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Giannoukakis N. Tolerogenic dendritic cells in type 1 diabetes: no longer a concept. Front Immunol 2023; 14:1212641. [PMID: 37388741 PMCID: PMC10303908 DOI: 10.3389/fimmu.2023.1212641] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 05/31/2023] [Indexed: 07/01/2023] Open
Abstract
Tolerogenic dendritic cells (tDC) arrest the progression of autoimmune-driven dysglycemia into clinical, insulin-requiring type 1 diabetes (T1D) and preserve a critical mass of β cells able to restore some degree of normoglycemia in new-onset clinical disease. The safety of tDC, generated ex vivo from peripheral blood leukocytes, has been demonstrated in phase I clinical studies. Accumulating evidence shows that tDC act via multiple layers of immune regulation arresting the action of pancreatic β cell-targeting effector lymphocytes. tDC share a number of phenotypes and mechanisms of action, independent of the method by which they are generated ex vivo. In the context of safety, this yields confidence that the time has come to test the best characterized tDC in phase II clinical trials in T1D, especially given that tDC are already being tested for other autoimmune conditions. The time is also now to refine purity markers and to "universalize" the methods by which tDC are generated. This review summarizes the current state of tDC therapy for T1D, presents points of intersection of the mechanisms of action that the different embodiments use to induce tolerance, and offers insights into outstanding matters to address as phase II studies are imminent. Finally, we present a proposal for co-administration and serially-alternating administration of tDC and T-regulatory cells (Tregs) as a synergistic and complementary approach to prevent and treat T1D.
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Affiliation(s)
- Nick Giannoukakis
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
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2
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Jeyagaran A, Lu CE, Zbinden A, Birkenfeld AL, Brucker SY, Layland SL. Type 1 diabetes and engineering enhanced islet transplantation. Adv Drug Deliv Rev 2022; 189:114481. [PMID: 36002043 PMCID: PMC9531713 DOI: 10.1016/j.addr.2022.114481] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 01/24/2023]
Abstract
The development of new therapeutic approaches to treat type 1 diabetes mellitus (T1D) relies on the precise understanding and deciphering of insulin-secreting β-cell biology, as well as the mechanisms responsible for their autoimmune destruction. β-cell or islet transplantation is viewed as a potential long-term therapy for the millions of patients with diabetes. To advance the field of insulin-secreting cell transplantation, two main research areas are currently investigated by the scientific community: (1) the identification of the developmental pathways that drive the differentiation of stem cells into insulin-producing cells, providing an inexhaustible source of cells; and (2) transplantation strategies and engineered transplants to provide protection and enhance the functionality of transplanted cells. In this review, we discuss the biology of pancreatic β-cells, pathology of T1D and current state of β-cell differentiation. We give a comprehensive view and discuss the different possibilities to engineer enhanced insulin-secreting cell/islet transplantation from a translational perspective.
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Affiliation(s)
- Abiramy Jeyagaran
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; NMI Natural and Medical Sciences Institute at the University Tübingen, 72770 Reutlingen, Germany
| | - Chuan-En Lu
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Aline Zbinden
- Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, German Center for Diabetes Research (DZD e.V.), Munich, Germany
| | - Sara Y Brucker
- Department of Women's Health, Eberhard Karls University, 72076 Tübingen, Germany
| | - Shannon L Layland
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; Department of Women's Health, Eberhard Karls University, 72076 Tübingen, Germany.
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3
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Odobasic D, Holdsworth SR. Emerging Cellular Therapies for Anti-myeloperoxidase Vasculitis and Other Autoimmune Diseases. Front Immunol 2021; 12:642127. [PMID: 34394071 PMCID: PMC8358391 DOI: 10.3389/fimmu.2021.642127] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 07/08/2021] [Indexed: 11/26/2022] Open
Abstract
Anti-myeloperoxidase vasculitis (MPO-AAV) is a life-threatening autoimmune disease which causes severe inflammation of small blood vessels, mainly in the kidney. As for many other autoimmune diseases, current treatments, which consist of general immunosuppressants, are partially effective, toxic and broadly immunosuppressive, causing significant and serious adverse effects in many patients. Therefore, there is an urgent need for more targeted and less harmful therapies. Tolerogenic dendritic cells, regulatory T cells and stem cells have emerged as attractive, new and safer options for the treatment for various autoimmune diseases due to their unique and selective immunosuppressive capacity. In this review, we will discuss how these cellular therapies offer potential to become novel and safer treatments for MPO-AAV.
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Affiliation(s)
- Dragana Odobasic
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, VIC, Australia
| | - Stephen R Holdsworth
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, VIC, Australia.,Department of Nephrology, Monash Health, Clayton, VIC, Australia.,Department of Immunology, Monash Health, Clayton, VIC, Australia
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4
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Ríos-Ríos WDJ, Sosa-Luis SA, Torres-Aguilar H. Current advances in using tolerogenic dendritic cells as a therapeutic alternative in the treatment of type 1 diabetes. World J Diabetes 2021; 12:603-615. [PMID: 33995848 PMCID: PMC8107985 DOI: 10.4239/wjd.v12.i5.603] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/26/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β-cells of the pancreatic islets by autoreactive T cells, leading to high blood glucose levels and severe long-term complications. The typical treatment indicated in T1D is exogenous insulin administration, which controls glucose levels; however, it does not stop the autoimmune process. Various strategies have been implemented aimed at stopping β-cell destruction, such as cellular therapy. Dendritic cells (DCs) as an alternative in cellular therapy have gained great interest for autoimmune disease therapy due to their plasticity to acquire immunoregulatory properties both in vivo and in vitro, performing functions such as anti-inflammatory cytokine secretion and suppression of autoreactive lymphocytes, which are dependent of their tolerogenic phenotype, displayed by features such as semimature phenotype, low surface expression of stimulatory molecules to prime T cells, as well as the elevated expression of inhibitory markers. DCs may be obtained and propagated easily in optimal amounts from peripheral blood or bone marrow precursors, such as monocytes or hematopoietic stem cells, respectively; therefore, various protocols have been established for tolerogenic (tol)DCs manufacturing for therapeutic research in the treatment of T1D. In this review, we address the current advances in the use of tolDCs for T1D therapy, encompassing protocols for their manufacturing, the data obtained from preclinical studies carried out, and the status of clinical research evaluating the safety, feasibility, and effectiveness of tolDCs.
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Affiliation(s)
- William de Jesús Ríos-Ríos
- Department of Biochemical Sciences Faculty, Universidad Autónoma “Benito Juárez” de Oaxaca, Oaxaca 68120, Mexico
| | - Sorely Adelina Sosa-Luis
- Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City 07360, Mexico
| | - Honorio Torres-Aguilar
- Department of Biochemical Sciences Faculty, Universidad Autónoma “Benito Juárez” de Oaxaca, Oaxaca 68120, Mexico
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5
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Zhuang Q, Cai H, Cao Q, Li Z, Liu S, Ming Y. Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation. Front Immunol 2020; 11:552988. [PMID: 33123131 PMCID: PMC7573100 DOI: 10.3389/fimmu.2020.552988] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 08/12/2020] [Indexed: 12/19/2022] Open
Abstract
Over a half century, organ transplantation has become an effective method for the treatment of end-stage visceral diseases. Although the application of immunosuppressants (IS) minimizes the rate of allograft rejection, the common use of IS bring many adverse effects to transplant patients. Moreover, true transplant tolerance is very rare in clinical practice. Dendritic cells (DCs) are thought to be the most potent antigen-presenting cells, which makes a bridge between innate and adaptive immunity. Among their subsets, a small portion of DCs with immunoregulatory function was known as tolerogenic DC (Tol-DC). Previous reports demonstrated the ability of adoptively transferred Tol-DC to approach transplant tolerance in animal models. In this study, we summarized the properties, ex vivo generation, metabolism, and clinical attempts of Tol-DC. Tol-DC is expected to become a substitute for IS to enable patients to achieve immune tolerance in the future.
