| 1. |
- Burman, Joachim, et al.
(författare)
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Assessing tissue damage in multiple sclerosis: A biomarker approach
- 2014
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 130:2, s. 81-89
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Magnetic resonance imaging (MRI) of the brain and spinal cord is the gold standard for assessing disease activity in multiple sclerosis (MS). MRI is an excellent instrument for determination of accumulated damage to the brain and spinal cord, but tells us little about ongoing tissue damage. In this study, biomarkers of oligodendrocyte, axonal and astrocyte injury were related to MRI and clinical findings and used to assess tissue damage in MS. Materials and methods: Cerebrospinal fluid from 44 patients with relapsing-remitting MS, 20 with secondary progressive MS and 15 controls were investigated with ELISA to determine levels of myelin basic protein (MBP), neurofilament light (NFL) and glial fibrillary acidic protein (GFAp). Patients underwent MRI of the brain and spinal cord, and gadolinium enhancing lesions, T1 lesions and T2 lesions were counted. Results: Patients in clinical relapse and patients with nonsymptomatic gadolinium enhancing lesions had high levels of MBP and NFL, indicating ongoing damage to oligodendrocytes and axons. The level of MBP dropped quickly within a week from the onset of a relapse, whereas NFL remained elevated for several weeks and GFAp slowly rose during the course of a relapse. Relapsing-remitting MS patients without gadolinium enhancing lesions had values of MBP, NFL and GFAp similar to controls, while patients with secondary progressive disease had moderately increased values of all biomarkers. Conclusions: Analysis of MBP, NFL and GFAp provides direct means to measure tissue damage and is a useful addition to our methods for evaluation of MS. © 2014 John Wiley & Sons A/S.
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| 2. |
- Fransson, Moa, et al.
(författare)
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CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery
- 2012
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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 9, s. 112-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). In the murine experimental autoimmune encephalomyelitis (EAE) model of MS, T regulatory (Treg) cell therapy has proved to be beneficial, but generation of stable CNS-targeting Tregs needs further development. Here, we propose gene engineering to achieve CNS-targeting Tregs from naive CD4 cells and demonstrate their efficacy in the EAE model.METHODSCD4+T cells were modified utilizing a lentiviral vector system to express a chimeric antigen receptor (CAR) targeting myelin oligodendrocyte glycoprotein (MOG) in trans with the murine FoxP3 gene that drives Treg differentiation. The cells were evaluated in vitro for suppressive capacity and in C57BL/6 mice to treat EAE. Cells were administered by intranasal (i.n.) cell delivery.RESULTSThe engineered Tregs demonstrated suppressive capacity in vitro and could efficiently access various regions in the brain via i.n cell delivery. Clinical score 3 EAE mice were treated and the engineered Tregs suppressed ongoing encephalomyelitis as demonstrated by reduced disease symptoms as well as decreased IL-12 and IFNgamma mRNAs in brain tissue. Immunohistochemical markers for myelination (MBP) and reactive astrogliosis (GFAP) confirmed recovery in mice treated with engineered Tregs compared to controls. Symptomfree mice were echallenged with a second EAE-inducing inoculum but remained healthy, demonstrating the sustained effect of engineered Tregs.CONCLUSIONCNS-targeting Tregs delivered i.n. localized to the CNS and efficiently suppressed ongoing inflammation leading to diminished disease symptoms.
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| 3. |
- Liljenfeldt, Lina, et al.
(författare)
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Enhanced therapeutic anti-tumor immunity induced by co-administration of 5-fluorouracil and adenovirus expressing CD40 ligand
- 2014
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Ingår i: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 63:3, s. 273-282
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Tidskriftsartikel (refereegranskat)abstract
- Bystander immune activation by chemotherapy has recently gained extensive interest and provided support for the clinical use of chemotherapeutic agents in combination with immune enhancers. The CD40 ligand (CD40L; CD154) is a potent regulator of the anti-tumor immune response and recombinant adenovirus (RAd)-mediated CD40L gene therapy has been effective in various cancer models and in man. In this study we have assessed the combined effect of local RAd-CD40L and 5-fluorouracil (5-FU) administration on a syngeneic MB49 mouse bladder tumor model. Whereas MB49 cells implanted into immunocompetent mice responded poorly to RAd-CD40L or 5-FU alone, administration of both agents dramatically decreased tumor growth, increased survival of the mice and induced systemic MB49-specific immunity. This combination treatment was ineffective in athymic nude mice, highlighting an important role for T cell mediated anti-tumor immunity for full efficacy. 5-FU up-regulated the expression of Fas and immunogenic cell death markers in MB49 cells and cytotoxic T lymphocytes from mice receiving RAd-CD40L immunotherapy efficiently lysed 5-FU treated MB49 cells in a Fas ligand-dependent manner. Furthermore, local RAd-CD40L and 5-FU administration induced a shift of myeloid-derived suppressor cell phenotype into a less suppressive population. Collectively, these data suggest that RAd-CD40L gene therapy is a promising adjuvant treatment to 5-FU for the management of bladder cancer.
