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1.  Targeting of Human Antigen-Presenting Cell Subsets 
Journal of Virology  2013;87(20):11304-11308.
Antigen-presenting cells are a heterogeneous group of cells that are characterized by their functional specialization. Consequently, targeting specific antigen-presenting cell subsets offers opportunities to induce distinct T cell responses. Here we report on the generation and use of nanobodies (Nbs) to target lentivectors specifically to human lymph node-resident myeloid dendritic cells, demonstrating that Nbs represent a powerful tool to redirect lentivectors to human antigen-presenting cell subsets.
doi:10.1128/JVI.01498-13
PMCID: PMC3807283  PMID: 23864630
2.  Immunogenicity of targeted lentivectors 
Oncotarget  2014;5(3):704-715.
To increase the safety and possibly efficacy of HIV-1 derived lentivectors (LVs) as an anti-cancer vaccine, we recently developed the Nanobody (Nb) display technology to target LVs to antigen presenting cells (APCs). In this study, we extend these data with exclusive targeting of LVs to conventional dendritic cells (DCs), which are believed to be the main cross-presenting APCs for the induction of a TH1-conducted antitumor immune response. The immunogenicity of these DC-subtype targeted LVs was compared to that of broad tropism, general APC-targeted and non-infectious LVs. Intranodal immunization with ovalbumin encoding LVs induced proliferation of antigen specific CD4+ T cells, irrespective of the LVs' targeting ability. However, the cytokine secretion profile of the restimulated CD4+ T cells demonstrated that general APC targeting induced a similar TH1-profile as the broad tropism LVs while transduction of conventional DCs alone induced a similar and less potent TH1 profile as the non-infectious LVs. This observation contradicts the hypothesis that conventional DCs are the most important APCs and suggests that the activation of other APCs is also meaningful. Despite these differences, all targeted LVs were able to stimulate cytotoxic T lymphocytes, be it to a lesser extent than broad tropism LVs. Furthermore this induction was shown to be dependent on type I interferon for the targeted and non-infectious LVs, but not for broad tropism LVs. Finally we demonstrated that the APC-targeted LVs were as potent in therapy as broad tropism LVs and as such deliver on their promise as safer and efficacious LV-based vaccines.
PMCID: PMC3996667  PMID: 24519916
lentivector; targeting; antigen presenting cell; vaccine; antitumor immunotherapy
3.  Design of an Optimized Wilms' Tumor 1 (WT1) mRNA Construct for Enhanced WT1 Expression and Improved Immunogenicity In Vitro and In Vivo 
Tumor antigen–encoding mRNA for dendritic cell (DC)-based vaccination has gained increasing popularity in recent years. Within this context, two main strategies have entered the clinical trial stage: the use of mRNA for ex vivo antigen loading of DCs and the direct application of mRNA as a source of antigen for DCs in vivo. DCs transfected with mRNA-encoding Wilms' tumor 1 (WT1) protein have shown promising clinical results. Using a stepwise approach, we re-engineered a WT1 cDNA-carrying transcription vector to improve the translational characteristics and immunogenicity of the transcribed mRNA. Different modifications were performed: (i) the WT1 sequence was flanked by the lysosomal targeting sequence of dendritic cell lysosomal-associated membrane protein to enhance cytoplasmic expression; (ii) the nuclear localization sequence (NLS) of WT1 was deleted to promote shuttling from the nucleus to the cytoplasm; (iii) the WT1 DNA sequence was optimized in silico to improve translational efficiency; and (iv) this WT1 sequence was cloned into an optimized RNA transcription vector. DCs electroporated with this optimized mRNA showed an improved ability to stimulate WT1-specific T-cell immunity. Furthermore, in a murine model, we were able to show the safety, immunogenicity, and therapeutic activity of this optimized mRNA. This work is relevant for the future development of improved mRNA-based vaccine strategies K.
doi:10.1038/mtna.2013.54
PMCID: PMC3889186  PMID: 24253259
4.  Role of non-classical MHC class I molecules in cancer immunosuppression 
Oncoimmunology  2013;2(11):e26491.
