| 1. |
- Teige, Anna, et al.
(författare)
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CD1-dependent regulation of chronic central nervous system inflammation in experimental autoimmune encephalomyelitis.
- 2004
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Ingår i: Journal of Immunology. - 1550-6606. ; 172:1, s. 186-194
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Tidskriftsartikel (refereegranskat)abstract
- The existence of T cells restricted for the MHC I-like molecule CD1 is well established, but the function of these cells is still obscure; one implication is that CD1-dependent T cells regulate autoimmunity. In this study, we investigate their role in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, using CD1-deficient mice on a C57BL/6 background. We show that CD1-/- mice develop a clinically more severe and chronic EAE compared with CD1+/+ C57BL/6 mice, which was histopathologically confirmed with increased demyelination and CNS infiltration in CD1-/- mice. Autoantigen rechallenge in vitro revealed similar T cell proliferation in CD1+/+ and CD1-/- mice but an amplified cytokine response in CD1-/- mice as measured by both the Th1 cytokine IFN-{gamma} and the Th2 cytokine IL-4. Investigation of cytokine production at the site of inflammation showed a CNS influx of TGF-{beta}1-producing cells early in the disease in CD1+/+ mice, which was absent in the CD1-/- mice. Passive transfer of EAE using an autoreactive T cell line induced equivalent disease in both groups, which suggested additional requirements for activation of the CD1-dependent regulatory pathway(s). When immunized with CFA before T cell transfer, the CD1-/- mice again developed an augmented EAE compared with CD1+/+ mice. We suggest that CD1 exerts its function during CFA-mediated activation, regulating development of EAE both through enhancing TGF-{beta}1 production and through limiting autoreactive T cell activation, but not necessarily via effects on the Th1/Th2 balance.
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| 2. |
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| 3. |
- Wichert, Stina, et al.
(författare)
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A single-arm, open-label, phase 2 clinical trial evaluating disease response following treatment with BI-505, a human anti-intercellular adhesion molecule-1 monoclonal antibody, in patients with smoldering multiple myeloma
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: Smoldering multiple myeloma (SMM) is an indolent disease stage, considered to represent the transition phase from the premalignant MGUS (Monoclonal Gammopathy of Undetermined Significance) state towards symptomatic multiple myeloma (MM). Even though this diagnosis provides an opportunity for early intervention, few treatment studies have been done and the current standard of care is observation until progression. BI-505, a monoclonal antibody directed against intercellular adhesion molecule 1 (ICAM-1) with promising anti-myeloma activity in preclinical trials, is a possible treatment approach for this patient category with potential to eliminate tumor cells with minimal long-term side effects. BI-505 was well tolerated in an earlier phase 1 trial. Methods and findings: In this phase 2 trial the effects of BI-505 in patients with SMM were studied. Four patients were enrolled and three of them completed the first cycle of treatment defined as 5 doses of BI-505, a total of 43 mg/kg BW, over a 7-week period. In the three evaluable patients, BI-505 showed a benign safety profile. None of the patients achieved a response as defined per protocol. EudraCT number: 2012-004884-29. Conclusions: The study was conducted to assess the efficacy, safety and pharmacodynamics of BI-505 in patients with SMM. BI-505 showed no clinically relevant efficacy on disease activity in these patients with SMM, even if well tolerated. Trial registration: ClinicalTrials.gov Identifier: NCT01838369.
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| 4. |
- Hansson, Markus, et al.
(författare)
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A phase 1 dose-escalation study of antibody BI-505 in relapsed/refractory multiple myeloma.
- 2015
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 21:12, s. 2730-2736
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients. Experimental design: BI-505 was given intravenously, every two weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses. Results: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate and those attributed to study medication were mostly limited to the first dose, and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505's half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at 10 mg/kg doses. Using the International Myeloma Working Group criteria, seven patients on extended therapy had stable disease for more than two months. Conclusion: BI-505 can be safely administered at doses that saturate myeloma cell ICAM-1 receptors in patients. This study was registered at www.clinicaltrials.gov (NCT01025206).
