacity of intestinal B cells. Analysis of Il10+/EGFP mice crossed with additional gene-deficient strains and B cell co-transfer studies demonstrated that microbiota-induced IL-10-producing intestinal B cells ameliorated chronic T cell-mediated colitis in a TLR2, MyD88 and PI3K-dependent fashion. In vitro studies implicated PI3Kp110δ and AKT downstream signaling. These studies demonstrated that resident enteric bacteria activated intestinal IL-10-producing B cells through TLR2, MyD88 and PI3K pathways. These B cells reduced colonic T cell activation and maintained mucosal homeostasis in response to intestinal microbiota.
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Affiliation(s)
- Yoshiyuki Mishima
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill (UNC), Chapel Hill, North Carolina, USA
- Department of Internal Medicine II, Shimane University Faculty of Medicine, Izumo, Shimane, Japan
| | - Akihiko Oka
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill (UNC), Chapel Hill, North Carolina, USA
- Department of Internal Medicine II, Shimane University Faculty of Medicine, Izumo, Shimane, Japan
| | - Bo Liu
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill (UNC), Chapel Hill, North Carolina, USA
| | - Jeremy W. Herzog
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill (UNC), Chapel Hill, North Carolina, USA
| | - Chang Soo Eun
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill (UNC), Chapel Hill, North Carolina, USA
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, South Korea
| | - Ting-Jia Fan
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill (UNC), Chapel Hill, North Carolina, USA
- Department of Microbiology and Immunology
| | | | - Ian M. Carroll
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill (UNC), Chapel Hill, North Carolina, USA
- Department of Nutrition
| | - Jonathan J. Hansen
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill (UNC), Chapel Hill, North Carolina, USA
- Department of Microbiology and Immunology
| | - Liang Chen
- Lineberger Comprehensive Cancer Center, Department of Genetics, and
| | - Justin E. Wilson
- Lineberger Comprehensive Cancer Center, Department of Genetics, and
| | | | - Jenny P.Y. Ting
- Lineberger Comprehensive Cancer Center, Department of Genetics, and
| | - Tomonori Nochi
- Department of Medicine, Division of Infectious Diseases, UNC, Chapel Hill, North Carolina, USA
- Mucosal Immunology Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Angela Wahl
- Department of Medicine, Division of Infectious Diseases, UNC, Chapel Hill, North Carolina, USA
| | - J. Victor Garcia
- Department of Medicine, Division of Infectious Diseases, UNC, Chapel Hill, North Carolina, USA
| | - Christopher L. Karp
- Division of Molecular Immunology, Department of Pediatrics, Cincinnati Children’s Hospital Research Center, Cincinnati, Ohio, USA
| | - R. Balfour Sartor
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill (UNC), Chapel Hill, North Carolina, USA
- Department of Microbiology and Immunology
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23
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Zhang B, Dai Q, Jin X, Liang D, Li X, Lu H, Liu Y, Ding J, Gao Q, Wen Y. Phosphoinositide 3-kinase/protein kinase B inhibition restores regulatory T cell's function in pulmonary sarcoidosis. J Cell Physiol 2019; 234:19911-19920. [PMID: 30945303 DOI: 10.1002/jcp.28589] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 03/04/2019] [Accepted: 03/06/2019] [Indexed: 12/28/2022]
Abstract
Sarcoidosis is a systemic granulomatous disease associated with Th1/ regulatory T cells (Treg) paradigm. PI3K/Akt signaling, critical for maintaining Treg's homeostasis, is aberrantly activated in sarcoidosis patients. Here we tested the role of the PI3K inhibitors, LY294002 and BKM120, in immune modulation in experimental pulmonary sarcoidosis, concerning Th1/Th17/Treg immune profile detected by fluorescence-activated cell sorting analysis or quantitative polymerase chain reaction, as well as the effect on Treg's suppressive functions. Our investigation showed abnormal activation of PI3K/Akt signaling both in lung and Treg in pulmonary sarcoidosis, along with decreased frequency and damaged function of Treg. Blockage of PI3K suppressed this signaling in Treg, rebalanced Th1/Treg, inhibited the production of inflammatory cytokines, and enhanced Treg's function. These results demonstrate the key role of the PI3K/Akt signaling in regulating Th1/Th2 rebalances and indicates that PI3K/Akt signaling is critical for the optimal Treg responses in pulmonary sarcoidosis. Thus, PI3K inhibitors have potential for therapeutic translation, and can be candidate for add-on drugs to treat pulmonary sarcoidosis.