Growing neoplasms employ various mechanisms to evade immunosurveillance. The expression of non-classical MHC class I molecules by both immune and malignant cells in the tumor microenvironment constitute of the strategies used by tumors to circumvent the cytotoxic activity of effector cells of the immune system. The overexpression of HLA-G, -E, and -F is a common finding across a variety of malignancies. However, while the presence of HLA-G and HLA-E has been recently correlated with poor clinical outcome, information on the clinicopathological significance of HLA-F is limited. In the present review, we summarize studies on non-classical MHC class I molecules with special emphasis on their role in the modulation of anticancer immune responses.
doi:10.4161/onci.26491
PMCID: PMC3894240  PMID: 24482746
antigen presentation; cancer; immunomodulation; NK cells; non-classical MHC class I molecules; T cells
5.  Assessing T-cell responses in anticancer immunotherapy 
Oncoimmunology  2013;2(10):e26148.
Since dendritic cells operate as professional antigen-presenting cells (APCs) and hence are capable of jumpstarting the immune system, they have been exploited to develop a variety of immunotherapeutic regimens against cancer. In the few past years, myeloid-derived suppressor cells (MDSCs) have been shown to mediate robust immunosuppressive functions, thereby inhibiting tumor-targeting immune responses. Thus, we propose that the immunomodulatory activity of MDSCs should be carefully considered for the development of efficient anticancer immunotherapies.
doi:10.4161/onci.26148
PMCID: PMC3825722  PMID: 24244902
antigen presentation; cancer; dendritic cells; myeloid-derived suppressor cell; T cells
6.  Preclinical Evaluation of Invariant Natural Killer T Cells in the 5T33 Multiple Myeloma Model 
PLoS ONE  2013;8(5):e65075.
Immunomodulators have been used in recent years to reactivate host anti-tumor immunity in several hematological malignancies. This report describes the effect of activating natural killer T (NKT) cells by α-Galactosylceramide (α-GalCer) in the 5T33MM model of multiple myeloma (MM). NKT cells are T lymphocytes, co-expressing T and NK receptors, while invariant NKT cells (iNKTs) also express a unique semi-invariant TCR α-chain. We followed iNKT numbers during the development of the disease in both 5T33MM mice and MM patients and found that their numbers dropped dramatically at the end stage of the disease, leading to a loss of total IFN-γ secretion. We furthermore observed that α-GalCer treatment significantly increased the survival of 5T33MM diseased mice. Taken together, our data demonstrate for the first time the possibility of using a preclinical murine MM model to study the effects of α-GalCer and show promising results of α-GalCer treatment in a low tumor burden setting.
doi:10.1371/journal.pone.0065075
PMCID: PMC3669090  PMID: 23741460
7.  Retroviral and lentiviral vectors for the induction of immunological tolerance 
Scientifica  2012;2012:694137.
doi:10.6064/2012/694137
PMCID: PMC3605697  PMID: 23526794
Autoimmune disease; arthritis; co-stimulation; dendritic cell; immunotherapy; signalling; T cell; tolerance; MAPK; NF-κB; microRNA
8.  PD-L1/PD-1 Co-Stimulation, a Brake for T cell Activation and a T cell Differentiation Signal 
For T cell activation, three signals have to be provided from the antigen presenting cell; Signal 1 (antigen recognition), signal 2 (co-stimulation) and signal 3 (cytokine priming). Blocking negative co-stimulation during antigen presentation to T cells is becoming a promising therapeutic strategy to enhance cancer immunotherapy. Here we will focus on interference with PD-1/PD-L1 negative co-stimulation during antigen presentation to T cells as a therapeutic approach. We will discuss the potential mechanisms and the therapeutic consequences by which interference/inhibition with this interaction results in anti-tumour immunity. Particularly, we will comment on whether blocking negative co-stimulation provides differentiation signals to T cells undergoing antigen presentation. A major dogma in immunology states that T cell differentiation signals are given by cytokines and chemokines (signal 3) rather than co-stimulation (signal 2). We will discuss whether this is the case when blocking PD-L1/PD-1 negative co-stimulation.
doi:10.4172/2155-9899.S12-006
PMCID: PMC3605779  PMID: 23525238
Cancer; Co-stimulation; Dendritic cell; Immunotherapy; PD-L1; PD-1; CD80
9.  MODULATING CO-STIMULATION DURING ANTIGEN PRESENTATION TO ENHANCE CANCER IMMUNOTHERAPY 
One of the key roles of the immune system is the identification of potentially dangerous pathogens or tumour cells, and raising a wide range of mechanisms to eliminate them from the organism. One of these mechanisms is activation and expansion of antigen-specific cytotoxic T cells, after recognition of antigenic peptides on the surface of antigen presenting cells such as dendritic cells (DCs). However, DCs also process and present autoantigens. Therefore, antigen presentation has to occur in the appropriate context to either trigger immune responses or establishing immunological tolerance. This is achieved by co-stimulation of T cells during antigen presentation. Co-stimulation consists on the simultaneous binding of ligand-receptor molecules at the immunological synapse which will determine the type and extent of T cell responses. In addition, the type of cytokines/chemokines present during antigen presentation will influence the polarisation of T cell responses, whether they lead to tolerance, antibody responses or cytotoxicity. In this review, we will focus on approaches manipulating co-stimulation during antigen presentation, and the role of cytokine stimulation on effective T cell responses. More specifically, we will address the experimental strategies to interfere with negative co-stimulation such as that mediated by PD-L1 (Programmed cell death 1 ligand 1)/PD-1 (Programmed death 1) to enhance anti-tumour immunity.