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| 5. |
- Liu, Yawei, et al.
(författare)
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Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE.
- 2006
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 12:5, s. 518-525
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Tidskriftsartikel (refereegranskat)abstract
- Neurons have been neglected as cells with a major immune-regulatory function because they do not express major histocompatibility complex class II. Our data show that neurons are highly immune regulatory, having a crucial role in governing T-cell response and central nervous system (CNS) inflammation. Neurons induce the proliferation of activated CD4+ T cells through B7-CD28 and transforming growth factor (TGF)-beta1–TGF-beta receptor signaling pathways, resulting in amplification of T-cell receptor signaling through phosphorylated ZAP-70, interleukin (IL)-2 and IL-9. The interaction between neurons and T cells results in the conversion of encephalitogenic T cells to CD25+TGF-beta1+CTLA-4+FoxP3+ T regulatory (Treg) cells that suppress encephalitogenic T cells and inhibit experimental autoimmune encephalomyelitis. Suppression is dependent on cytotoxic T lymphocyte antigen (CTLA)-4 but not TGF-beta1. Autocrine action of TGF-beta1, however, is important for the proliferative arrest of Treg cells. Blocking the B7 and TGF-beta pathways prevents the CNS-specific generation of Treg cells. These findings show that generation of neuron-dependent Treg cells in the CNS is instrumental in regulating CNS inflammation.
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| 6. |
- Liu, Yawei, et al.
(författare)
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Suppression of EAE by oral tolerance is independent of endogenous IFN-beta whereas treatment with recombinant IFN-beta ameliorates EAE.
- 2010
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Ingår i: Immunology and Cell Biology. - : Wiley. - 1440-1711 .- 0818-9641. ; 88, s. 468-476
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Tidskriftsartikel (refereegranskat)abstract
- IFN-beta is anticipated to have an important function in mucosal tolerance, as it is one of the major cytokines produced by plasmacytoid dendritic cells, and has recently been suggested as central to the maintenance of mucosal homeostasis. Here, we have investigated whether oral tolerance is dependent on endogenous IFN-beta by feeding low-dose self-antigen myelin basic protein to IFN-beta(-/-) mice with subsequent induction of experimental autoimmune encephalomyelitis (EAE). Our study shows that oral tolerance was readily induced in IFN-beta(-/-) mice compared with their wild-type littermates (IFN-beta(+/+)). The non-self-antigen ovalbumin induced oral tolerance in both groups. These data indicate that endogenous IFN-beta is not required for induction of oral tolerance, whereas delivery of recombinant IFN-beta results in significant reduction in clinical score of EAE. Oral tolerance induction was associated with lower production of antigen-specific IFN-gamma, no shift toward antigen-specific Th2, Th17 or TGF-beta response was observed. Oral tolerance in IFN-beta(-/-) mice was also associated with the induction of regulatory and memory T cells in the mucosal-associated immune organs, however this was not a prerequisite for establishment of oral tolerance.Immunology and Cell Biology advance online publication, 12 January 2010; doi:10.1038/icb.2009.111.
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| 7. |
- Matheu, Victor, et al.
(författare)
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Local therapy with CpG motifs in a murine model of allergic airway inflammation in IFN-beta knock-out mice.