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Affiliation(s)
- Bin Zhang
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| | - Qianqian Dai
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| | - Xuguang Jin
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| | - Dongmei Liang
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| | - Xiaojie Li
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| | - Haiyan Lu
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| | - Yu Liu
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| | - Jingjing Ding
- Department of Respiratory Medicine, Jiangsu Key Laboratory of Molecular Medicine, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Qian Gao
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| | - Yanting Wen
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
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24
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Wang Z, Vaughan TY, Zhu W, Chen Y, Fu G, Medrzycki M, Nishio H, Bunting ST, Hankey-Giblin PA, Nusrat A, Parkos CA, Wang D, Wen R, Bunting KD. Gab2 and Gab3 Redundantly Suppress Colitis by Modulating Macrophage and CD8 + T-Cell Activation. Front Immunol 2019; 10:486. [PMID: 30936879 PMCID: PMC6431666 DOI: 10.3389/fimmu.2019.00486] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 02/22/2019] [Indexed: 12/13/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is a multi-factorial chronic inflammation of the gastrointestinal tract prognostically linked to CD8+ T-cells, but little is known about their mechanism of activation during initiation of colitis. Here, Grb2-associated binding 2/3 adaptor protein double knockout mice (Gab2/3−/−) were generated. Gab2/3−/− mice, but not single knockout mice, developed spontaneous colitis. To analyze the cellular mechanism, reciprocal bone marrow (BM) transplantation demonstrated a Gab2/3−/− hematopoietic disease-initiating process. Adoptive transfer showed individual roles for macrophages and T-cells in promoting colitis development in vivo. In spontaneous disease, intestinal intraepithelial CD8+ but much fewer CD4+, T-cells from Gab2/3−/− mice with rectal prolapse were more proliferative. To analyze the molecular mechanism, reduced PI3-kinase/Akt/mTORC1 was observed in macrophages and T-cells, with interleukin (IL)-2 stimulated T-cells showing increased pSTAT5. These results illustrate the importance of Gab2/3 collectively in signaling responses required to control macrophage and CD8+ T-cell activation and suppress chronic colitis.
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Affiliation(s)
- Zhengqi Wang
- Division of Hem/Onc/BMT, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, United States
| | - Tamisha Y Vaughan
- Division of Hem/Onc/BMT, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, United States
| | - Wandi Zhu
- Division of Hem/Onc/BMT, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, United States
| | - Yuhong Chen
- BloodCenter of Wisconsin, Milwaukee, WI, United States
| | - Guoping Fu
- BloodCenter of Wisconsin, Milwaukee, WI, United States
| | - Magdalena Medrzycki
- Division of Hem/Onc/BMT, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, United States
| | - Hikaru Nishio
- Department of Pathology, Emory University, Atlanta, GA, United States
| | - Silvia T Bunting
- Department of Pathology, Children's Healthcare of Atlanta, Atlanta, GA, United States
| | - Pamela A Hankey-Giblin
- Department of Veterinary Science, Pennsylvania State University, University Park, PA, United States
| | - Asma Nusrat
- Department of Pathology, Emory University, Atlanta, GA, United States.,Department of Pathology, University of Michigan, Ann Arbor, MI, United States
| | - Charles A Parkos
- Department of Pathology, Emory University, Atlanta, GA, United States.,Department of Pathology, University of Michigan, Ann Arbor, MI, United States
| | - Demin Wang
- BloodCenter of Wisconsin, Milwaukee, WI, United States
| | - Renren Wen
- BloodCenter of Wisconsin, Milwaukee, WI, United States
| | - Kevin D Bunting
- Division of Hem/Onc/BMT, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, United States
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25
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Dong S, Harrington BK, Hu EY, Greene JT, Lehman AM, Tran M, Wasmuth RL, Long M, Muthusamy N, Brown JR, Johnson AJ, Byrd JC. PI3K p110δ inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression. J Clin Invest 2018; 129:122-136. [PMID: 30457982 DOI: 10.1172/jci99386] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 10/02/2018] [Indexed: 12/20/2022] Open
Abstract
Targeted therapy with small molecules directed at essential survival pathways in leukemia represents a major advance, including the phosphatidylinositol-3'-kinase (PI3K) p110δ inhibitor idelalisib. Here, we found that genetic inactivation of p110δ (p110δD910A/D910A) in the Eμ-TCL1 murine chronic lymphocytic leukemia (CLL) model impaired B cell receptor signaling and B cell migration, and significantly delayed leukemia pathogenesis. Regardless of TCL1 expression, p110δ inactivation led to rectal prolapse in mice resembling autoimmune colitis in patients receiving idelalisib. Moreover, we showed that p110δ inactivation in the microenvironment protected against CLL and acute myeloid leukemia. After receiving higher numbers of TCL1 leukemia cells, half of p110δD910A/D910A mice spontaneously recovered from high disease burden and resisted leukemia rechallenge. Despite disease resistance, p110δD910A/D910A mice exhibited compromised CD4+ and CD8+ T cell response, and depletion of CD4+ or CD8+ T cells restored leukemia. Interestingly, p110δD910A/D910A mice showed significantly impaired Treg expansion that associated with disease clearance. Reconstitution of p110δD910A/D910A mice with p110δWT/WT Tregs reversed leukemia resistance. Our findings suggest that p110δ inhibitors may have direct antileukemic and indirect immune-activating effects, further supporting that p110δ blockade may have a broader immune-modulatory role in types of leukemia that are not sensitive to p110δ inhibition.