PMCID: PMC3428911  PMID: 22945252
Cancer; Co-stimulation; Dendritic cell; Immunotherapy; Signalling; T cell; B7; PD-L1; PD-L2; CTLA4; PD-1; CD80; MAPK; NF-κB
10.  mRNA 
Two decades ago, mRNA became the focus of research in molecular medicine and was proposed as an active pharmaceutical ingredient for the therapy of cancer. In this regard, mRNA has been mainly used for ex vivo modification of antigen-presenting cells (APCs), such as dendritic cells (DCs). This vaccination strategy has proven to be safe, well tolerated and capable of inducing tumor antigen-specific immune responses. Recently, the direct application of mRNA for in situ modification of APCs, hence immunization was shown to be feasible and at least as effective as DC-based immunization in pre-clinical models. It is believed that application of mRNA as an off-the-shelf vaccine represents an important step in the development of future cancer immunotherapeutic strategies. Here, we will discuss the use of ex vivo mRNA-modified DCs and “naked mRNA” for cancer immunotherapy focusing on parameters such as the employed DC subtype, DC activation stimulus and route of immunization. In addition, we will provide an overview on the clinical trials published so far, trying to link their outcome to the aforementioned parameters.
doi:10.4161/hv.22661
PMCID: PMC3859745  PMID: 23291946
mRNA; dendritic cell; immunotherapy; cancer
11.  Targeting lentiviral vectors for cancer immunotherapy 
Current cancer therapy reviews  2011;7(4):248-260.
Delivery of tumour-associated antigens (TAA) in a way that induces effective, specific immunity is a challenge in anti-cancer vaccine design. Circumventing tumour-induced tolerogenic mechanisms in vivo is also critical for effective immunotherapy. Effective immune responses are induced by professional antigen presenting cells, in particular dendritic cells (DC). This requires presentation of the antigen to both CD4+ and CD8+ T cells in the context of strong co-stimulatory signals. Lentiviral vectors have been tested as vehicles, for both ex vivo and in vivo delivery of TAA and/or activation signals to DC, and have been demonstrated to induce potent T cell mediated immune responses that can control tumour growth. This review will focus on the use of lentiviral vectors for in vivo gene delivery to DC, introducing strategies to target DC, either targeting cell entry or gene expression to improve safety of the lentiviral vaccine or targeting dendritic cell activation pathways to enhance performance of the lentiviral vaccine. In conclusion, this review highlights the potential of lentiviral vectors as a generally applicable ‘off-the-shelf’ anti-cancer immunotherapeutic.
doi:10.2174/157339411797642605
PMCID: PMC3442241  PMID: 22983382
dendritic cell; lentiviral vector; cancer; immunotherapy
12.  The role of SMAC mimetics in regulation of tumor cell death and immunity 
Oncoimmunology  2012;1(6):965-967.
Mimetics of second mitochondria-derived activator of caspases (SMAC) enhance tumor cell death in a variety of cancers. Several molecular mechanisms of action have been identified. However, it was only recently that the modus of action was linked to stimulation of anti-tumor immunity. Here we comment on these findings, highlighting several remaining questions.
doi:10.4161/onci.20369
PMCID: PMC3489761  PMID: 23162773
SMAC; lentiviral vector; dendritic cell; T cell; cancer
13.  Inhibition of Firefly Luciferase by General Anesthetics: Effect on In Vitro and In Vivo Bioluminescence Imaging 
PLoS ONE  2012;7(1):e30061.
Bioluminescence imaging is routinely performed in anesthetized mice. Often isoflurane anesthesia is used because of its ease of use and fast induction/recovery. However, general anesthetics have been described as important inhibitors of the luciferase enzyme reaction.