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Affiliation(s)
- Quan Zhuang
- Transplantation Center of the 3rd Xiangya Hospital, Central South University, Changsha, China.,Research Center of National Health Ministry on Transplantation Medicine, Changsha, China
| | - Haozheng Cai
- Transplantation Center of the 3rd Xiangya Hospital, Central South University, Changsha, China
| | - Qingtai Cao
- Hunan Normal University School of Medicine, Changsha, China
| | - Zixin Li
- Hunan Normal University School of Medicine, Changsha, China
| | - Shu Liu
- Transplantation Center of the 3rd Xiangya Hospital, Central South University, Changsha, China.,Research Center of National Health Ministry on Transplantation Medicine, Changsha, China
| | - Yingzi Ming
- Transplantation Center of the 3rd Xiangya Hospital, Central South University, Changsha, China.,Research Center of National Health Ministry on Transplantation Medicine, Changsha, China
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Elucidating the Role of Ezh2 in Tolerogenic Function of NOD Bone Marrow-Derived Dendritic Cells Expressing Constitutively Active Stat5b. Int J Mol Sci 2020; 21:ijms21186453. [PMID: 32899608 PMCID: PMC7554732 DOI: 10.3390/ijms21186453] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 08/27/2020] [Indexed: 12/28/2022] Open
Abstract
Tolerogenic dendritic cells (toDCs) are crucial to controlling the development of autoreactive T cell responses and the prevention of autoimmunity. We have reported that NOD.CD11cStat5b-CA transgenic mice expressing a constitutively active (CA) form of Stat5b under the control of a CD11c promoter are protected from diabetes and that Stat5b-CA-expressing DCs are tolerogenic and halt ongoing diabetes in NOD mice. However, the molecular mechanisms by which Stat5b-CA modulates DC tolerogenic function are not fully understood. Here, we used bone marrow-derived DCs (BMDCs) from NOD.CD11cStat5b-CA transgenic mice (Stat5b-CA.BMDCs) and found that Stat5b-CA.BMDCs displayed high levels of MHC class II, CD80, CD86, PD-L1, and PD-L2 and produced elevated amounts of TGFβ but low amounts of TNFα and IL-23. Stat5b-CA.BMDCs upregulated Irf4 and downregulated Irf8 genes and protein expression and promoted CD11c+CD11b+ DC2 subset differentiation. Interestingly, we found that the histone methyltransferase Ezh2 and Stat5b-CA bound gamma-interferon activated site (GAS) sequences in the Irf8 enhancer IRF8 transcription, whereas Stat5b but not Ezh2 bound GAS sequences in the Irf4 promoter to enhance IRF4 transcription. Injection of Stat5b-CA.BMDCs into prediabetic NOD mice halted progression of islet inflammation and protected against diabetes. Importantly, inhibition of Ezh2 in tolerogenic Stat5b-CA.BMDCs reduced their ability to prevent diabetes development in NOD recipient mice. Taken together, our data suggest that the active form of Stat5b induces tolerogenic DC function by modulating IRF4 and IRF8 expression through recruitment of Ezh2 and highlight the fundamental role of Ezh2 in Stat5b-mediated induction of tolerogenic DC function.
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7
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Madelon N, Montanari E, Gruaz L, Pimenta J, Muller YD, Bühler LH, Puga Yung GL, Seebach JD. Prolongation of rat-to-mouse islets xenograft survival by co-transplantation of autologous IL-10 differentiated murine tolerogenic dendritic cells. Xenotransplantation 2020; 27:e12584. [PMID: 31984564 DOI: 10.1111/xen.12584] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 12/06/2019] [Accepted: 01/05/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Tolerogenic dendritic cells (DCs) represent a promising approach to promote transplantation tolerance. In this study, the potential of autologous bone marrow (BM)-derived murine DC to protect rat-to-mouse islets xenografts was analyzed. METHODS Tolerogenic DCs were generated by differentiating BM cells in the presence of granulocyte-macrophage colony-stimulating factor and interleukin 10 (IL-10, IL-10 DC). The phenotype of IL-10 DC was characterized in vitro by expression of costimulatory/inhibitory molecules (flow cytometry) and cytokines (Luminex and ELISA), their function by phagocytosis and T-cell stimulation assays. To study transplant tolerance in vivo, rat islets were transplanted alone or in combination with autologous murine IL-10 DC under the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice. Xenograft survival was evaluated by monitoring glycemia, cellular infiltration of xenografts by microscopy and flow cytometry 10 days post-transplantation. RESULTS Compared with control DC, IL-10 DC exhibited lower levels of major histocompatibility complex class II, costimulatory molecules (CD40, CD86, CD205), lower production of pro-inflammatory cytokines (IL-12p70, TNF, IL-6), and higher production of IL-10. Phagocytosis of xenogeneic rat splenocytes was not impaired in IL-10 DC, whereas stimulation of T-cell proliferation was reduced in the presence of IL-10 DC. Xenograft survival of rat islets in diabetic mice co-transplanted with autologous murine IL-10 DC was significantly prolonged from 12 to 21 days, without additional immunosuppressive treatment. Overall, infiltration of xenografts by T cells and myeloid cells was not different in IL-10 DC recipient mice, but enriched for CD8+ T cells and myeloid cells with suppressor-associated phenotype. CONCLUSIONS Autologous IL-10-differentiated DC with tolerogenic properties prolong rat-to-mouse islets xenograft survival, potentially by locally inducing immune regulatory cells, indicating their potential for regulatory immune cell therapy in xenotransplantation.
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Affiliation(s)
- Natacha Madelon
- Laboratory of Translational Immunology, Division of Immunology and Allergology, Department of Medical Specialties, Medical Faculty, Geneva University Hospitals, Geneva, Switzerland
| | - Elisa Montanari
- Department of Surgery, Medical Faculty, Cell Isolation and Transplantation Center, Geneva University Hospitals, Geneva, Switzerland
| | - Lyssia Gruaz
- Laboratory of Translational Immunology, Division of Immunology and Allergology, Department of Medical Specialties, Medical Faculty, Geneva University Hospitals, Geneva, Switzerland
| | - Joel Pimenta
- Department of Surgery, Medical Faculty, Cell Isolation and Transplantation Center, Geneva University Hospitals, Geneva, Switzerland
| | - Yannick D Muller
- Laboratory of Translational Immunology, Division of Immunology and Allergology, Department of Medical Specialties, Medical Faculty, Geneva University Hospitals, Geneva, Switzerland
| | - Leo H Bühler
- Department of Surgery, Medical Faculty, Cell Isolation and Transplantation Center, Geneva University Hospitals, Geneva, Switzerland
| | - Gisella L Puga Yung
- Laboratory of Translational Immunology, Division of Immunology and Allergology, Department of Medical Specialties, Medical Faculty, Geneva University Hospitals, Geneva, Switzerland
| | - Jörg D Seebach
- Laboratory of Translational Immunology, Division of Immunology and Allergology, Department of Medical Specialties, Medical Faculty, Geneva University Hospitals, Geneva, Switzerland
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8
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Odobasic D, Oudin V, Ito K, Gan PY, Kitching AR, Holdsworth SR. Tolerogenic Dendritic Cells Attenuate Experimental Autoimmune Antimyeloperoxidase Glomerulonephritis. J Am Soc Nephrol 2019; 30:2140-2157. [PMID: 31444274 DOI: 10.1681/asn.2019030236] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 07/16/2019] [Indexed: 12/30/2022] Open
Abstract
Background Because of their capacity to induce antigen-specific immunosuppression, tolerogenic dendritic cells are a promising tool for treatment of autoimmune conditions, such as GN caused by autoimmunity against myeloperoxidase (MPO). METHODS We sought to generate tolerogenic dendritic cells to suppress anti-MPO GN by culturing bone marrow cells with an NFκB inhibitor (BAY 11-7082) and exposing them to a pulse of MPO. After administering these MPO/BAY dendritic cells or saline to mice with established anti-MPO or anti-methylated BSA (mBSA) immunity, we assessed immune responses and GN. We also examined mechanisms of action of MPO/BAY dendritic cells. RESULTS MPO/BAY dendritic cells decreased anti-MPO immunity and GN without inhibiting immune responses against mBSA; they also induced IL-10-producing regulatory T cells in MPO-immunized mice without affecting IL-10+ CD4+Foxp3- type 1 regulatory T cells or regulatory B cells. MPO/BAY dendritic cells did not inhibit anti-MPO immunity when CD4+Foxp3+ cells were depleted in vivo, showing that regulatory T cells are required for their effects. Coculture experiments with dendritic cells and CD4+Foxp3- or CD4+Foxp3+ cells showed that MPO/BAY dendritic cells generate Foxp3+ regulatory T cells from CD4+Foxp3- cells through several pathways, and induce IL-10+ regulatory T cells via inducible costimulator (ICOS), which was confirmed in vivo. Transfer of MPO/BAY dendritic cell-induced regulatory T cells in vivo, with or without anti-IL-10 receptor antibody, demonstrated that they suppress anti-MPO immunity and GN via IL-10. CONCLUSIONS MPO/BAY dendritic cells attenuate established anti-MPO autoimmunity and GN in an antigen-specific manner through ICOS-dependent induction of IL-10-expressing regulatory T cells. This suggests that autoantigen-loaded tolerogenic dendritic cells may represent a novel antigen-specific therapeutic option for anti-MPO GN.