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Affiliation(s)
- Shuai Dong
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy.,Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center
| | - Bonnie K Harrington
- Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center.,College of Veterinary Medicine
| | - Eileen Y Hu
- Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center.,Medical Scientist Training Program
| | - Joseph T Greene
- Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center.,Molecular, Cellular, and Developmental Biology Program, and
| | - Amy M Lehman
- Center for Biostatistics, The Ohio State University, Columbus, Ohio, USA
| | - Minh Tran
- Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center
| | - Ronni L Wasmuth
- Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center
| | - Meixiao Long
- Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center
| | - Natarajan Muthusamy
- Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center
| | - Jennifer R Brown
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Amy J Johnson
- Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center.,Janssen Research and Development LLC, Spring House, Pennsylvania, USA
| | - John C Byrd
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy.,Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center
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26
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Aksoy E, Saveanu L, Manoury B. The Isoform Selective Roles of PI3Ks in Dendritic Cell Biology and Function. Front Immunol 2018; 9:2574. [PMID: 30498491 PMCID: PMC6249308 DOI: 10.3389/fimmu.2018.02574] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 10/18/2018] [Indexed: 11/20/2022] Open
Abstract
Phosphoinositide-3 kinases (PI3Ks) generate 3-phosphorylated phosphoinositide lipids that are implicated in many biological processes in homeostatic states and pathologies such as cancer, inflammation and autoimmunity. Eight isoforms of PI3K exist in mammals and among them the class I PI3K, p110γ, and PI3Kδ, and class III Vps34 being the most expressed and well characterized in immune cells. Following engagement of pathogen recognition receptors (PRRs), PI3Ks coordinate vital cellular processes of signaling and vesicular trafficking in innate phagocytes such as macrophages and professional antigen presenting dendritic cells (DCs). Although previous studies demonstrated the involvement of PI3K isoforms in innate and adaptive immune cell types, the role of PI3Ks with respect to DC biology has been enigmatic. Thus, this review, based on studies involving PI3K isoforms, highlight how the different PI3Ks isoforms could regulate DC functions such as antigen processing and presentation including PRR responses.
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Affiliation(s)
- Ezra Aksoy
- Centre for Biochemical Pharmacology, William Harvey Research Institute, Bart's and the London School of Medicine Queen Mary University of London, London, United Kingdom
| | - Loredana Saveanu
- Institut National de la Santé et de la Recherche Médicale, Unité UMR 1149, Centre de Recherche sur l'Inflammation, Paris, France
- Université Paris Diderot, Faculté de Médecine Xavier Bichat, Paris, France
| | - Bénédicte Manoury
- Institut Necker Enfants Malades, Institut National de la Santé et de la Recherche Médicale, Unité 1151, Paris, France
- Centre National de la Recherche Scientifique, Unité 8253, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France
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27
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Cohen SB, Bainter W, Johnson JL, Lin TY, Wong JCY, Wallace JG, Jones J, Qureshi S, Mir F, Qamar F, Cantley LC, Geha RS, Chou J. Human primary immunodeficiency caused by expression of a kinase-dead p110δ mutant. J Allergy Clin Immunol 2018; 143:797-799.e2. [PMID: 30336224 DOI: 10.1016/j.jaci.2018.10.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 09/25/2018] [Accepted: 10/08/2018] [Indexed: 11/16/2022]
Affiliation(s)
- Sarah Beaussant Cohen
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass
| | - Wayne Bainter
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass
| | | | - Ting-Yu Lin
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY
| | - Jenny C Y Wong
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY
| | - Jacqueline G Wallace
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass
| | - Jennifer Jones
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass
| | - Sonia Qureshi
- Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan
| | - Fatima Mir
- Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan
| | - Farah Qamar
- Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan
| | | | - Raif S Geha
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass
| | - Janet Chou
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
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Amano MT, Castoldi A, Andrade-Oliveira V, Latancia MT, Terra FF, Correa-Costa M, Breda CNS, Felizardo RJF, Pereira WO, da Silva MB, Miyagi MYS, Aguiar CF, Hiyane MI, Silva JS, Moura IC, Camara NOS. The lack of PI3Kγ favors M1 macrophage polarization and does not prevent kidney diseases progression. Int Immunopharmacol 2018; 64:151-161. [PMID: 30176533 DOI: 10.1016/j.intimp.2018.08.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 07/29/2018] [Accepted: 08/15/2018] [Indexed: 01/08/2023]
Abstract
Acute kidney injury (AKI) and chronic kidney disease (CKD) are major concerns in worldwide public health, and their pathophysiology involves immune cells activation, being macrophages one of the main players of both processes. It is suggested that metabolic pathways could contribute to macrophage modulation and phosphatidylinositol‑3 kinase (PI3K) pathway was shown to be activated in kidneys subjected to ischemia and reperfusion as well as unilateral ureteral obstruction (UUO). Although PI3K inhibition is mostly associated with anti-inflammatory response, its use in kidney injuries has been shown controversial results, which indicates the need for further studies. Our aim was to unveil the role of PI3Kγ in macrophage polarization and in kidney diseases development. We analyzed bone-marrow macrophages polarization from wild-type (WT) and PI3Kγ knockout (PI3K KO) animals. We observed increased expression of M1 (CD86, CCR7, iNOS, TNF, CXCL9, CXCL10, IL-12 and IL-23) and decreased of M2 (CD206, Arg-1, FIZZ1 and YM1) markers in the lack of PI3Kγ. And this modulation was accompanied by higher levels of inflammatory cytokines in PI3K KO M1 cells. PI3K KO mice had increased M1 in steady state kidneys, and no protection was observed in these mice after acute and chronic kidney insults. On the contrary, they presented higher levels of protein-to-creatinine ratio and Kim-1 expression and increased tubular injury. In conclusion, our findings demonstrated that the lack of PI3Kγ favors M1 macrophages polarization providing an inflammatory-prone environment, which does not prevent kidney diseases progression.