Aim
To investigate frequently used mouse anesthetics for their direct effect on the luciferase reaction, both in vitro and in vivo.
Materials and Methods
isoflurane, sevoflurane, desflurane, ketamine, xylazine, medetomidine, pentobarbital and avertin were tested in vitro on luciferase-expressing intact cells, and for non-volatile anesthetics on intact cells and cell lysates. In vivo, isoflurane was compared to unanesthetized animals and different anesthetics. Differences in maximal photon emission and time-to-peak photon emission were analyzed.
Results
All volatile anesthetics showed a clear inhibitory effect on the luciferase activity of 50% at physiological concentrations. Avertin had a stronger inhibitory effect of 80%. For ketamine and xylazine, increased photon emission was observed in intact cells, but this was not present in cell lysate assays, and was most likely due to cell toxicity and increased cell membrane permeability. In vivo, the highest signal intensities were measured in unanesthetized mice and pentobarbital anesthetized mice, followed by avertin. Isoflurane and ketamine/medetomidine anesthetized mice showed the lowest photon emission (40% of unanesthetized), with significantly longer time-to-peak than unanesthetized, pentobarbital or avertin-anesthetized mice. We conclude that, although strong inhibitory effects of anesthetics are present in vitro, their effect on in vivo BLI quantification is mainly due to their hemodynamic effects on mice and only to a lesser extent due to the direct inhibitory effect.
doi:10.1371/journal.pone.0030061
PMCID: PMC3254645  PMID: 22253879
14.  Retroviral and Lentiviral Vectors for the Induction of Immunological Tolerance 
Scientifica  2012;2012:694137.
Retroviral and lentiviral vectors have proven to be particularly efficient systems to deliver genes of interest into target cells, either in vivo or in cell cultures. They have been used for some time for gene therapy and the development of gene vaccines. Recently retroviral and lentiviral vectors have been used to generate tolerogenic dendritic cells, key professional antigen presenting cells that regulate immune responses. Thus, three main approaches have been undertaken to induce immunological tolerance; delivery of potent immunosuppressive cytokines and other molecules, modification of intracellular signalling pathways in dendritic cells, and de-targeting transgene expression from dendritic cells using microRNA technology. In this review we briefly describe retroviral and lentiviral vector biology, and their application to induce immunological tolerance.
doi:10.6064/2012/694137
PMCID: PMC3605697  PMID: 23526794
15.  Lentiviral vectors in gene therapy: their current status and future potential 
Summary
The concept of gene therapy originated in the mid 20th century and was perceived as a revolutionary technology with the promise to cure almost any disease of which the molecular basis was understood. Since then, several gene vectors have been developed, and the feasibility of gene therapy shown in many animal models of human disease. However, clinical efficacy could not be demonstrated until the beginning of the new century in a small-scale clinical trial curing an otherwise fatal immunodeficiency disorder in children. This first success – achieved after retroviral therapy - was later on overshadowed by the occurrence of vector-related leukaemia in a significant number of the treated children, demonstrating that the future success of gene therapy depends on our understanding of vector biology. This has led to the development of later generation vectors with improved efficiency, specificity and safety. Amongst these are HIV-1 lentivirus-based vectors (lentivectors), which are being increasingly used in basic and applied research. Human gene therapy clinical trials are currently under way using lentivectors in a wide range of human diseases. The intention of this review is to describe the main scientific steps leading to the engineering of HIV-1 lentiviral vectors, and place them in the context of current human gene therapy.
doi:10.1007/s00005-010-0063-4
PMCID: PMC2837622  PMID: 20143172
gene therapy; lentivirus-based vector
16.  Selective ERK Activation Differentiates Mouse and Human Tolerogenic Dendritic Cells, Expands Antigen-Specific Regulatory T Cells, and Suppresses Experimental Inflammatory Arthritis 
Arthritis and rheumatism  2011;63(1):84-95.
Objective
Most therapeutic treatments for autoimmune arthritis rely on immunosuppressive drugs, which have side effects. Although a previous study by our group showed that specific ERK activation suppressed immune responses, its application in a therapeutic setting has never been tested. The aim of the present study was to define the ERK-dependent immunosuppressive mechanisms and to apply selective ERK activation for the treatment of experimental inflammatory arthritis.
Methods
A constitutively active ERK activator was coexpressed with a model antigen using lentivectors. Immunosuppressive mechanisms were characterized at the level of dendritic cell (DC) function, differentiation of antigen-specific Treg cells, and inhibition of inflammatory T cells. Administration of the ERK activator with antigen as a strategy to suppress inflammatory arthritis was tested in an experimental mouse model.