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Affiliation(s)
- Dragana Odobasic
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Australia;
| | - Virginie Oudin
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Australia
| | - Kenji Ito
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Australia.,Division of Nephrology and Rheumatology, Fukuoka University School of Medicine, Fukuoka, Japan; and
| | - Poh-Yi Gan
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Australia
| | - A Richard Kitching
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Australia.,Department of Pediatric Nephrology.,Nephrology, and
| | - Stephen R Holdsworth
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Australia.,Nephrology, and.,Immunology, Monash Health, Clayton, Australia
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9
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Zhong M, Zhong C, Cui W, Wang G, Zheng G, Li L, Zhang J, Ren R, Gao H, Wang T, Li X, Che J, Gohda E. Induction of tolerogenic dendritic cells by activated TGF-β/Akt/Smad2 signaling in RIG-I-deficient stemness-high human liver cancer cells. BMC Cancer 2019; 19:439. [PMID: 31088527 PMCID: PMC6515680 DOI: 10.1186/s12885-019-5670-9] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 05/02/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Dendritic cells (DCs) alter their role from being immunostimulatory to immunosuppressive at advanced stages of tumor progression, but the influence of cancer stem cells (CSCs) and their secreted factors on generation and phenotypic change of DCs is unknown. Retinoic acid-inducible gene I (RIG-I) plays a role in regulation of other cellular processes including leukemic stemness besides its antiviral function. METHODS Short hairpin RNA-mediated gene silencing was employed to generate stable RIG-I-knocked-down human hepatocellular carcinoma (HCC) cell lines. Expression levels of genes and proteins in spheres of those HCC cells were determined by quantitative real-time PCR and Western bot, respectively. Levels of secreted cytokines were measured by ELISA. The surface molecule expression levels of DCs were analyzed using flow cytometry. The ability of DCs to induce proliferation of T cells was assessed by a mixed lymphocyte reaction (MLR) assay. RESULTS RIG-I-knocked-down HCC cells showed upregulated expression of stem cell marker genes, enhanced secretion of factors suppressing in vitro generation of DCs into the conditioned medium (CM), and induction of a phenotype of tumor-infiltrating DCs (TIDCs) with low levels of DC markers in their tumors in nude mice. Those DCs and TIDCs showed reduced MLR, indicating RIG-I deficiency-induced immunotolerance. The RIG-I-deficient HCC cells secreted more TGF-β1 than did reference cells. The tumors formed after injection of RIG-I-deficient HCC cells had higher TGF-β1 contents than did tumors derived from control cells. DC generation and MLR suppressed by the CM of RIG-I-deficient HCC cells were restored by an anti-TGF-β1 antibody. TGF-β1-induced phosphorylation of Smad2 and Akt was enhanced in RIG-I-deficient HCC spheres, knockdown of AKT gene expression abolishing the augmentation of TGF-β1-induced Smad2 phosphorylation. Akt and p-Akt were co-immunoprecipitated with Smad2 in cytoplasmic proteins of RIG-I-deficient spheres but not in those of control spheres, the amounts of co-immunoprecipitated Akt and p-Akt being increased by TGF-β stimulation. CONCLUSIONS Our results demonstrate that RIG-I deficiency in HCC cells induced their stemness, enhanced secretion and signaling of TGF-β1, tolerogenic TIDCs and less generation of DCs, and the results suggest involvement of TGF-β1 in those RIG-I deficiency-induced tolerogenic changes and involvement of CSCs in DC-mediated immunotolerance.
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Affiliation(s)
- Ming Zhong
- Institute of Tumor Pharmacology, Jining Medical College, Xueyuan Road 669, Rizhao, 276826 China
| | - Cheng Zhong
- Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Wen Cui
- Institute of Tumor Pharmacology, Jining Medical College, Xueyuan Road 669, Rizhao, 276826 China
| | - Guanghui Wang
- Institute of Tumor Pharmacology, Jining Medical College, Xueyuan Road 669, Rizhao, 276826 China
| | - Gongpu Zheng
- Institute of Tumor Pharmacology, Jining Medical College, Xueyuan Road 669, Rizhao, 276826 China
| | - Li Li
- Institute of Tumor Pharmacology, Jining Medical College, Xueyuan Road 669, Rizhao, 276826 China
| | - Jing Zhang
- Institute of Tumor Pharmacology, Jining Medical College, Xueyuan Road 669, Rizhao, 276826 China
| | - Rujing Ren
- Institute of Tumor Pharmacology, Jining Medical College, Xueyuan Road 669, Rizhao, 276826 China
| | - Huijei Gao
- Institute of Tumor Pharmacology, Jining Medical College, Xueyuan Road 669, Rizhao, 276826 China
| | | | - Xin Li
- People’s Hospital of Rizhao, Rizhao, China
| | - Jiantu Che
- S&V Biological Science and Technology Co., Ltd., Beijing, China
| | - Eiichi Gohda
- Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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10
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Funda DP, Palová-Jelínková L, Goliáš J, Kroulíková Z, Fajstová A, Hudcovic T, Špíšek R. Optimal Tolerogenic Dendritic Cells in Type 1 Diabetes (T1D) Therapy: What Can We Learn From Non-obese Diabetic (NOD) Mouse Models? Front Immunol 2019; 10:967. [PMID: 31139178 PMCID: PMC6527741 DOI: 10.3389/fimmu.2019.00967] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 04/15/2019] [Indexed: 12/21/2022] Open
Abstract
Tolerogenic dendritic cells (tolDCs) are explored as a promising standalone or combination therapy in type 1 diabetes (T1D). The therapeutic application of tolDCs, including in human trials, has been tested also in other autoimmune diseases, however, T1D displays some unique features. In addition, unlike in several disease-induced animal models of autoimmune diseases, the prevalent animal model for T1D, the NOD mouse, develops diabetes spontaneously. This review compares evidence of various tolDCs approaches obtained from animal (mainly NOD) models of T1D with a focus on parameters of this cell-based therapy such as protocols of tolDC preparation, antigen-specific vs. unspecific approaches, doses of tolDCs and/or autoantigens, application schemes, application routes, the migration of tolDCs as well as their preventive, early pre-onset intervention or curative effects. This review also discusses perspectives of tolDC therapy and areas of preclinical research that are in need of better clarification in animal models in a quest for effective and optimal tolDC therapies of T1D in humans.
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Affiliation(s)
- David P Funda
- Institute of Microbiology of the Czech Academy of Sciences, v.v.i., Prague, Czechia
| | - Lenka Palová-Jelínková
- SOTIO a s., Prague, Czechia.,Department of Immunology, 2nd Medical School, Charles University, Prague, Czechia
| | - Jaroslav Goliáš
- Institute of Microbiology of the Czech Academy of Sciences, v.v.i., Prague, Czechia
| | - Zuzana Kroulíková
- Institute of Microbiology of the Czech Academy of Sciences, v.v.i., Prague, Czechia
| | - Alena Fajstová
- Institute of Microbiology of the Czech Academy of Sciences, v.v.i., Prague, Czechia
| | - Tomáš Hudcovic
- Institute of Microbiology of the Czech Academy of Sciences, v.v.i., Prague, Czechia
| | - Radek Špíšek
- SOTIO a s., Prague, Czechia.,Department of Immunology, 2nd Medical School, Charles University, Prague, Czechia
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11
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Funes SC, Manrique de Lara A, Altamirano-Lagos MJ, Mackern-Oberti JP, Escobar-Vera J, Kalergis AM. Immune checkpoints and the regulation of tolerogenicity in dendritic cells: Implications for autoimmunity and immunotherapy. Autoimmun Rev 2019; 18:359-368. [PMID: 30738957 DOI: 10.1016/j.autrev.2019.02.006] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The immune system is responsible for defending the host from a large variety of potential pathogens, while simultaneously avoiding immune reactivity towards self-components. Self-tolerance has to be tightly maintained throughout several central and peripheral processes; immune checkpoints are imperative for regulating the immunity/tolerance balance. Dendritic cells (DCs) are specialized cells that capture antigens, and either activate or inhibit antigen-specific T cells. Therefore, they play a key role at inducing and maintaining immune tolerance. DCs that suppress the immune response have been called tolerogenic dendritic cells (tolDCs). Given their potential as a therapy to prevent transplant rejection and autoimmune damage, several strategies are under development to generate tolDCs, in order to avoid activation and expansion of self-reactive T cells. In this article, we summarize the current knowledge relative to the main features of tolDCs, their mechanisms of action and their therapeutic use for autoimmune diseases. Based on the literature reviewed, autologous antigen-specific tolDCs might constitute a promising strategy to suppress autoreactive T cells and reduce detrimental inflammatory processes.