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Affiliation(s)
- Mariane T Amano
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil; Instituto Sírio-Libanês de Ensino e Pesquisa, Hospital Sírio-Libanês, Sao Paulo, Brazil.
| | - Angela Castoldi
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Vinicius Andrade-Oliveira
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Marcela T Latancia
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil; Instituto Sírio-Libanês de Ensino e Pesquisa, Hospital Sírio-Libanês, Sao Paulo, Brazil
| | - Fernanda F Terra
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Matheus Correa-Costa
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Cristiane N S Breda
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Raphael J F Felizardo
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Welbert O Pereira
- School of Medicine, Faculdade Israelita de Ciências da Saúde Albert Einstein, Sao Paulo, Brazil
| | - Marina B da Silva
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Mariana Y S Miyagi
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Cristhiane F Aguiar
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Meire I Hiyane
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - João S Silva
- Department of Biochemistry and Immunology, Medical School Ribeirão Preto, FMRP, University of Sao Paulo, Sao Paulo, Brazil
| | - Ivan C Moura
- INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris, France; Paris Descartes - Sorbonne Paris Cité University, Paris, France; CNRS ERL 8254, Imagine Institute, Laboratory of Excellence GR-Ex, Paris, France
| | - Niels O S Camara
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil; Laboratory of Renal Pathology, Faculty of Medicine, University of São Paulo, Sao Paulo, Brazil
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Suppression of Th17 Cell Response in the Alleviation of Dextran Sulfate Sodium-Induced Colitis by Ganoderma lucidum Polysaccharides. J Immunol Res 2018; 2018:2906494. [PMID: 29888292 PMCID: PMC5985119 DOI: 10.1155/2018/2906494] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 02/19/2018] [Accepted: 03/07/2018] [Indexed: 01/01/2023] Open
Abstract
Background Ganoderma lucidum polysaccharides (GLP) has anti-inflammatory and immunomodulatory effects. Dysregulated immune responses are involved in the pathogenesis of dextran sulfate sodium (DSS)-induced colitis. The aim of this study was to assess the therapeutic potential of GLP to alleviate DSS-induced colitis. Methods The mice were administered with GLP by intragastric gavage daily for two weeks prior to the DSS treatment. Mice were orally administered with 2.5% DSS dissolved in drinking water with GLP or water treatment for 6 days. The mice were killed on day 7 after induction of colitis. Survival rates, body weight loss, colon lengths, histological changes, and disease activity index scores (DAI) were evaluated. Results GLP significantly improved survival rates, colon length shortening, body weight loss, histopathological score, and DAI scores in mice with DSS-induced colitis. GLP markedly suppressed the secretions of TNF-α, IL-1β, IL-6, IL-17A, and IL-4 and significantly affected populations of Th17 cells, B cells, NK cells, and NKT cells in the lamina propria lymphocytes. Conclusions GLP prevented inflammation, maintained intestinal homeostasis, and regulated the intestinal immunological barrier functions in mice with DSS-induced colitis.
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Abstract
Inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis, is characterized by chronic intestinal inflammation due to a complex interaction of genetic determinants, disruption of mucosal barriers, aberrant inflammatory signals, loss of tolerance, and environmental triggers. Importantly, the incidence of pediatric IBD is rising, particularly in children younger than 10 years. In this review, we discuss the clinical presentation of these patients and highlight environmental exposures that may affect disease risk, particularly among people with a background genetic risk. With regard to both children and adults, we review advancements in understanding the intestinal epithelium, the mucosal immune system, and the resident microbiota, describing how dysfunction at any level can lead to diseases like IBD. We conclude with future directions for applying advances in IBD genetics to better understand pathogenesis and develop therapeutics targeting key pathogenic nodes.
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Affiliation(s)
- Joanna M Peloquin
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease and.,Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114.,Harvard Medical School, Boston, Massachusetts 02115; , , ,
| | - Gautam Goel
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114.,Harvard Medical School, Boston, Massachusetts 02115; , , ,
| | - Eduardo J Villablanca
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease and.,Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114.,Harvard Medical School, Boston, Massachusetts 02115; , , ,
| | - Ramnik J Xavier
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease and.,Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114.,Harvard Medical School, Boston, Massachusetts 02115; , , , .,Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142.,Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
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Lampson BL, Brown JR. PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma. Expert Opin Investig Drugs 2017; 26:1267-1279. [PMID: 28945111 DOI: 10.1080/13543784.2017.1384815] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION The efficacy of the prototypical phosphatidylinositol-3-kinase (PI3K) inhibitor idelalisib for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL) has led to development of multiple compounds targeting this pathway. Areas Covered: We review the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of B cell receptor signaling, blockade of microenvironmental pro-survival signals, and enhancement of anti-tumor immunity. We examine toxicities of idelalisib, including bacterial infections (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110δ in regulatory T cells). We evaluate PI3K inhibitors that have entered trials for the treatment of lymphoma, focusing on agents with selectivity for PI3Kα and PI3Kδ. Expert Opinion: PI3K inhibitors, particularly those that target p110δ, have robust efficacy in the treatment of CLL and iNHL. However, idelalisib has infectious and autoimmune toxicities that limit its use. Outside of trials, idelalisib should be restricted to CLL patients with progression on ibrutinib or iNHL patients with progression on two prior therapies. Whether newer PI3K inhibitors will demonstrate differentiated toxicity profiles in comparable patient populations while retaining efficacy remains to be seen.