- 2005
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 6:1, s. 25-25
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: CpG oligodeoxynucleotides (CpG-ODN) are capable of inducing high amounts of type I IFNs with many immunomodulatory properties. Furthermore, type-I IFNs have been proposed to play a key role in mediating effects of CpG-ODN. The precise role of IFN-beta in the immunomodulatory effects of CpG-ODN is not known. OBJECTIVE: Here, we aimed to elucidate the role of IFN-beta in the anti-allergic effect of CpG motifs. METHODS: We assessed the immune response in OVA-primed/OVA-challenged IFN-beta knockout (-/-) mice compared to wild type (WT) control, after intranasal and systemic treatment with synthetic CpG motifs. RESULTS: Vaccination with CpG-ODN reduced the number of cells in airways of OVA-sensitized WT but not IFN-beta-/- mice. Although airway eosinophilia was reduced in both treated groups, they were significantly higher in IFN-beta-/- mice. Other inflammatory cells, such as lymphocytes and macrophages were enhanced in airways by CpG treatment in IFN-beta-/- mice. The ratio of IFN-gamma/IL-4 cytokines in airways was significantly skewed to a Th1 response in WT compared to IFN-beta-/- group. In contrast, IL-4 and IgE were reduced with no differences between groups. Ag-specific T-cell proliferation, Th1-cytokines such as IFN-gamma, IL-2 and also IL-12 were significantly lower in IFN-beta-/- mice. Surprisingly, we discovered that intranasal treatment of mice with CpG-ODN results in mild synovitis particularly in IFN-beta-/- mice. CONCLUSION: Our results indicate that induction of Th1 response by therapy with CpG-ODN is only slightly and partially dependent on IFN-beta, while IFN-beta is not an absolute requirement for suppression of airway eosinophilia and IgE. Furthermore, our finding of mild synovitis is a warning for possible negative effects of CpG-ODN vaccination.
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| 8. |
- Mattsson, Jenny, et al.
(författare)
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Accelerating target deconvolution for therapeutic antibody candidates using highly parallelized genome editing
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic antibodies are transforming the treatment of cancer and autoimmune diseases. Today, a key challenge is finding antibodies against new targets. Phenotypic discovery promises to achieve this by enabling discovery of antibodies with therapeutic potential without specifying the molecular target a priori. Yet, deconvoluting the targets of phenotypically discovered antibodies remains a bottleneck; efficient deconvolution methods are needed for phenotypic discovery to reach its full potential. Here, we report a comprehensive investigation of a target deconvolution approach based on pooled CRISPR/Cas9. Applying this approach within three real-world phenotypic discovery programs, we rapidly deconvolute the targets of 38 of 39 test antibodies (97%), a success rate far higher than with existing approaches. Moreover, the approach scales well, requires much less work, and robustly identifies antibodies against the major histocompatibility complex. Our data establish CRISPR/Cas9 as a highly efficient target deconvolution approach, with immediate implications for the development of antibody-based drugs.
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| 9. |
- Roghanian, Ali, et al.
(författare)
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Antagonistic Human FcγRIIB (CD32B) Antibodies Have Anti-Tumor Activity and Overcome Resistance to Antibody Therapy In Vivo.
- 2015
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Ingår i: Cancer Cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 27:4, s. 473-488
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic antibodies have transformed cancer therapy, unlocking mechanisms of action by engaging the immune system. Unfortunately, cures rarely occur and patients display intrinsic or acquired resistance. Here, we demonstrate the therapeutic potential of targeting human (h) FcγRIIB (CD32B), a receptor implicated in immune cell desensitization and tumor cell resistance. FcγRIIB-blocking antibodies prevented internalization of the CD20-specific antibody rituximab, thereby maximizing cell surface accessibility and immune effector cell mediated antitumor activity. In hFcγRIIB-transgenic (Tg) mice, FcγRIIB-blocking antibodies effectively deleted target cells in combination with rituximab, and other therapeutic antibodies, from resistance-prone stromal compartments. Similar efficacy was seen in primary human tumor xenografts, including with cells from patients with relapsed/refractory disease. These data support the further development of hFcγRIIB antibodies for clinical assessment.