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Affiliation(s)
- Samanta C Funes
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
| | - Amaranta Manrique de Lara
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; Instituto de Biotecnología, Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, Mexico.
| | - María J Altamirano-Lagos
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
| | - Juan P Mackern-Oberti
- Instituto de Medicina y Biología Experimental de Cuyo, IMBECU, CONICET, Mendoza, Argentina; Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina.
| | - Jorge Escobar-Vera
- Laboratorio de Genética, Departamento Biomédico, Facultad de Ciencias de la Salud, Universidad de Antofagasta, Antofagasta, Chile.
| | - Alexis M Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; Departamento de Endocrinología, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
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12
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Recino A, Gan SU, Sia KC, Sawyer Y, Trendell J, Kay R, Gribble FM, Reimann F, Foale R, Notaridou M, Holmes N, Lever A, Lee KO, Nathwani A, Cooke A, Calne R, Wallberg M. Immunosuppression overcomes insulin- and vector-specific immune responses that limit efficacy of AAV2/8-mediated insulin gene therapy in NOD mice. Gene Ther 2019; 26:40-56. [PMID: 30514969 PMCID: PMC6514884 DOI: 10.1038/s41434-018-0052-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 10/09/2018] [Accepted: 11/06/2018] [Indexed: 12/23/2022]
Abstract
We report the restoration of euglycaemia in chemically induced diabetic C57BL/6 mice and spontaneously diabetic Non Obese Diabetic (NOD) mice by intravenous systemic administration of a single-stranded adeno-associated virus (ssAAV2/8) codon optimised (co) vector encoding furin cleavable human proinsulin under a liver-specific promoter. There were no immunological barriers to efficacy of insulin gene therapy in chemically induced C57BL/6 mice, which enjoyed long-lasting correction of hyperglycaemia after therapy, up to 250 days. Euglycaemia was also restored in spontaneously diabetic NOD mice, although these mice required a 7-10-fold higher dose of vector to achieve similar efficacy as the C57BL/6 mice and the immunodeficient NODscid mice. We detected CD8+ T cell reactivity to insulin and mild inflammatory infiltration in the livers of gene therapy recipient NOD mice, neither of which were observed in the treated C57BL/6 mice. Efficacy of the gene therapy in NOD mice was partially improved by targeting the immune system with anti-CD4 antibody treatment, while transfer of NOD mouse AAV2/8-reactive serum to recipients prevented successful restoration of euglycaemia in AAV2/8-HLP-hINSco-treated NODscid mice. Our data indicate that both immune cells and antibodies form a barrier to successful restoration of euglycaemia in autoimmune diabetic recipient mice with insulin gene therapy, but that this barrier can be overcome by increasing the dose of vector and by suppressing immune responses.
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Affiliation(s)
- Asha Recino
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.
| | - Shu Uin Gan
- Department of Surgery, National University of Singapore, Singapore, Singapore
| | - Kian Chuan Sia
- Department of Surgery, National University of Singapore, Singapore, Singapore
| | - Yvonne Sawyer
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Jenny Trendell
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Richard Kay
- Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK
| | - Fiona M Gribble
- Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK
| | - Frank Reimann
- Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK
| | - Rob Foale
- Dick White Referrals, Station Farm, Six Mile Bottom, Suffolk, UK
| | | | - Nick Holmes
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Andrew Lever
- Department of Medicine, University of Cambridge, Cambridge, UK
- Department of Medicine, National University of Singapore, Singapore, Singapore
| | - Kok Onn Lee
- Department of Medicine, National University of Singapore, Singapore, Singapore
| | - Amit Nathwani
- Department of Haematology, UCL Cancer Institute, London, UK
| | - Anne Cooke
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Roy Calne
- Department of Surgery, National University of Singapore, Singapore, Singapore
- Department of Medicine, National University of Singapore, Singapore, Singapore
- Department of Surgery, University of Cambridge, Cambridge, UK
| | - Maja Wallberg
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.
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13
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Perez-Basterrechea M, Esteban MM, Vega JA, Obaya AJ. Tissue-engineering approaches in pancreatic islet transplantation. Biotechnol Bioeng 2018; 115:3009-3029. [PMID: 30144310 DOI: 10.1002/bit.26821] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/08/2018] [Accepted: 08/14/2018] [Indexed: 12/15/2022]
Abstract
Pancreatic islet transplantation is a promising alternative to whole-pancreas transplantation as a treatment of type 1 diabetes mellitus. This technique has been extensively developed during the past few years, with the main purpose of minimizing the complications arising from the standard protocols used in organ transplantation. By using a variety of strategies used in tissue engineering and regenerative medicine, pancreatic islets have been successfully introduced in host patients with different outcomes in terms of islet survival and functionality, as well as the desired normoglycemic control. Here, we describe and discuss those strategies to transplant islets together with different scaffolds, in combination with various cell types and diffusible factors, and always with the aim of reducing host immune response and achieving islet survival, regardless of the site of transplantation.
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Affiliation(s)
- Marcos Perez-Basterrechea
- Unidad de Terapia Celular y Medicina Regenerativa, Servicio de Hematología y Hemoterapia, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.,Plataforma de Terapias Avanzadas, Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Manuel M Esteban
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
| | - Jose A Vega
- Departamento de Morfología y Biología Celular, Universidad de Oviedo, Oviedo, Spain.,Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - Alvaro J Obaya
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
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14
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Benson RA, Garcon F, Recino A, Ferdinand JR, Clatworthy MR, Waldmann H, Brewer JM, Okkenhaug K, Cooke A, Garside P, Wållberg M. Non-Invasive Multiphoton Imaging of Islets Transplanted Into the Pinna of the NOD Mouse Ear Reveals the Immediate Effect of Anti-CD3 Treatment in Autoimmune Diabetes. Front Immunol 2018; 9:1006. [PMID: 29867981 PMCID: PMC5968092 DOI: 10.3389/fimmu.2018.01006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 04/23/2018] [Indexed: 12/16/2022] Open
Abstract
We present a novel and readily accessible method facilitating cellular time-resolved imaging of transplanted pancreatic islets. Grafting of islets to the mouse ear pinna allows non-invasive, in vivo longitudinal imaging of events in the islets and enables improved acquisition of experimental data and use of fewer experimental animals than is possible using invasive techniques, as the same mouse can be assessed for the presence of islet infiltrating cells before and after immune intervention. We have applied this method to investigating therapeutic protection of beta cells through the well-established use of anti-CD3 injection, and have acquired unprecedented data on the nature and rapidity of the effect on the islet infiltrating T cells. We demonstrate that infusion of anti-CD3 antibody leads to immediate effects on islet infiltrating T cells in islet grafts in the pinna of the ear, and causes them to increase their speed and displacement within 20 min of infusion. This technique overcomes several technical challenges associated with intravital imaging of pancreatic immune responses and facilitates routine study of beta islet cell development, differentiation, and function in health and disease.
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Affiliation(s)
- Robert A. Benson
- College of Medical, Veterinary & Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Fabien Garcon
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom
| | - Asha Recino
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | - John R. Ferdinand
- Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Menna R. Clatworthy
- Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Herman Waldmann
- Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
| | - James M. Brewer
- College of Medical, Veterinary & Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Klaus Okkenhaug
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | - Anne Cooke
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | - Paul Garside
- College of Medical, Veterinary & Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Maja Wållberg
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
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15
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Obregon C, Kumar R, Pascual MA, Vassalli G, Golshayan D. Update on Dendritic Cell-Induced Immunological and Clinical Tolerance. Front Immunol 2017; 8:1514. [PMID: 29250057 PMCID: PMC5715373 DOI: 10.3389/fimmu.2017.01514] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 10/26/2017] [Indexed: 12/18/2022] Open
Abstract
Dendritic cells (DCs) as highly efficient antigen-presenting cells are at the interface of innate and adaptive immunity. As such, they are key mediators of immunity and antigen-specific immune tolerance. Due to their functional specialization, research efforts have focused on the characterization of DCs subsets involved in the initiation of immunogenic responses and in the maintenance of tissue homeostasis. Tolerogenic DCs (tolDCs)-based therapies have been designed as promising strategies to prevent and control autoimmune diseases as well as allograft rejection after solid organ transplantation (SOT). Despite successful experimental studies and ongoing phase I/II clinical trials using autologous tolDCs in patients with type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and in SOT recipients, additional basic research will be required to determine the optimal DC subset(s) and conditioning regimens for tolDCs-based treatments in vivo. In this review, we discuss the characteristics of human DCs and recent advances in their classification, as well as the role of DCs in immune regulation and their susceptibility to in vitro or in vivo manipulation for the development of tolerogenic therapies, with a focus on the potential of tolDCs for the treatment of autoimmune diseases and the prevention of allograft rejection after SOT.