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Affiliation(s)
- Benjamin L Lampson
- a Department of Medical Oncology , Dana-Farber Cancer Institute , Boston , MA , USA
| | - Jennifer R Brown
- a Department of Medical Oncology , Dana-Farber Cancer Institute , Boston , MA , USA
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Emerging role of BCR signaling inhibitors in immunomodulation of chronic lymphocytic leukemia. Blood Adv 2017; 1:1867-1875. [PMID: 29296833 DOI: 10.1182/bloodadvances.2017006809] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 08/18/2017] [Indexed: 12/22/2022] Open
Abstract
Approved therapies that target the B-cell receptor (BCR) signaling pathway, such as ibrutinib and idelalisib, are known to show activity in chronic lymphocytic leukemia (CLL) via their direct effects on crucial survival pathways in malignant B cells. However, these therapies also have effects on T cells in CLL by mediating toxicity and possibly controlling disease. By focusing on the effects of BCR signaling inhibitors on the T-cell compartment, we may gain new insights into the comprehensive biological outcomes of systemic treatment to further understand mechanisms of drug efficacy, predict the toxicity or adverse events, and identify novel combinatorial therapies. Here, we review T-cell abnormalities in preclinical models and patient samples, finding that CLL T cells orchestrate immune dysfunction and immune-related complications. We then continue to address the effects of clinically available small molecule BCR signaling inhibitors on the immune cells, especially T cells, in the context of concomitant immune-mediated adverse events and implications for future treatment strategies. Our review suggests potentially novel mechanisms of action related to BCR inhibitors, providing a rationale to extend their use to other cancers and autoimmune disorders.
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PI3K p85α Subunit-deficient Macrophages Protect Mice from Acute Colitis due to the Enhancement of IL-10 Production. Sci Rep 2017; 7:6187. [PMID: 28733636 PMCID: PMC5522489 DOI: 10.1038/s41598-017-06464-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 06/13/2017] [Indexed: 12/21/2022] Open
Abstract
We investigated the role of the PI3K p85α subunit in the development of acute colitis with a focus on intestinal macrophages. Experimental acute colitis was induced using 3% dextran sulfate sodium (DSS) in drinking water for 7 days. The severity of DSS-induced acute colitis was significantly attenuated in p85α hetero-deficient (p85α+/−) mice compared with WT mice. The expression of proinflammatory mediators in intestinal macrophages isolated from the inflamed colonic mucosa was significantly suppressed in p85α+/− colitis mice compared with WT colitis mice. Interestingly, we found that bone marrow-derived macrophages (BMDMs) from p85α+/− mice produced a significantly higher amount of IL-10 than BMDMs from WT mice. The adoptive transfer of p85α+/− BMDMs, but not WT BMDMs, significantly improved the severity in WT colitis mice, and this effect was reversed by anti-IL-10 antibody. Furthermore, the expression of IL-10 in the intestinal macrophages of p85α+/− normal colonic mucosa was significantly higher than that in the intestinal macrophages of WT normal colonic mucosa. The present results demonstrate that p85α+/− mice exhibit a reduced susceptibility to DSS-induced acute colitis. Our study suggests that a deficiency of PI3K p85α enhances the production of IL-10 in intestinal macrophages, thereby suppressing the development of DSS-induced acute colitis.
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Sang LX, Chang B, Zhu JF, Yang FL, Li Y, Jiang XF, Wang DN, Lu CL, Sun X. Sodium selenite ameliorates dextran sulfate sodium-induced chronic colitis in mice by decreasing Th1, Th17, and γδT and increasing CD4(+)CD25(+) regulatory T-cell responses. World J Gastroenterol 2017; 23:3850-3863. [PMID: 28638225 PMCID: PMC5467071 DOI: 10.3748/wjg.v23.i21.3850] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Revised: 12/29/2016] [Accepted: 03/15/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To assess the effect of sodium selenite on the severity of dextran sulfate sodium (DSS)-induced colitis in C57BL/6 mice.
METHODS Mice were randomly divided into four groups (n = 10/group): normal group, selenium (Se) group, chronic colitis group, and Se + chronic colitis group. The mice were sacrificed on day 26. Survival rates, clinical symptoms, colon length, and histological changes were determined. The percentages and absolute numbers of immune system cells in the lamina propria lymphocytes (LPL) of the colon, the expression of mRNA in colon tissue, and the concentrations of Th1, Th17, and Treg cytokines in LPL from the large intestine, were measured.