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| 10. |
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| 11. |
- Teige, Ingrid
(författare)
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Regulation of CNS inflammation upon T cell interaction with CNS resident cells
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple Sclerosis (MS), is a neurologic, autoimmune disease characterized by CNS immune cell infiltration and demyelination. To experimentally study MS, we have utilized the mouse model Experimental Autoimmune Encephalomyelitis (EAE). EAE is induced through immunization with myelin antigens, which elicits an autoreactive Th1 cell response. Encephalitogenic T cells migrate into the CNS where they receive antigen specific restimulation via CNS specific APCs, which causes inflammation and demyelination. Our aim with the present study was to investigate various aspects of T cell regulation in EAE. The potential immunoregulatory role of CD1d restricted T cells was evaluated using CD1d deficient mice (CD1-/-). Our results suggests that CD1d restricted T cells regulate EAE, both through down-regulation of peripheral autoreactive T cell cytokine responses and through up-regulation of TGF-beta1 production within the CNS. Next, we investigated the regulatory pathway mediated by IFN-beta, a common treatment for MS. From the results we concluded that IFN-beta is expressed in the CNS upon inflammation, where it represses glial cell activation and capacity to re-stimulate infiltrating encephalitogenic T cells. Furthermore, we could show that IFN-beta increases the glial cell expression of CD1d. IFN-beta has also been implicated to be important in the induction of oral tolerance, however, by using IFN-beta-/- mice and EAE, we showed that oral tolerance induction is not dependent on IFN-beta. Finally, in a study designed to evaluate possible immunoregualatory functions of neurons, we demonstrated that upon interaction with TGF-beta1 producing neurons, encephalitogenic T cells aquire a regulatory phenotype with the capacity to inhibit EAE development.
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| 12. |
- Treschow, Alexandra, et al.
(författare)
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Stromal cells and osteoclasts are responsible for exacerbated collagen-induced arthritis in interferon-beta-deficient mice
- 2005
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Ingår i: Arthritis and Rheumatism. - Hoboken, NJ : John Wiley & Sons. - 0004-3591 .- 1529-0131. ; 52:12, s. 3739-3748
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Clinical trials using interferon-beta (IFNbeta) in the treatment of rheumatoid arthritis have shown conflicting results. We undertook this study to understand the mechanisms of IFNbeta in arthritis at a physiologic level. METHODS: Collagen-induced arthritis (CIA) was induced in IFNbeta-deficient and control mice. The role of IFNbeta was investigated in both the priming and effector phases of the disease. The effect of IFNbeta deficiency on synovial cells, macrophages, and fibroblasts from preimmunized mice was analyzed by flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assay. Differences in osteoclast maturation were determined in situ by histology of arthritic and naive paws and by in vitro maturation studies of naive bone marrow cells. The importance of IFNbeta-producing fibroblasts was determined by transferring fibroblasts into mice at the time of CIA immunization. RESULTS: Mice lacking IFNbeta had a prolonged disease with a higher incidence compared with control mice. IFNbeta deficiency was found to influence the effector phase, but not the priming phase, of arthritis. Compared with control mice, IFNbeta-deficient mice had greater infiltration of CD11b+ cells and greater production of tumor necrosis factor alpha in vivo, and their macrophages and fibroblasts were both more activated in vitro. Moreover, IFNbeta-deficient mice generated a greater number of osteoclasts in vitro, and mice immunized to induce arthritis, but not naive mice, had a greater number of osteoclasts in vivo compared with control mice. Importantly, IFNbeta-competent fibroblasts were able to ameliorate arthritis in IFNbeta-deficient recipients. CONCLUSION: Our data indicate that IFNbeta is involved in regulating the activation state of osteoclasts and stromal cells, including macrophages and fibroblasts, but that it has little effect on T cells. © 2005, American College of Rheumatology.
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| 13. |
- Veitonmäki, Niina, et al.
(författare)
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A human icam-1 antibody isolated by a function-first approach has potent macrophage-dependent antimyeloma activity in vivo.
- 2013
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Ingår i: Cancer Cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 23:4, s. 502-515
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Tidskriftsartikel (refereegranskat)abstract
- We isolated a tumor B-cell-targeting antibody, BI-505, from a highly diversified human phage-antibody library, using a pioneering "function-first" approach involving screening for (1) specificity for a tumor B cell surface receptor, (2) induction of tumor programmed cell death, and (3) enhanced in vivo antitumor activity compared to currently used treatments. BI-505 bound to intercellular adhesion molecule-1, identifying a previously unrecognized role for this receptor as a therapeutic target in cancer. The BI-505 epitope was strongly expressed on the surface of multiple myeloma cells from both newly diagnosed and relapsed patients. BI-505 had potent macrophage-dependent antimyeloma activity and conferred enhanced survival compared to currently used treatments in advanced experimental models of multiple myeloma.
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