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- Jordan, Stanley C, et al.
(author)
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IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation.
- 2017
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In: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 377:5, s. 442-453
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Journal article (peer-reviewed)abstract
- BACKGROUND: Donor-specific antibodies create an immunologic barrier to transplantation. Current therapies to modify donor-specific antibodies are limited and ineffective in the most highly HLA-sensitized patients. The IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS), an endopeptidase, cleaves human IgG into F(ab')2 and Fc fragments inhibiting complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which suggests that IdeS might be useful for desensitization. We report on the combined experience of two independently performed open-label, phase 1-2 trials (conducted in Sweden and the United States) that assessed the efficacy of IdeS with regard to desensitization and transplantation of a kidney from an HLA-incompatible donor.METHODS: We administered IdeS to 25 highly HLA-sensitized patients (11 patients in Uppsala or Stockholm, Sweden, and 14 in Los Angeles) before the transplantation of a kidney from an HLA-incompatible donor. Frequent monitoring for adverse events, outcomes, donor-specific antibodies, and renal function was performed, as were renal biopsies. Immunosuppression after transplantation consisted of tacrolimus, mycophenolate mofetil, and glucocorticoids. Patients in the U.S. study also received intravenous immune globulin and rituximab after transplantation to prevent antibody rebound.RESULTS: Recipients in the U.S. study had a significantly longer cold ischemia time (the time elapsed between procurement of the organ and transplantation), a significantly higher rate of delayed graft function, and significantly higher levels of class I donor-specific antibodies than those in the Swedish study. A total of 38 serious adverse events occurred in 15 patients (5 events were adjudicated as being possibly related to IdeS). At transplantation, total IgG and HLA antibodies were eliminated. A total of 24 of 25 patients had perfusion of allografts after transplantation. Antibody-mediated rejection occurred in 10 patients (7 patients in the U.S. study and 3 in the Swedish study) at 2 weeks to 5 months after transplantation; all these patients had a response to treatment. One graft loss, mediated by non-HLA IgM and IgA antibodies, occurred.CONCLUSIONS: IdeS reduced or eliminated donor-specific antibodies and permitted HLA-incompatible transplantation in 24 of 25 patients. (Funded by Hansa Medical; ClinicalTrials.gov numbers, NCT02224820 , NCT02426684 , and NCT02475551 .).
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| 2. |
- Lorant, Tomas, 1975-, et al.
(author)
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Safety, immunogenicity, pharmacokinetics, and efficacy of degradation of anti-HLA antibodies by IdeS (imlifidase) in chronic kidney disease patients
- 2018
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In: American Journal of Transplantation. - : Elsevier BV. - 1600-6135 .- 1600-6143. ; 18:11, s. 2752-2762
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Journal article (peer-reviewed)abstract
- Safety, immunogenicity, pharmacokinetics, and efficacy of the IgG-degrading enzyme of Streptococcus pyogenes (IdeS [imlifidase]) were assessed in a single-center, open-label ascending-dose study in highly sensitized patients with chronic kidney disease. Eight patients with cytotoxic PRAs (median cytotoxic PRAs of 64%) at enrollment received 1 or 2 intravenous infusions of IdeS on consecutive days (0.12 mg/kg body weight ×2 [n = 3]; 0.25 mg/kg ×1 [n = 3], or 0.25 mg/kg ×2 [n = 2]). IgG degradation was observed in all subjects after IdeS treatment, with <1% plasma IgG remaining within 48 hours and remaining low up to 7 days. Mean fluorescence intensity values of HLA class I and II reactivity were substantially reduced in all patients, and C1q binding to anti-HLA was abolished. IdeS also cleaved the IgG-type B cell receptor on CD19+ memory B cells. Anti-IdeS antibodies developed 1 week after treatment, peaking at 2 weeks. A few hours after the second IdeS infusion, 1 patient received a deceased donor kidney offer. At enrollment, the patient had a positive serum crossmatch (HLA-B7), detected by complement-dependent cytotoxicity, flow cytometry, and multiplex bead assays. After IdeS infusion (0.12 mg/kg ×2) and when the HLA-incompatible donor (HLA-B7+) kidney was offered, the HLA antibody profile was negative. The kidney was transplanted successfully.