RESULTS Se significantly ameliorated the symptoms of colitis and histological injury (P < 0.05 each), increasing the proportions of neutrophils and CD4+ CD25+ T cells (P < 0.05 each) and decreasing the proportions of γδT cells, CD4+, CD4+CD44+, and CD4+ CD69+ T cells in LPL (P < 0.05 each). Moreover, Se reduced the expression of IL-6, IFN-γ, IL-17A, IL-21, T-bet, and RORγt (P < 0.05 each), but enhanced the expression of IL-10 and Foxp3 (P < 0.05 each).
CONCLUSION These results suggest that Se protects against DSS-induced chronic colitis perhaps by increasing the number of CD4(+)CD25(+) Tregs that suppress the secretion of proinflammatory cytokines and populations of Th1, Th17, and γδT cells.
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Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer Discov 2016; 6:1090-1105. [PMID: 27655435 PMCID: PMC5293166 DOI: 10.1158/2159-8290.cd-16-0716] [Citation(s) in RCA: 206] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 08/02/2016] [Indexed: 12/28/2022]
Abstract
The PI3K pathway is hyperactivated in most cancers, yet the capacity of PI3K inhibitors to induce tumor cell death is limited. The efficacy of PI3K inhibition can also derive from interference with the cancer cells' ability to respond to stromal signals, as illustrated by the approved PI3Kδ inhibitor idelalisib in B-cell malignancies. Inhibition of the leukocyte-enriched PI3Kδ or PI3Kγ may unleash antitumor T-cell responses by inhibiting regulatory T cells and immune-suppressive myeloid cells. Moreover, tumor angiogenesis may be targeted by PI3K inhibitors to enhance cancer therapy. Future work should therefore also explore the effects of PI3K inhibitors on the tumor stroma, in addition to their cancer cell-intrinsic impact. SIGNIFICANCE The PI3K pathway extends beyond the direct regulation of cancer cell proliferation and survival. In B-cell malignancies, targeting PI3K purges the tumor cells from their protective microenvironment. Moreover, we propose that PI3K isoform-selective inhibitors may be exploited in the context of cancer immunotherapy and by targeting angiogenesis to improve drug and immune cell delivery. Cancer Discov; 6(10); 1090-105. ©2016 AACR.
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Affiliation(s)
- Klaus Okkenhaug
- Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom.
| | - Mariona Graupera
- Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
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Wiestner A. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia. Haematologica 2016; 100:1495-507. [PMID: 26628631 DOI: 10.3324/haematol.2014.119123] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Chronic lymphocytic leukemia is a malignancy of mature auto-reactive B cells. Genetic and functional studies implicate B-cell receptor signaling as a pivotal pathway in its pathogenesis. Full B-cell receptor activation requires tumor-microenvironment interactions in lymphoid tissues. Spleen tyrosine kinase, Bruton's tyrosine kinase, and the phosphatidylinositol 3-kinase (PI3K) δ isoform are essential for B-cell receptor signal transduction but also mediate the effect of other pathways engaged in chronic lymphocytic leukemia cells in the tissue-microenvironment. Orally bioavailable inhibitors of spleen tyrosine kinase, Bruton's tyrosine kinase, or PI3Kδ, induce high rates of durable responses. Ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, and idelalisib, a selective inhibitor of PI3Kδ, have obtained regulatory approval in chronic lymphocytic leukemia. Ibrutinib and idelalisib are active in patients with high-risk features, achieving superior disease control in difficult-to-treat patients than prior best therapy, making them the preferred agents for chronic lymphocytic leukemia with TP53 aberrations and for patients resistant to chemoimmunotherapy. In randomized trials, both ibrutinib, versus ofatumumab, and idelalisib in combination with rituximab, versus placebo with rituximab improved survival in relapsed/refractory chronic lymphocytic leukemia. Responses to B-cell receptor inhibitors are mostly partial, and within clinical trials treatment is continued until progression or occurrence of intolerable side effects. Ibrutinib and idelalisib are, overall, well tolerated; notable adverse events include increased bruising and incidence of atrial fibrillation on ibrutinib and colitis, pneumonitis and transaminase elevations on idelalisib. Randomized trials investigate the role of B-cell receptor inhibitors in first-line therapy and the benefit of combinations. This review discusses the biological basis for targeted therapy of chronic lymphocytic leukemia with B-cell receptor inhibitors, and summarizes the clinical experience with these agents.
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Affiliation(s)
- Adrian Wiestner
- Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
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Phosphoinositide 3-Kinase (PI3K) Subunit p110δ Is Essential for Trophoblast Cell Differentiation and Placental Development in Mouse. Sci Rep 2016; 6:28201. [PMID: 27306493 PMCID: PMC4910077 DOI: 10.1038/srep28201] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 05/31/2016] [Indexed: 12/24/2022] Open
Abstract
Maternal PI3K p110δ has been implicated in smaller litter sizes in mice, but its underlying mechanism remains unclear. The placenta is an indispensable chimeric organ that supports mammalian embryonic development. Using a mouse model of genetic inactivation of PI3K p110δ (p110δD910A/D910A), we show that fetuses carried by p110δD910A/D910A females were growth retarded and showed increased mortality in utero mainly during placentation. The placentas in p110δD910A/D910A females were anomalously anemic, exhibited thinner spongiotrophoblast layer and looser labyrinth zone, which indicate defective placental vasculogenesis. In addition, p110δ was detected in primary trophoblast giant cells (P-TGC) at early placentation. Maternal PI3K p110δ inactivation affected normal TGCs generation and expansion, impeded the branching of chorioallantoic placenta but enhanced the expression of matrix metalloproteinases (MMP-2, MMP-12). Poor vasculature support for the developing fetoplacental unit resulted in fetal death or gross growth retardation. These data, taken together, provide the first in vivo evidence that p110δ may play an important role in placental vascularization through manipulating trophoblast giant cell.