Results
Selective ERK activation induced mouse and human DCs to secrete bioactive transforming growth factor β, a process required for suppression of T cell responses and differentiation of antigen-specific Treg cells. Treg cells strongly proliferated after antigen reencounter in inflammatory conditions, and these cells exhibited antigen-dependent suppressive activities. Inflammatory arthritis was effectively inhibited through antigen-specific mechanisms. Importantly, this strategy did not rely on identification of the initiating arthritogenic antigen. Equivalent mechanisms were demonstrated in human monocyte–derived DCs, setting the scene for a possible rapid translation of this approach to patients with rheumatoid arthritis.
Conclusion
This strategy of selective ERK activation resulted in an effective therapeutic protocol, with substantial advantages over DC or T cell vaccination.
doi:10.1002/art.30099
PMCID: PMC3040564  PMID: 20967853
17.  HIV-1 Lentiviral Vector Immunogenicity Is Mediated by Toll-Like Receptor 3 (TLR3) and TLR7▿  
Journal of Virology  2010;84(11):5627-5636.
Lentiviral vectors are promising vaccine vector candidates that have been tested extensively in preclinical models of infectious disease and cancer immunotherapy. They are also used in gene therapy clinical trials both for the ex vivo modification of cells and for direct in vivo injection. It is therefore critical to understand the mechanism(s) by which such vectors might stimulate the immune system. We evaluated the effect of lentiviral vectors on myeloid dendritic cells (DC), the main target of lentiviral transduction following subcutaneous immunization. The activation of DC cultures was independent of the lentiviral pseudotype but dependent on cell entry and reverse transcription. In vivo-transduced DC also displayed a mature phenotype, produced tumor necrosis factor alpha (TNF-α), and stimulated naive CD8+ T cells. The lentiviral activation of DC was Toll-like receptor (TLR) dependent, as it was inhibited in TRIF/MyD88 knockout (TRIF/MyD88−/−) DC. TLR3−/− or TLR7−/− DC were less activated, and reverse transcription was important for the activation of TLR7−/− DC. Moreover, lentivirally transduced DC lacking TLR3 or TLR7 had an impaired capacity to induce antigen-specific CD8+ T-cell responses. In conclusion, we demonstrated TLR-dependent DC activation by lentiviral vectors, explaining their immunogenicity. These data allow the rational development of strategies to manipulate the host's immune response to the transgene.
doi:10.1128/JVI.00014-10
PMCID: PMC2876620  PMID: 20237085
18.  Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function 
The Journal of Clinical Investigation  2010;120(8):2889-2899.
Abetalipoproteinemia (ABL) is a rare Mendelian disorder of lipid metabolism due to genetic deficiency in microsomal triglyceride transfer protein (MTP). It is associated with defects in MTP-mediated lipid transfer onto apolipoprotein B (APOB) and impaired secretion of APOB-containing lipoproteins. Recently, MTP was shown to regulate the CD1 family of lipid antigen-presenting molecules, but little is known about immune function in ABL patients. Here, we have shown that ABL is characterized by immune defects affecting presentation of self and microbial lipid antigens by group 1 (CD1a, CD1b, CD1c) and group 2 (CD1d) CD1 molecules. In dendritic cells isolated from ABL patients, MTP deficiency was associated with increased proteasomal degradation of group 1 CD1 molecules. Although CD1d escaped degradation, it was unable to load antigens and exhibited functional defects similar to those affecting the group 1 CD1 molecules. The reduction in CD1 function resulted in impaired activation of CD1-restricted T and invariant natural killer T (iNKT) cells and reduced numbers and phenotypic alterations of iNKT cells consistent with central and peripheral CD1 defects in vivo. These data highlight MTP as a unique regulator of human metabolic and immune pathways and reveal that ABL is not only a disorder of lipid metabolism but also an immune disease involving CD1.