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| 4. |
- Lindqvist, Camilla A, et al.
(författare)
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FoxP3+ T-Cells in Patients with B-Cell Chronic Lymphocytic Leukemia Express Cytolytic Markers and Kill Autologous B-Cells
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Recent reports indicate that infiltration of FoxP3+ cells into the tumor area may be associated with better overall survival of patients with B-cell malignancies, which is in contrast to patients with non-hematopoetic tumors. Here, we demonstrate a possible mechanism to these findings. Since the tumor cell in lymphoma originates from the immune system we hypothesized that FoxP3+ T regulatory cells (Tregs) may have a suppressive role in tumor progression in patients with B-cell malignancies. Peripheral blood was collected from 14 patients with B-cell chronic lymphocytic leukemia (B-CLL) and their Tregs were evaluated for cytolytic markers such as FasL and CD107a. We found that both conventional Tregs (CD4+ FoxP3+CD127low T-cells) and FoxP3+CD127high T-cells were significantly increased in patients with B-CLL compared to healthy controls. Further, both groups of FoxP3+ cells displayed higher expression of the degranulation marker CD107a indicating perforin/granzyme release. A flow cytometry-based cytotoxicity assay demonstrated that purified Tregs from both patients and healthy controls could kill autologous B-cells in vitro. In conclusion, FoxP3+ T-cells in patients with CLL show effector phenotype and may be involved in tumor cell control by their natural capacity to kill B-cells.
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| 5. |
- Lindqvist, Camilla A, et al.
(författare)
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Peripheral T Lymphocytes, Including FoxP3+ T-Cells, Exhibit a Cytotoxic Phenotype in Patients with B-Cell Lymphoma
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Recent studies have shown that high levels of FoxP3+ cells within lymphoma-affected lymph nodes are associated with a better outcome of patients with B-cell lymphoma. This finding is opposite to what has been seen in patients with solid non-hematopoietic tumors. In an attempt to better understand the role of FoxP3+ cell in lymphoma, we collected peripheral blood from 17 patients and determined the level of T regulatory cells (CD3+CD4+FoxP3+CD127low lymphocytes) and FoxP3+CD127high T-cells (CD3+CD4+FoxP3+CD127high lymphocytes). The two subgroups of FoxP3+ T-cells, as well as conventional FoxP3- T-cells, were further analyzed for presence of cytotoxic markers such as FasL and CD107a. Patient plasma was analyzed for the immunosuppressive cytokines IL-10 and TGF-β. Finally, the proliferative capacity of T-cells was assessed using Alamar Blue assay. In lymphoma patients, both FoxP3+ T-cells and conventional T-cells had elevated levels of cytotoxic markers. No significant increase in IL-10 or TGF-β was detected and most patient T-cells had a normal proliferative capacity. This is the first, to our knowledge, study showing a cytotoxic phenotype of FoxP3+ T-cells in patients with B-cell lymphoma.
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| 6. |
- Lindqvist, Camilla A, et al.
(författare)
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T Regulatory Cells in B-Cell Malignancy : Tumor Support or Kiss of Death?
- 2012
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Ingår i: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 135:4, s. 255-260
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Forskningsöversikt (refereegranskat)abstract
- It is well established that T regulatory cells (Tregs) counteract tumor immunity. However, conflicting results describing the role of Tregs in hematological tumors warrant further investigations to clarify the interactions between Tregs and the tumor. B-cell malignancy derives from different stages of B-cell development and differentiation in which T-cells play a profound role. The transformed B-cell may still be in need of T-cell help to thrive but simultaneously they may be recognized and destroyed by cytotoxic lymphocytes. Recent reports demonstrate that Tregs can suppress and even kill B-cells as part of their normal function to rescue the body from autoimmunity. An emerging body of evidence points out that Tregs inhibit tumor-specific T-cells but may also have a role in suppressing the progression of the B-cell tumor. In this review, we discuss the origin and function of Tregs and their role in patients with B-cell tumors.
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