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| 3. |
- Bäckryd, Emmanuel, 1974-, et al.
(author)
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Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma
- 2017
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In: Journal of Pain Research. - : DOVE MEDICAL PRESS LTD. - 1178-7090. ; 10
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Journal article (peer-reviewed)abstract
- In addition to central hyperexcitability and impaired top-down modulation, chronic inflammation probably plays a role in the pathophysiology of fibromyalgia (FM). Indeed, on the basis of both animal experiments and human studies involving the analysis of cytokines and other inflammation-related proteins in different body fluids, neuroinflammatory mechanisms are considered to be central to the pathophysiology of many chronic pain conditions. However, concerning FM, previous human plasma/serum and/or cerebrospinal fluid (CSF) cytokine studies have looked only at a few predetermined cytokine candidates. Instead of analyzing only a few substances at a time, we used a new multiplex protein panel enabling simultaneous analysis of 92 inflammation-related proteins. Hence, we investigated the CSF and plasma inflammatory profiles of 40 FM patients compared with CSF from healthy controls (n= 10) and plasma from blood donor controls (n= 46). Using multivariate data analysis by projection, we found evidence of both neuroinflammation (as assessed in CSF) and chronic systemic inflammation (as assessed in plasma). Two groups of proteins (one for CSF and one for plasma) highly discriminating between patients and controls are presented. Notably, we found high levels of CSF chemokine CX3CL1 (also known as fractalkine). In addition, previous findings concerning IL-8 in FM were replicated, in both CSF and plasma. This is the first time that such an extensive inflammatory profile has been described for FM patients. Hence, FM seems to be characterized by objective biochemical alterations, and the lingering characterization of its mechanisms as essentially idiopathic or even psychogenic should be seen as definitively outdated.
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| 5. |
- Larsson, Måns, 1989, et al.
(author)
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A cross-season correspondence dataset for robust semantic segmentation
- 2019
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In: Proceedings of the IEEE Computer Society Conference on Computer Vision and Pattern Recognition. - 1063-6919. ; 2019-June, s. 9524-9534
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Conference paper (peer-reviewed)abstract
- In this paper, we present a method to utilize 2D-2D point matches between images taken during different image conditions to train a convolutional neural network for semantic segmentation. Enforcing label consistency across the matches makes the final segmentation algorithm robust to seasonal changes. We describe how these 2D-2D matches can be generated with little human interaction by geometrically matching points from 3D models built from images. Two cross-season correspondence datasets are created providing 2D-2D matches across seasonal changes as well as from day to night. The datasets are made publicly available to facilitate further research. We show that adding the correspondences as extra supervision during training improves the segmentation performance of the convolutional neural network, making it more robust to seasonal changes and weather conditions.
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| 6. |
- Larsson, Måns, 1989, et al.
(author)
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Fine-Grained Segmentation Networks: Self-Supervised Segmentation for Improved Long-Term Visual Localization
- 2019
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In: Proceedings of the IEEE International Conference on Computer Vision. - 1550-5499. ; 2019-October:October, s. 31-41
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Conference paper (peer-reviewed)abstract
- Long-term visual localization is the problem of estimating the camera pose of a given query image in a scene whose appearance changes over time. It is an important problem in practice, for example, encountered in autonomous driving. In order to gain robustness to such changes, long-term localization approaches often use segmantic segmentations as an invariant scene representation, as the semantic meaning of each scene part should not be affected by seasonal and other changes. However, these representations are typically not very discriminative due to the limited number of available classes. In this paper, we propose a new neural network, the Fine-Grained Segmentation Network (FGSN), that can be used to provide image segmentations with a larger number of labels and can be trained in a self-supervised fashion. In addition, we show how FGSNs can be trained to output consistent labels across seasonal changes. We demonstrate through extensive experiments that integrating the fine-grained segmentations produced by our FGSNs into existing localization algorithms leads to substantial improvements in localization performance.
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