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Affiliation(s)
- Carolina Obregon
- Department of Medicine, Transplantation Centre and Transplantation Immunopathology Laboratory, Service of Immunology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Rajesh Kumar
- Department of Medicine, Transplantation Centre and Transplantation Immunopathology Laboratory, Service of Immunology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Manuel Antonio Pascual
- Department of Medicine, Transplantation Centre and Transplantation Immunopathology Laboratory, Service of Immunology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.,Department of Surgery, Transplantation Centre, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Giuseppe Vassalli
- Département coeur-vaisseaux, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.,Fondazione Cardiocentro Ticino, Swiss Institute of Regenerative Medicine (SIRM), Lugano, Switzerland
| | - Déla Golshayan
- Department of Medicine, Transplantation Centre and Transplantation Immunopathology Laboratory, Service of Immunology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.,Department of Surgery, Transplantation Centre, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
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16
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Wallberg M, Recino A, Phillips J, Howie D, Vienne M, Paluch C, Azuma M, Wong FS, Waldmann H, Cooke A. Anti-CD3 treatment up-regulates programmed cell death protein-1 expression on activated effector T cells and severely impairs their inflammatory capacity. Immunology 2017; 151:248-260. [PMID: 28211040 PMCID: PMC5418468 DOI: 10.1111/imm.12729] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 02/03/2017] [Accepted: 02/13/2017] [Indexed: 01/07/2023] Open
Abstract
T cells play a key role in the pathogenesis of type 1 diabetes, and targeting the CD3 component of the T‐cell receptor complex provides one therapeutic approach. Anti‐CD3 treatment can reverse overt disease in spontaneously diabetic non‐obese diabetic mice, an effect proposed to, at least in part, be caused by a selective depletion of pathogenic cells. We have used a transfer model to further investigate the effects of anti‐CD3 treatment on green fluorescent protein (GFP)+ islet‐specific effector T cells in vivo. The GFP expression allowed us to isolate the known effectors at different time‐points during treatment to assess cell presence in various organs as well as gene expression and cytokine production. We find, in this model, that anti‐CD3 treatment does not preferentially deplete the transferred effector cells, but instead inhibits their metabolic function and their production of interferon‐γ. Programmed cell death protein 1 (PD‐1) expression was up‐regulated on the effector cells from anti‐CD3‐treated mice, and diabetes induced through anti‐PD‐L1 antibody could only be reversed with anti‐CD3 antibody if the anti‐CD3 treatment lasted beyond the point when the anti‐PD‐L1 antibody was washed out of the system. This suggests that PD‐1/PD‐L1 interaction plays an important role in the anti‐CD3 antibody mediated protection. Our data demonstrate an additional mechanism by which anti‐CD3 therapy can reverse diabetogenesis.
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Affiliation(s)
- Maja Wallberg
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Asha Recino
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Jenny Phillips
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Duncan Howie
- Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
| | - Margaux Vienne
- Department of Pathology, University of Cambridge, Cambridge, UK
| | | | - Miyuki Azuma
- Department of Molecular Immunology Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - F Susan Wong
- Diabetes Research Group, Institute of Molecular and Experimental Medicine, Cardiff School of Medicine, Cardiff University, Cardiff, UK
| | - Herman Waldmann
- Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
| | - Anne Cooke
- Department of Pathology, University of Cambridge, Cambridge, UK
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17
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Delaune V, Berney T, Lacotte S, Toso C. Intraportal islet transplantation: the impact of the liver microenvironment. Transpl Int 2017; 30:227-238. [DOI: 10.1111/tri.12919] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 11/09/2016] [Accepted: 01/16/2017] [Indexed: 12/20/2022]
Affiliation(s)
- Vaihere Delaune
- Hepatology and Transplantation Laboratory; Department of Surgery; Faculty of Medicine; University of Geneva; Geneva Switzerland
- Divisions of Abdominal and Transplantation Surgery; Department of Surgery; Geneva University Hospitals; Geneva Switzerland
| | - Thierry Berney
- Divisions of Abdominal and Transplantation Surgery; Department of Surgery; Geneva University Hospitals; Geneva Switzerland
- Cell Transplantation Laboratory; Department of Surgery; Faculty of Medicine; University of Geneva; Geneva Switzerland
| | - Stéphanie Lacotte
- Hepatology and Transplantation Laboratory; Department of Surgery; Faculty of Medicine; University of Geneva; Geneva Switzerland
| | - Christian Toso
- Hepatology and Transplantation Laboratory; Department of Surgery; Faculty of Medicine; University of Geneva; Geneva Switzerland
- Divisions of Abdominal and Transplantation Surgery; Department of Surgery; Geneva University Hospitals; Geneva Switzerland
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18
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da Silva MB, da Cunha FF, Terra FF, Camara NOS. Old game, new players: Linking classical theories to new trends in transplant immunology. World J Transplant 2017; 7:1-25. [PMID: 28280691 PMCID: PMC5324024 DOI: 10.5500/wjt.v7.i1.1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/16/2016] [Accepted: 12/07/2016] [Indexed: 02/05/2023] Open
Abstract
The evolutionary emergence of an efficient immune system has a fundamental role in our survival against pathogenic attacks. Nevertheless, this same protective mechanism may also establish a negative consequence in the setting of disorders such as autoimmunity and transplant rejection. In light of the latter, although research has long uncovered main concepts of allogeneic recognition, immune rejection is still the main obstacle to long-term graft survival. Therefore, in order to define effective therapies that prolong graft viability, it is essential that we understand the underlying mediators and mechanisms that participate in transplant rejection. This multifaceted process is characterized by diverse cellular and humoral participants with innate and adaptive functions that can determine the type of rejection or promote graft acceptance. Although a number of mediators of graft recognition have been described in traditional immunology, recent studies indicate that defining rigid roles for certain immune cells and factors may be more complicated than originally conceived. Current research has also targeted specific cells and drugs that regulate immune activation and induce tolerance. This review will give a broad view of the most recent understanding of the allogeneic inflammatory/tolerogenic response and current insights into cellular and drug therapies that modulate immune activation that may prove to be useful in the induction of tolerance in the clinical setting.
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19
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Madelon N, Puga Yung GL, Seebach JD. Human anti-pig NK cell and CD8 + T-cell responses in the presence of regulatory dendritic cells. Xenotransplantation 2016; 23:479-489. [PMID: 27862343 DOI: 10.1111/xen.12279] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 09/28/2016] [Accepted: 10/09/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND Dendritic cells (DC) play a major role in natural killer (NK) cell and cytotoxic T lymphocyte (CTL) activation leading to cell-mediated xenogeneic responses. In contrast, the use of in vitro differentiated regulatory DC may represent an attractive approach to protect porcine endothelial cells (pEC) from human cell-mediated immune responses. In this study, we evaluated the potential of human regulatory DC to reduce xenogeneic NK cell and CTL responses to pEC. METHODS Human monocytes were differentiated into DC with GM-CSF and IL-4 in the absence or presence of rapamycin or IL-10. The effect of regulatory DC on xenogeneic NK cell and CTL responses was evaluated by analyzing phenotype, IFNγ production, degranulation, and cytotoxicity by flow cytometry and cytotoxicity assays. RESULTS Upon maturation with LPS, Rapa-DC and IL-10-DC displayed different phenotypes and cytokine production profiles. In contrast to untreated DC, both Rapa-DC and IL-10-DC induced significantly less IFNγ production and NK cell degranulation in response to pEC, but did not affect NK cell-mediated pEC lysis. Low production of IL-18 by Rapa-DC, and of IL-12 by IL-10-DC were linked to the deficient IFNγ production by NK cells as shown by partial reversion of IFNγ production upon cytokine reconstitution. In contrast to untreated DC efficiently generating xenoantigen-specific CTL, priming of CTL in the presence of IL-10-DC was impaired as shown by lower IFNγ production and cytotoxicity of CTL in response to pEC. CONCLUSION Both Rapa-DC and IL-10-DC controlled human anti-porcine NK cell responses, in particular IFNγ production, whereas IL-10-DC presented stronger regulatory properties of anti-porcine CTL responses. These in vitro findings indicate that regulatory DC could be a useful tool to promote xenograft tolerance in vivo.
