ORCID Profile
0000-0003-4974-1371
Current Organisation
University of Cambridge
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Publisher: The American Association of Immunologists
Date: 07-2010
Abstract: Biological therapies, even humanized mAbs, may induce antiglobulin responses that impair efficacy. We tested a novel strategy to induce tolerance to a therapeutic mAb. Twenty patients with relapsing–remitting multiple sclerosis received an initial cycle of alemtuzumab (C ath-1H), up to 120 mg over 5 d, preceded by 500 mg SM3. This Ab differs from alemtuzumab by a single point mutation and is designed not to bind to cells. Twelve months later, they received a second cycle of alemtuzumab, up to 72 mg over 3 d. One month after that, 4 of 19 (21%) patients had detectable serum anti-alemtuzumab Abs compared with 145 of 197 (74%) patients who received two cycles of alemtuzumab without SM3 in the phase 2 CAMMS223 trial (p & 0.001). The efficacy and safety profile of alemtuzumab was unaffected by SM3 pretreatment. Long-lasting “high-zone” tolerance to a biological therapy may be induced by pretreatment with a high i.v. dose of a drug variant, altered to reduce target-binding.
Publisher: Cold Spring Harbor Laboratory
Date: 27-07-2020
DOI: 10.1101/2020.07.24.20161786
Abstract: The majority of variation in outcome following severe traumatic brain injury (TBI) remains unexplained by currently recognised prognostic factors, suggesting a contribution from unaccounted variables. One key candidate variable is neuroinflammation, including the generation of autoantibodies against brain specific antigens which have been described in some in iduals following TBI. Here we hypothesised that autoantibody responses following TBI would differ between in iduals, and would explain a proportion of outcome variance. We developed a custom protein microarray to characterise the generation of autoantibodies to both central nervous system and systemic antigens in the acute-phase of TBI (within ten days of injury), and to determine their late (6-12 months) and long-term (6-13 years) persistence. We identified two distinct patterns of response. The first was a broad response to the majority of antigens tested, predominantly IgM-mediated in the acute-phase, then IgG-dominant at late and long-term time-points. The second was of dominant responses to certain antigens, most frequently myelin-associated glycopeptide (MAG), which persisted for several months post-TBI but then subsequently resolved. Exploratory analyses suggested that patients with a greater acute IgM response experienced worse outcomes than predicted. Furthermore, late persistence of anti-MAG IgM autoantibodies correlated with serum neurofilament light concentrations, suggesting an association with ongoing neurodegeneration over the first year post-injury. Our results show that autoantibody production occurs in some in iduals following TBI, can persist for many years, and may affect patient outcome. The complexity of responses mean that conventional approaches based on measuring responses to single antigenic targets may be misleading.
Publisher: American Medical Association (AMA)
Date: 15-01-2019
Publisher: The American Association of Immunologists
Date: 07-2021
Abstract: Most of the variation in outcome following severe traumatic brain injury (TBI) remains unexplained by currently recognized prognostic factors. Neuroinflammation may account for some of this difference. We hypothesized that TBI generated variable autoantibody responses between in iduals that would contribute to outcome. We developed a custom protein microarray to detect autoantibodies to both CNS and systemic Ags in serum from the acute-phase (the first 7 d), late (6–12 mo), and long-term (6–13 y) intervals after TBI in human patients. We identified two distinct patterns of immune response to TBI. The first was a broad response to the majority of Ags tested, predominantly IgM mediated in the acute phase, then IgG dominant at late and long-term time points. The second was responses to specific Ags, most frequently myelin-associated glycopeptide (MAG), which persisted for several months post-TBI but then subsequently resolved. Exploratory analyses suggested that patients with a greater acute IgM response experienced worse outcomes than predicted from current known risk factors, suggesting a direct or indirect role in worsening outcome. Furthermore, late persistence of anti-MAG IgM autoantibodies correlated with raised serum neurofilament light concentrations at these time points, suggesting an association with ongoing neurodegeneration over the first year postinjury. Our results show that autoantibody production occurs in some in iduals following TBI, can persist for many years, and is associated with worse patient outcome. The complexity of responses means that conventional approaches based on measuring responses to single antigenic targets may be misleading.