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Pittini Á, Casaravilla C, Allen JE, Díaz Á. Pharmacological inhibition of PI3K class III enhances the production of pro- and anti-inflammatory cytokines in dendritic cells stimulated by TLR agonists. Int Immunopharmacol 2016; 36:213-217. [PMID: 27168056 PMCID: PMC4907315 DOI: 10.1016/j.intimp.2016.04.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 04/19/2016] [Indexed: 01/25/2023]
Affiliation(s)
- Álvaro Pittini
- Cátedra de Inmunología, Departamento de Biociencias (Facultad de Química) e Instituto de Química Biológica (Facultad de Ciencias), Universidad de la República, Montevideo, Uruguay
| | - Cecilia Casaravilla
- Cátedra de Inmunología, Departamento de Biociencias (Facultad de Química) e Instituto de Química Biológica (Facultad de Ciencias), Universidad de la República, Montevideo, Uruguay
| | - Judith E Allen
- Institute of Immunology and Infection Research Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, UK
| | - Álvaro Díaz
- Cátedra de Inmunología, Departamento de Biociencias (Facultad de Química) e Instituto de Química Biológica (Facultad de Ciencias), Universidad de la República, Montevideo, Uruguay.
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Gracias DT, Boesteanu AC, Fraietta JA, Hope JL, Carey AJ, Mueller YM, Kawalekar OU, Fike AJ, June CH, Katsikis PD. Phosphatidylinositol 3-Kinase p110δ Isoform Regulates CD8+ T Cell Responses during Acute Viral and Intracellular Bacterial Infections. THE JOURNAL OF IMMUNOLOGY 2016; 196:1186-98. [PMID: 26740110 DOI: 10.4049/jimmunol.1501890] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 12/03/2015] [Indexed: 11/19/2022]
Abstract
The p110δ isoform of PI3K is known to play an important role in immunity, yet its contribution to CTL responses has not been fully elucidated. Using murine p110δ-deficient CD8(+) T cells, we demonstrated a critical role for the p110δ subunit in the generation of optimal primary and memory CD8(+) T cell responses. This was demonstrated in both acute viral and intracellular bacterial infections in mice. We show that p110δ signaling is required for CD8(+) T cell activation, proliferation and effector cytokine production. We provide evidence that the effects of p110δ signaling are mediated via Akt activation and through the regulation of TCR-activated oxidative phosphorylation and aerobic glycolysis. In light of recent clinical trials that employ drugs targeting p110δ in certain cancers and other diseases, our study suggests caution in using these drugs in patients, as they could potentially increase susceptibility to infectious diseases. These studies therefore reveal a novel and direct role for p110δ signaling in in vivo CD8(+) T cell immunity to microbial pathogens.
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Affiliation(s)
- Donald T Gracias
- Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129
| | - Alina C Boesteanu
- Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129
| | - Joseph A Fraietta
- Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104
| | - Jennifer L Hope
- Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129; Department of Immunology, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands; and
| | - Alison J Carey
- Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129; Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA 19129
| | - Yvonne M Mueller
- Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129; Department of Immunology, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands; and
| | - Omkar U Kawalekar
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104
| | - Adam J Fike
- Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129
| | - Carl H June
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104
| | - Peter D Katsikis
- Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129; Department of Immunology, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands; and
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Abstract
B cells provide immunity to extracellular pathogens by secreting a diverse repertoire of antibodies with high affinity and specificity for exposed antigens. The B cell receptor (BCR) is a transmembrane antibody, which facilitates the clonal selection of B cells producing secreted antibodies of the same specificity. The diverse antibody repertoire is generated by V(D)J recombination of heavy and light chain genes, whereas affinity maturation is mediated by activation-induced cytidine deaminase (AID)-mediated mutagenesis. These processes, which are essential for the generation of adaptive humoral immunity, also render B cells susceptible to chromosomal rearrangements and point mutations that in some cases lead to cancer. In this chapter, we will review the central role of PI3K s in mediating signals from the B cell receptor that not only facilitate the development of functional B cell repertoire, but also support the growth and survival of neoplastic B cells, focusing on chronic lymphocytic leukemia (CLL) B cells. Perhaps because of the central role played by PI3K in BCR signaling, B cell leukemia and lymphomas are the first diseases for which a PI3K inhibitor has been approved for clinical use.