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Affiliation(s)
- Natacha Madelon
- Laboratory of Transplantation Immunology, Division of Immunology and Allergology, Department of Medical Specialties, University Hospitals and Medical Faculty, Geneva, Switzerland
| | - Gisella L Puga Yung
- Laboratory of Transplantation Immunology, Division of Immunology and Allergology, Department of Medical Specialties, University Hospitals and Medical Faculty, Geneva, Switzerland
| | - Jörg D Seebach
- Laboratory of Transplantation Immunology, Division of Immunology and Allergology, Department of Medical Specialties, University Hospitals and Medical Faculty, Geneva, Switzerland
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20
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Sniping the scout: Targeting the key molecules in dendritic cell functions for treatment of autoimmune diseases. Pharmacol Res 2016; 107:27-41. [DOI: 10.1016/j.phrs.2016.02.023] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 02/23/2016] [Accepted: 02/23/2016] [Indexed: 02/07/2023]
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21
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Yoo S, Ha SJ. Generation of Tolerogenic Dendritic Cells and Their Therapeutic Applications. Immune Netw 2016; 16:52-60. [PMID: 26937232 PMCID: PMC4770100 DOI: 10.4110/in.2016.16.1.52] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 02/05/2016] [Accepted: 02/07/2016] [Indexed: 02/06/2023] Open
Abstract
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that bridge innate and adaptive immune responses, thereby leading to immune activation. DCs have been known to recognize pathogen-associated molecular patterns such as lipopolysaccharides (LPS) and nucleic acids via their pattern recognition receptors, which trigger signaling of their maturation and effector functions. Furthermore, DCs take up and process antigens as a form of peptide loaded on the major histocompatibility complex (MHC) and present them to T cells, which are responsible for the adaptive immune response. Conversely, DCs can also play a role in inducing immune suppression under specific circumstances. From this perspective, the role of DCs is related to tolerance rather than immunity. Immunologists refer to these special DCs as tolerogenic DCs (tolDCs). However, the definition of tolDCs is controversial, and there is limited information on their development and characteristics. In this review, we discuss the current concept of tolDCs, cutting-edge methods for generating tolDCs in vitro, and future applications of tolDCs, including clinical use.
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Affiliation(s)
- Seungbo Yoo
- System Immunology Laboratory, Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Sang-Jun Ha
- System Immunology Laboratory, Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul 03722, Korea
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22
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Metabolism Is Central to Tolerogenic Dendritic Cell Function. Mediators Inflamm 2016; 2016:2636701. [PMID: 26980944 PMCID: PMC4766347 DOI: 10.1155/2016/2636701] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Accepted: 12/31/2015] [Indexed: 12/13/2022] Open
Abstract
Immunological tolerance is a fundamental tenant of immune homeostasis and overall health. Self-tolerance is a critical component of the immune system that allows for the recognition of self, resulting in hyporeactivity instead of immunogenicity. Dendritic cells are central to the establishment of dominant immune tolerance through the secretion of immunosuppressive cytokines and regulatory polarization of T cells. Cellular metabolism holds the key to determining DC immunogenic or tolerogenic cell fate. Recent studies have demonstrated that dendritic cell maturation leads to a shift toward a glycolytic metabolic state and preferred use of glucose as a carbon source. In contrast, tolerogenic dendritic cells favor oxidative phosphorylation and fatty acid oxidation. This dichotomous metabolic reprogramming of dendritic cells drives differential cellular function and plays a role in pathologies, such as autoimmune disease. Pharmacological alterations in metabolism have promising therapeutic potential.
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23
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Staels W, De Groef S, Heremans Y, Coppens V, Van Gassen N, Leuckx G, Van de Casteele M, Van Riet I, Luttun A, Heimberg H, De Leu N. Accessory cells for β-cell transplantation. Diabetes Obes Metab 2016; 18:115-24. [PMID: 26289770 DOI: 10.1111/dom.12556] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 07/22/2015] [Accepted: 08/13/2015] [Indexed: 12/16/2022]
Abstract
Despite recent advances, insulin therapy remains a treatment, not a cure, for diabetes mellitus with persistent risk of glycaemic alterations and life-threatening complications. Restoration of the endogenous β-cell mass through regeneration or transplantation offers an attractive alternative. Unfortunately, signals that drive β-cell regeneration remain enigmatic and β-cell replacement therapy still faces major hurdles that prevent its widespread application. Co-transplantation of accessory non-islet cells with islet cells has been shown to improve the outcome of experimental islet transplantation. This review will highlight current travails in β-cell therapy and focuses on the potential benefits of accessory cells for islet transplantation in diabetes.
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MESH Headings
- Animals
- Cell Proliferation
- Cell Separation/trends
- Cells, Cultured
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/pathology
- Diabetes Mellitus, Type 1/surgery
- Diabetes Mellitus, Type 2/immunology
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/pathology
- Diabetes Mellitus, Type 2/surgery
- Endothelial Progenitor Cells/cytology
- Endothelial Progenitor Cells/immunology
- Endothelial Progenitor Cells/pathology
- Endothelial Progenitor Cells/transplantation
- Graft Rejection/immunology
- Graft Rejection/metabolism
- Graft Rejection/prevention & control
- Graft Survival
- Humans
- Immune Tolerance
- Insulin-Secreting Cells/cytology
- Insulin-Secreting Cells/immunology
- Insulin-Secreting Cells/metabolism
- Insulin-Secreting Cells/transplantation
- Islets of Langerhans Transplantation/adverse effects
- Islets of Langerhans Transplantation/immunology
- Mesenchymal Stem Cell Transplantation/adverse effects
- Mesenchymal Stem Cell Transplantation/trends
- Neural Crest/cytology
- Neural Crest/immunology
- Neural Crest/pathology
- Neural Crest/transplantation
- Stem Cell Transplantation/adverse effects
- Stem Cell Transplantation/trends
- T-Lymphocytes, Regulatory/cytology
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/pathology
- T-Lymphocytes, Regulatory/transplantation
- Transplantation, Autologous/adverse effects
- Transplantation, Autologous/trends
- Transplantation, Heterotopic/adverse effects
- Transplantation, Heterotopic/trends
- Transplantation, Homologous/adverse effects
- Transplantation, Homologous/trends
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Affiliation(s)
- W Staels
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
- Division of Pediatric Endocrinology, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium
- Department of Pediatrics and Genetics, Ghent University, Ghent, Belgium
| | - S De Groef
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Y Heremans
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - V Coppens
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - N Van Gassen
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - G Leuckx
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - M Van de Casteele
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - I Van Riet
- Department Hematology Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - A Luttun
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium
| | - H Heimberg
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - N De Leu
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
- Department of Endocrinology, UZ Brussel, Brussels, Belgium
- Department of Endocrinology, ASZ Aalst, Aalst, Belgium
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24
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Barbera Betancourt A, Emery JL, Recino A, Wong FS, Cooke A, Okkenhaug K, Wallberg M. Inhibition of Phosphoinositide 3-Kinase p110delta Does Not Affect T Cell Driven Development of Type 1 Diabetes Despite Significant Effects on Cytokine Production. PLoS One 2016; 11:e0146516. [PMID: 26783747 PMCID: PMC4718552 DOI: 10.1371/journal.pone.0146516] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 12/18/2015] [Indexed: 12/19/2022] Open
Abstract
Type 1 diabetes is caused by the destruction of insulin producing beta cells by the immune system. The p110δ isoform of PI3K is expressed primarily in cells of haematopoietic origin and the catalytic activity of p110δ is important for the activation of these cells. Targeting of this pathway offers an opportunity to reduce immune cell activity without unwanted side effects. We have explored the effects of a specific p110δ isoform inhibitor, IC87114, on diabetogenic T cells both in vitro and in vivo, and find that although pharmacological inhibition of p110δ has a considerable impact on the production of pro-inflammatory cytokines, it does not delay the onset of diabetes after adoptive transfer of diabetogenic cells. Further, we demonstrate that combination treatment with CTLA4-Ig does not improve the efficacy of treatment, but instead attenuates the protective effects seen with CTLA4-Ig treatment alone. Our results suggest that decreased IL-10 production by Foxp3+ CD4+ T cells in the presence of IC87114 negates individual anti-inflammatory effects of IC8114 and CTLA4-Ig.