doi:10.1172/JCI42703
PMCID: PMC2912200  PMID: 20592474
19.  Dendritic Cells for Active Anti-Cancer Immunotherapy: Targeting Activation Pathways Through Genetic Modification 
Tumour immunotherapy has become a treatment modality for cancer, harnessing the immune system to recognize and eradicate tumour cells specifically. It is based on the expression of tumour associated antigens (TAA) by the tumour cells and aims at the induction of TAA-specific effector T cell responses, whilst overruling various mechanisms that can hamper the anti-tumour immune response, e.g. regulatory T cells (Treg). (Re-) activation of effector T cells requires the completion of a carefully orchestrated series of specific steps. Particularly important is the provision of TAA presentation and strong stimulatory signals, delivered by co-stimulatory surface molecules and cytokines. These can only be delivered by professional antigen-presenting cells, in particular dendritic cells (DC). Therefore, DC need to be loaded with TAA and appropriately activated. It is not surprising that an extensive part of DC research has focused on the delivery of both TAA and activation signals to DC, developing a one step approach to obtain potent stimulatory DC. The simultaneous delivery of TAA and activation signals is therefore the topic of this review, emphasizing the role of DC in mediating T cell activation and how we can manipulate DC for the pill-pose of enhancing tumour immunotherapy. As we gain a better understanding of the molecular and cellular mechanisms that mediate induction of TAA-specific T cells, rational approaches for the activation of T cell responses can be developed for the treatment of cancer.
PMCID: PMC2797000  PMID: 19857199
Dendritic cell; toll like receptor; transcription factor; cytotoxic T lymphocytes; gene therapy; cancer
20.  Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice 
Clinical immunology (Orlando, Fla.)  2008;127(2):176-187.
A deficit in IL-4 production has been previously reported in both diabetic human patients and non-obese diabetic (NOD) mice. In addition, re-introducing IL-4 into NOD mice systemically, or as a transgene, led to a beneficial outcome in most studies. Here, we show that prediabetic, 12-wk old female NOD mice have a deficit in IL-4 expression in the pancreatic lymph nodes (PLN) compared to age-matched diabetes-resistant NOD.B10 mice. By bioluminescence imaging, we demonstrated that the PLN was preferentially targeted by bone marrow-derived dendritic cells (DCs) following intravenous (IV) administration. Following IV injection of DCs transduced to express IL-4 (DC/IL-4) into 12-wk old NOD mice, it was possible to significantly delay or prevent the onset of hyperglycemia. We then focused on the PLN to monitor, by microarray analysis, changes in gene expression induced by DC/IL-4 and observed a rapid normalization of the expression of many genes, that were otherwise under-expressed compared to NOD.B10 PLN. The protective effect of DC/IL-4 required both MHC and IL-4 expression by the DCs. Thus, adoptive cellular therapy, using DCs modified to express IL-4, offers an effective, tissue-targeted cellular therapy to prevent diabetes in NOD mice at an advanced stage of pre-diabetes, and may offer a safe approach to consider for treatment of high risk human pre-diabetic patients.
doi:10.1016/j.clim.2007.12.009
PMCID: PMC2453076  PMID: 18337172
21.  Selective ERK Activation Differentiates Mouse and Human Tolerogenic Dendritic Cells, Expands Antigen-Specific Regulatory T Cells, and Suppresses Experimental Inflammatory Arthritis 
Arthritis and Rheumatism  2011;63(1):84-95.
Objective
Most therapeutic treatments for autoimmune arthritis rely on immunosuppressive drugs, which have side effects. Although a previous study by our group showed that specific ERK activation suppressed immune responses, its application in a therapeutic setting has never been tested. The aim of the present study was to define the ERK-dependent immunosuppressive mechanisms and to apply selective ERK activation for the treatment of experimental inflammatory arthritis.
Methods
A constitutively active ERK activator was coexpressed with a model antigen using lentivectors. Immunosuppressive mechanisms were characterized at the level of dendritic cell (DC) function, differentiation of antigen-specific Treg cells, and inhibition of inflammatory T cells. Administration of the ERK activator with antigen as a strategy to suppress inflammatory arthritis was tested in an experimental mouse model.
Results
Selective ERK activation induced mouse and human DCs to secrete bioactive transforming growth factor β, a process required for suppression of T cell responses and differentiation of antigen-specific Treg cells. Treg cells strongly proliferated after antigen reencounter in inflammatory conditions, and these cells exhibited antigen-dependent suppressive activities. Inflammatory arthritis was effectively inhibited through antigen-specific mechanisms. Importantly, this strategy did not rely on identification of the initiating arthritogenic antigen. Equivalent mechanisms were demonstrated in human monocyte–derived DCs, setting the scene for a possible rapid translation of this approach to patients with rheumatoid arthritis.
Conclusion
This strategy of selective ERK activation resulted in an effective therapeutic protocol, with substantial advantages over DC or T cell vaccination.
doi:10.1002/art.30099
PMCID: PMC3040564  PMID: 20967853

Results 1-21 (21)