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MESH Headings
- Animals
- B-Lymphocytes/cytology
- B-Lymphocytes/enzymology
- Cell Survival
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/enzymology
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/physiopathology
- Phosphatidylinositol 3-Kinases/genetics
- Phosphatidylinositol 3-Kinases/metabolism
- Receptors, Antigen, B-Cell/genetics
- Receptors, Antigen, B-Cell/metabolism
- Signal Transduction
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Affiliation(s)
- Klaus Okkenhaug
- Laboratory of Lymphocyte Signaling and Development, The Babraham Institute, Cambridge, CB22 3AT, UK.
| | - Jan A Burger
- Department of Leukemia, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
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41
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Abstract
Complex mechanisms are pulling the strings to initiate the development of inflammatory bowel disease. Current evidence indicates that an interaction of genetic susceptibilities (polymorphisms), environmental factors, and the host microbiota leads to a dysregulation of the mucosal immune system. In the past decades, the interleukin-10-deficient mouse has served as an excellent model to mirror the multifactorial nature of this disease. Here, we want to review in detail the interplay of the genetic factors, immune aspects, and especially summarize and discuss the role of the microbiota contributing to colitis development in the interleukin-10-deficient mouse model of inflammatory bowel disease as a multihit model.
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42
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Steinbach EC, Gipson GR, Sheikh SZ. Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+ CD45RB high T Cells into Immunodeficient Mice. J Vis Exp 2015:52533. [PMID: 25938395 PMCID: PMC4541583 DOI: 10.3791/52533] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
There are many different animal models available for studying the pathogenesis of human inflammatory bowel diseases (IBD), each with its own advantages and disadvantages. We describe here an experimental colitis model that is initiated by adoptive transfer of syngeneic splenic CD4(+)CD45RB(high) T cells into T and B cell deficient recipient mice. The CD4(+)CD45RB(high) T cell population that largely consists of naïve effector cells is capable of inducing chronic intestinal inflammation, closely resembling key aspects of human IBD. This method can be manipulated to study aspects of disease onset and progression. Additionally it can be used to study the function of innate, adaptive, and regulatory immune cell populations, and the role of environmental exposures, i.e., the microbiota, in intestinal inflammation. In this article we illustrate the methodology for inducing colitis with a step-by-step protocol. This includes a video demonstration of key technical aspects required to successfully develop this murine model of experimental colitis for research purposes.
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Affiliation(s)
- Erin C Steinbach
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill;
| | - Gregory R Gipson
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill
| | - Shehzad Z Sheikh
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill; Department of Genetics, University of North Carolina at Chapel Hill; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill
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43
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Shimizu T, Masuo Y, Takahashi S, Nakamichi N, Kato Y. Organic cation transporter Octn1-mediated uptake of food-derived antioxidant ergothioneine into infiltrating macrophages during intestinal inflammation in mice. Drug Metab Pharmacokinet 2015; 30:231-9. [PMID: 26003890 DOI: 10.1016/j.dmpk.2015.02.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2014] [Revised: 02/10/2015] [Accepted: 02/12/2015] [Indexed: 01/14/2023]
Abstract
OCTN1/SLC22A4 is expressed on apical membranes of small intestine, and is involved in gastrointestinal absorption of its substrates, including the food-derived antioxidant ergothioneine (ERGO). ERGO concentration in circulating blood of patients with inflammatory bowel disease (Crohn's disease) is lower than that in healthy volunteers; thus, circulating ERGO is a potential diagnostic marker, although the mechanisms underlying low ERGO concentration in patients are unknown. Here, we focused on intestinal macrophages, which infiltrate sites of inflammation, and examined possible first-pass uptake of ERGO by macrophages. ERGO concentration in blood was lower in mice with dextran sodium sulfate (DSS)-induced colitis than in controls. On the other hand, expression of octn1 gene product and ERGO concentration in intestinal tissues of DSS-treated mice were higher than in controls. Interestingly, lamina propria mononuclear cells (LPMCs) isolated from DSS-treated mice contained ERGO and showed [(3)H]ERGO uptake and Octn1 expression, whereas ERGO was undetectable in LPMCs of control mice. Functional expression of OCTN1 was also confirmed in LPS-stimulated human macrophage-like cell line, THP-1. In conclusion, OCTN1 is functionally expressed on activated intestinal macrophages, and ERGO uptake into these immune cells could contribute at least in part to the altered disposition of ERGO in intestinal inflammation.
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Affiliation(s)
- Takuya Shimizu
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan
| | - Yusuke Masuo
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan
| | - Saki Takahashi
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan
| | - Noritaka Nakamichi
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan
| | - Yukio Kato
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
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44
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Ortiz-Maldonado V, García-Morillo M, Delgado J. The biology behind PI3K inhibition in chronic lymphocytic leukaemia. Ther Adv Hematol 2015; 6:25-36. [PMID: 25642313 DOI: 10.1177/2040620714561581] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Phosphoinositide 3'-kinase (PI3K) is a key component of both chronic active and tonic B-cell receptor-signalling pathways. As such, PI3K inhibitors have emerged as promising therapeutic agents for diverse lymphoid malignancies, particularly chronic lymphocytic leukaemia. Multiple in vitro experiments and clinical trials have shown efficacy of these agents across all prognostic subgroups with a favourable toxicity profile. Moreover, in vitro studies suggest that combinations with monoclonal antibodies and/or other immune strategies could enhance the effect of PI3K inhibition.
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Affiliation(s)
| | - Marcial García-Morillo
- Hospital Clínic, Department of Medical Oncology Calle Villarroel, 170 08036 Barcelona, Spain
| | - Julio Delgado
- Hospital Clínic, Department of Haematology Calle Villarroel, 170 08036 Barcelona, Spain
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