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MESH Headings
- Adenine/analogs & derivatives
- Adenine/pharmacology
- Animals
- Cell Differentiation/drug effects
- Cell Differentiation/immunology
- Cells, Cultured
- Class I Phosphatidylinositol 3-Kinases
- Cytokines/biosynthesis
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/immunology
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/metabolism
- Female
- Mice
- Mice, Inbred C57BL
- Mice, Inbred CBA
- Mice, Inbred NOD
- Mice, SCID
- Mice, Transgenic
- Phosphatidylinositol 3-Kinases/genetics
- Phosphatidylinositol 3-Kinases/metabolism
- Phosphoinositide-3 Kinase Inhibitors
- Quinazolines/pharmacology
- T-Lymphocytes/drug effects
- T-Lymphocytes/physiology
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Affiliation(s)
- Ariana Barbera Betancourt
- Department of Pathology, University of Cambridge, Tennis Court Road, CB2 1QP Cambridge, United Kingdom
| | - Juliet L. Emery
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB22 3AT, United Kingdom
| | - Asha Recino
- Department of Pathology, University of Cambridge, Tennis Court Road, CB2 1QP Cambridge, United Kingdom
| | - F. Susan Wong
- Diabetes Research Group, Institute of Molecular and Experimental Medicine, Cardiff School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom
| | - Anne Cooke
- Department of Pathology, University of Cambridge, Tennis Court Road, CB2 1QP Cambridge, United Kingdom
| | - Klaus Okkenhaug
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB22 3AT, United Kingdom
| | - Maja Wallberg
- Department of Pathology, University of Cambridge, Tennis Court Road, CB2 1QP Cambridge, United Kingdom
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25
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Staphylococcus enterotoxin B-induced T cells can efficaciously protect against type 1 diabetes in non-obese diabetic mice. Cent Eur J Immunol 2015; 40:292-9. [PMID: 26648772 PMCID: PMC4655378 DOI: 10.5114/ceji.2015.54589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 05/26/2015] [Indexed: 11/17/2022] Open
Abstract
Type 1 diabetes (T1D), an autoimmune disease, can be protected against by natural killer T (NKT) cells. Several attempts demonstrate that NKT cells also can be produced by inducing with Staphylococcus enterotoxin B (SEB) in addition to its classical activated antigen α-galactosylceramide. Here, we examined a potential usage of SEB-induced T (SEB-T) cells for the treatment of T1D. We established the immunophenotypes of SEB-T cells via flow cytometry, and in consequence, enriched in CD8+NKT cells after SEB stimulated. A high level of transforming growth factor β (TGF-β), detected by RT-PCR and ELISA, was first observed to be expressed and secreted by these SEB-T cells. Mixed lymphocyte reactions indicated that SEB-T cells could not produce a response to mitogens and allogeneic lymphocyte, and can inhibit lymphocytes response to mitogens. In an animal model, our data indicated that infusion of SEB-T cells in non-obese diabetic mice was well tolerated and could ameliorate hyperglycemia and maintain the blood glucose nearly on normal level until sacrifice. Strikingly, infusion of SEB-T cells resulted in an increase in the serum TGF-β level. These data raise the possibility that SEB-T cells can protect against T1D, which is associated with NKT cells generated in these SEB-induced cells.
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26
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Mackern-Oberti JP, Llanos C, Riedel CA, Bueno SM, Kalergis AM. Contribution of dendritic cells to the autoimmune pathology of systemic lupus erythematosus. Immunology 2015; 146:497-507. [PMID: 26173489 DOI: 10.1111/imm.12504] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 06/23/2015] [Accepted: 07/03/2015] [Indexed: 12/16/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a heterogeneous disease in which excessive inflammation, autoantibodies and complement activation lead to multisystem tissue damage. The contribution of the individual genetic composition has been extensively studied, and several susceptibility genes related to immune pathways that participate in SLE pathogenesis have been identified. It has been proposed that SLE takes place when susceptibility factors interact with environmental stimuli leading to a deregulated immune response. Experimental evidence suggests that such events are related to the failure of T-cell and B-cell suppression mediated by defects in cell signalling, immune tolerance and apoptotic mechanism promoting autoimmunity. In addition, it has been reported that dendritic cells (DCs) from SLE patients, which are crucial in the modulation of peripheral tolerance to self-antigens, show an increased ratio of activating/inhibitory receptors on their surfaces. This phenotype and an augmented expression of co-stimulatory molecules is thought to be critical for disease pathogenesis. Accordingly, tolerogenic DCs can be a potential strategy for developing antigen-specific therapies to reduce detrimental inflammation without causing systemic immunosuppression. In this review article we discuss the most relevant data relative to the contribution of DCs to the triggering of SLE.
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Affiliation(s)
- Juan P Mackern-Oberti
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.,Institute of Medicine and Experimental Biology of Cuyo (IMBECU), Science and Technology Center (CCT) of Mendoza, National Council of Scientific and Technical Research (CONICET), Mendoza, Argentina.,Institute of Physiology, School of Medicine, National University of Cuyo, Mendoza, Argentina
| | - Carolina Llanos
- Millennium Institute on Immunology and Immunotherapy, Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Claudia A Riedel
- Millennium Institute on Immunology and Immunotherapy, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas y Facultad de Medicina, Universidad Andrés Bello, Santiago, Chile.,INSERM U1064, Nantes, France
| | - Susan M Bueno
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.,INSERM U1064, Nantes, France
| | - Alexis M Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,INSERM U1064, Nantes, France
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27
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Bernsen MR, Guenoun J, van Tiel ST, Krestin GP. Nanoparticles and clinically applicable cell tracking. Br J Radiol 2015; 88:20150375. [PMID: 26248872 DOI: 10.1259/bjr.20150375] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
In vivo cell tracking has emerged as a much sought after tool for design and monitoring of cell-based treatment strategies. Various techniques are available for pre-clinical animal studies, from which much has been learned and still can be learned. However, there is also a need for clinically translatable techniques. Central to in vivo cell imaging is labelling of cells with agents that can give rise to signals in vivo, that can be detected and measured non-invasively. The current imaging technology of choice for clinical translation is MRI in combination with labelling of cells with magnetic agents. The main challenge encountered during the cell labelling procedure is to efficiently incorporate the label into the cell, such that the labelled cells can be imaged at high sensitivity for prolonged periods of time, without the labelling process affecting the functionality of the cells. In this respect, nanoparticles offer attractive features since their structure and chemical properties can be modified to facilitate cellular incorporation and because they can carry a high payload of the relevant label into cells. While these technologies have already been applied in clinical trials and have increased the understanding of cell-based therapy mechanism, many challenges are still faced.
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Affiliation(s)
- Monique R Bernsen
- 1 Department of Radiology, Erasmus MC, Rotterdam, Netherlands.,2 Department of Nuclear Medicine, Erasmus MC, Rotterdam, Netherlands
| | - Jamal Guenoun
- 1 Department of Radiology, Erasmus MC, Rotterdam, Netherlands
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28
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Srivastava AK, Kadayakkara DK, Bar-Shir A, Gilad AA, McMahon MT, Bulte JWM. Advances in using MRI probes and sensors for in vivo cell tracking as applied to regenerative medicine. Dis Model Mech 2015; 8:323-36. [PMID: 26035841 PMCID: PMC4381332 DOI: 10.1242/dmm.018499] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The field of molecular and cellular imaging allows molecules and cells to be visualized in vivo non-invasively. It has uses not only as a research tool but in clinical settings as well, for example in monitoring cell-based regenerative therapies, in which cells are transplanted to replace degenerating or damaged tissues, or to restore a physiological function. The success of such cell-based therapies depends on several critical issues, including the route and accuracy of cell transplantation, the fate of cells after transplantation, and the interaction of engrafted cells with the host microenvironment. To assess these issues, it is necessary to monitor transplanted cells non-invasively in real-time. Magnetic resonance imaging (MRI) is a tool uniquely suited to this task, given its ability to image deep inside tissue with high temporal resolution and sensitivity. Extraordinary efforts have recently been made to improve cellular MRI as applied to regenerative medicine, by developing more advanced contrast agents for use as probes and sensors. These advances enable the non-invasive monitoring of cell fate and, more recently, that of the different cellular functions of living cells, such as their enzymatic activity and gene expression, as well as their time point of cell death. We present here a review of recent advancements in the development of these probes and sensors, and of their functioning, applications and limitations.
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Affiliation(s)
- Amit K Srivastava
- Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Deepak K Kadayakkara
- Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Amnon Bar-Shir
- Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Assaf A Gilad
- Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD 21205, USA
| | - Michael T McMahon
- Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD 21205, USA
| | - Jeff W M Bulte
- Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD 21205, USA. Department of Chemical & Biomolecular Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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29
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Yang L, Liao YT, Yang XF, Reng LW, Qi H, Li FR. Immune protective effect of human alpha-1-antitrypsin gene during β cell transplantation in diabetic mice. Immunol Res 2015; 62:71-80. [DOI: 10.1007/s12026-015-8636-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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30
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Role of dendritic cells in the initiation, progress and modulation of systemic autoimmune diseases. Autoimmun Rev 2015; 14:127-39. [DOI: 10.1016/j.autrev.2014.10.010] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 09/30/2014] [Indexed: 12/11/2022]
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31
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Orchestration of transplantation tolerance by regulatory dendritic cell therapy or in-situ targeting of dendritic cells. Curr Opin Organ Transplant 2015; 19:348-56. [PMID: 24926700 DOI: 10.1097/mot.0000000000000097] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Extensive research in murine transplant models over the past two decades has convincingly demonstrated the ability of regulatory dendritic cells (DCregs) to promote long-term allograft survival. We review important considerations regarding the source of therapeutic DCregs (donor or recipient) and their mode of action, in-situ targeting of DCregs, and optimal therapeutic regimens to promote DCreg function. RECENT FINDINGS Recent studies have defined protocols and mechanisms whereby ex-vivo-generated DCregs of donor or recipient origin subvert allogeneic T-cell responses and promote long-term organ transplant survival. Particular interest has focused on how donor antigen is acquired, processed and presented by autologous dendritic cells, on the stability of DCregs, and on in-situ targeting of dendritic cells to promote their tolerogenic function. New evidence of the therapeutic efficacy of DCregs in a clinically relevant nonhuman primate organ transplant model and production of clinical grade DCregs support early evaluation of DCreg therapy in human graft recipients. SUMMARY We discuss strategies currently used to promote dendritic cell tolerogenicity, including DCreg therapy and in-situ targeting of dendritic cells, with a view to improved understanding of underlying mechanisms and identification of the most promising strategies for therapeutic application.
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32
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Mackern-Oberti JP, Vega F, Llanos C, Bueno SM, Kalergis AM. Targeting dendritic cell function during systemic autoimmunity to restore tolerance. Int J Mol Sci 2014; 15:16381-417. [PMID: 25229821 PMCID: PMC4200801 DOI: 10.3390/ijms150916381] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 08/29/2014] [Accepted: 09/05/2014] [Indexed: 12/11/2022] Open
Abstract
Systemic autoimmune diseases can damage nearly every tissue or cell type of the body. Although a great deal of progress has been made in understanding the pathogenesis of autoimmune diseases, current therapies have not been improved, remain unspecific and are associated with significant side effects. Because dendritic cells (DCs) play a major role in promoting immune tolerance against self-antigens (self-Ags), current efforts are focusing at generating new therapies based on the transfer of tolerogenic DCs (tolDCs) during autoimmunity. However, the feasibility of this approach during systemic autoimmunity has yet to be evaluated. TolDCs may ameliorate autoimmunity mainly by restoring T cell tolerance and, thus, indirectly modulating autoantibody development. In vitro induction of tolDCs loaded with immunodominant self-Ags and subsequent cell transfer to patients would be a specific new therapy that will avoid systemic immunosuppression. Herein, we review recent approaches evaluating the potential of tolDCs for the treatment of systemic autoimmune disorders.
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Affiliation(s)
- Juan P Mackern-Oberti
- Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Portugal 49, Santiago 8330025, Chile.
| | - Fabián Vega
- Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 350, Santiago 8330033, Chile.
| | - Carolina Llanos
- Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 350, Santiago 8330033, Chile.
| | - Susan M Bueno
- Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Portugal 49, Santiago 8330025, Chile.
| | - Alexis M Kalergis
- Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Portugal 49, Santiago 8330025, Chile.
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33
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Moreau A, Vandamme C, Segovia M, Devaux M, Guilbaud M, Tilly G, Jaulin N, Le Duff J, Cherel Y, Deschamps JY, Anegon I, Moullier P, Cuturi MC, Adjali O. Generation and in vivo evaluation of IL10-treated dendritic cells in a nonhuman primate model of AAV-based gene transfer. Mol Ther Methods Clin Dev 2014; 1:14028. [PMID: 26015970 PMCID: PMC4420248 DOI: 10.1038/mtm.2014.28] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 04/30/2014] [Accepted: 05/10/2014] [Indexed: 01/20/2023]
Abstract
Preventing untoward immune responses against a specific antigen is a major challenge in different clinical settings such as gene therapy, transplantation, or autoimmunity. Following intramuscular delivery of recombinant adeno-associated virus (rAAV)-derived vectors, transgene rejection can be a roadblock to successful clinical translation. Specific immunomodulation strategies potentially leading to sustained transgene expression while minimizing pharmacological immunosuppression are desirable. Tolerogenic dendritic cells (TolDC) are potential candidates but have not yet been evaluated in the context of gene therapy, to our knowledge. Following intramuscular delivery of rAAV-derived vectors expressing an immunogenic protein in the nonhuman primate model, we assessed the immunomodulating potential of autologous bone marrow-derived TolDC generated in the presence of IL10 and pulsed with the transgene product. TolDC administered either intradermally or intravenously were safe and well tolerated. While the intravenous route showed a modest ability to modulate host immunity against the transgene product, intradermally delivery resulted in a robust vaccination of the macaques when associated to intramuscular rAAV-derived vectors-based gene transfer. These findings demonstrate the critical role of TolDC mode of injection in modulating host immunity. This study also provides the first evidence of the potential of TolDC-based immunomodulation in gene therapy.
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Affiliation(s)
- Aurélie Moreau
- INSERM UMR 1064, ITUN - Institut de Transplantation Urologie Nephrologie, CHU de Nantes, Center of Research in Transplantation and Immunology, Université de Nantes, Nantes, France
| | - Céline Vandamme
- INSERM UMR 1089/Atlantic Gene Therapies, CHU de Nantes/Université de Nantes, Nantes, France
| | - Mercedes Segovia
- INSERM UMR 1064, ITUN - Institut de Transplantation Urologie Nephrologie, CHU de Nantes, Center of Research in Transplantation and Immunology, Université de Nantes, Nantes, France
| | - Marie Devaux
- INSERM UMR 1089/Atlantic Gene Therapies, CHU de Nantes/Université de Nantes, Nantes, France
| | - Mickaël Guilbaud
- INSERM UMR 1089/Atlantic Gene Therapies, CHU de Nantes/Université de Nantes, Nantes, France
| | - Gaëlle Tilly
- INSERM UMR 1064, ITUN - Institut de Transplantation Urologie Nephrologie, CHU de Nantes, Center of Research in Transplantation and Immunology, Université de Nantes, Nantes, France
| | - Nicolas Jaulin
- INSERM UMR 1089/Atlantic Gene Therapies, CHU de Nantes/Université de Nantes, Nantes, France
| | - Johanne Le Duff
- INSERM UMR 1089/Atlantic Gene Therapies, CHU de Nantes/Université de Nantes, Nantes, France
| | - Yan Cherel
- ONIRIS, INRA UMR 703/Atlantic Gene Therapies, Nantes, France
| | | | - Ignacio Anegon
- INSERM UMR 1064, ITUN - Institut de Transplantation Urologie Nephrologie, CHU de Nantes, Center of Research in Transplantation and Immunology, Université de Nantes, Nantes, France
| | - Philippe Moullier
- INSERM UMR 1089/Atlantic Gene Therapies, CHU de Nantes/Université de Nantes, Nantes, France
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA
| | - Maria Cristina Cuturi
- INSERM UMR 1064, ITUN - Institut de Transplantation Urologie Nephrologie, CHU de Nantes, Center of Research in Transplantation and Immunology, Université de Nantes, Nantes, France
| | - Oumeya Adjali
- INSERM UMR 1089/Atlantic Gene Therapies, CHU de Nantes/Université de Nantes, Nantes, France
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34
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Wållberg M, Cooke A. Immune mechanisms in type 1 diabetes. Trends Immunol 2013; 34:583-91. [PMID: 24054837 DOI: 10.1016/j.it.2013.08.005] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2013] [Revised: 08/12/2013] [Accepted: 08/13/2013] [Indexed: 12/17/2022]
Abstract
There are three prerequisites for development of the autoimmune disease type 1 diabetes (T1D). First, β cell-reactive T cells need to be activated; second, the response needs to be proinflammatory; and finally, immune regulation of autoreactive responses must fail. Here, we describe our current understanding of the cell types and immune mechanisms involved in each of these steps leading to T1D. Novel findings regarding β cell involvement in its own destruction, the importance of the microbiota for instruction of the immune system, and recent data from studies in T1D patients are discussed. In addition, we summarise therapeutic approaches to T1D, and how these relate to the immune mechanisms involved in disease development.
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Affiliation(s)
- Maja Wållberg
- Department of Pathology, University of Cambridge, Tennis Court Rd, Cambridge CB21QP, UK.
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