Publisher: Springer Science and Business Media LLC
Date: 14-07-2020
DOI: 10.1186/S13550-020-00667-5
Abstract: Tracking cells in vivo using imaging can provide non-invasive information to understand the pharmacology, efficacy, and safety of novel cell therapies. Zirconium-89 ( t 1/2 = 78.4 h) has recently been used to synthesize [ 89 Zr]Zr(oxinate) 4 for cell tracking using positron emission tomography (PET). This work presents an in vitro approach to estimate the detection limit for in vivo PET imaging of Jurkat T cells directly labeled with [ 89 Zr]Zr(oxinate) 4 utilizing clinical PET/CT and PET/MRI. Jurkat T cells were labeled with varying concentrations of [ 89 Zr]Zr(oxinate) 4 to generate different cell-specific activities (0.43–31.91 kBq/10 6 cells). Different concentrations of labeled cell suspensions (10 4 , 10 5 , and 10 6 cells) were seeded on 6-well plates and into a 3 × 3 cubic-well plate with 1 cm 3 cubic wells as a gel matrix. Plates were imaged on clinical PET/CT and PET/MRI scanners for 30 min. The total activity in each well was determined by drawing volumes of interest over each well on PET images. The total cell-associated activity was measured using a well counter and correlated with imaging data. Simulations for non-specific signal were performed to model the effect of non-specific radioactivity on detection. Using this in vitro model, the lowest cell number that could be visualized on 6-well plate images was 6.8 × 10 4 , when the specific activity was 27.8 kBq/10 6 cells. For the 3 × 3 cubic-well, a plate of 3.3 × 10 4 cells could be detected on images with a specific activity of 15.4 kBq/10 6 cells. The results show the feasibility of detecting [ 89 Zr]Zr(oxinate) 4 -labeled Jurkat T cells on clinical PET systems. The results provide a best-case scenario, as in vivo detection using PET/CT or PET/MRI will be affected by cell number, specific activity per cell, the density of cells within the target volume, and non-specific signal. This work has important implications for cell labeling studies in patients, particularly when using radiosensitive cells (e.g., T cells), which require detection of low cell numbers while minimizing radiation dose per cell.
Publisher: Proceedings of the National Academy of Sciences
Date: 26-11-2013
Abstract: This paper identifies the mechanism by which patients with multiple sclerosis develop secondary autoimmunity after treatment with the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (C ath-1H). In identifying this mechanism, it shows that T-cell homeostatic proliferation can lead to autoimmunity in humans. Alemtuzumab is one of the most effective treatments of multiple sclerosis tested to date it is currently licensed in the European Union and under consideration by the Food and Drug Administration. Understanding what drives its most significant side effect is of clear clinical importance.
Publisher: BMJ
Date: 05-11-2012
Abstract: Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon β-1a for relapsing-remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined. The lymphocyte reconstitution (n=36 384 person years) and crude safety data (n=37 447 person years) are reported for the first patients with progressive MS to receive alemtuzumab (1991-1997). Reconstitution time was expressed as a geometric mean or, when a non-negligible number of in iduals failed to recover, as a median using survival analysis. Geometric mean recovery time (GMRT) of total lymphocyte counts to the lower limit of the normal range (LLN ≥1.0×10(9) cells/l) was 12.7 months (95% CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×10(9)/l) was 7.1 months (95% CI 5.3 to 9.5) median recovery times for CD8 (LLN ≥0.2×10(9) cells/l) and CD4 lymphocytes (LLN ≥0.4×10(9) cells/l) were 20 months and 35 months, respectively. However, CD8 and CD4 counts recovered to baseline levels in only 30% and 21% of patients, respectively. No infective safety concerns arose during 447 person years of follow-up. Lymphocyte counts recovered to LLN after a single course of alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets), but usually did not recover to baseline values. However, this long lasting lymphopenia in patients with a previously normal immune system was not associated with an increased risk of serious opportunistic infection.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.JNEUROIM.2019.04.005
Abstract: Traumatic brain injury (TBI) is the leading cause of death and disability in young adults in the developed world. The accuracy of early outcome-prediction remains poor even when all known prognostic factors are considered, suggesting important currently unidentified variables. In addition, whilst survival and neurological outcomes have improved markedly with the utilisation of therapies that optimise physiology, no treatments specifically modulate the underlying pathophysiology. The immunological response to TBI represents both a potential contributor to outcome heterogeneity and a therapeutically tractable component of the acute disease process. Furthermore, chronic inflammation has been linked with neurodegeneration, and may mark a bridge between acute brain injury and the subsequent neurodegenerative process seen in a proportion of patients following TBI. Given the complexity of the immune response and its varying functions ranging from repair of injury to bystander damage of healthy tissue, attempts at immunomodulatory intervention must necessarily be highly targeted towards the maladaptive facets of the inflammatory process. In this review we aim to provide an integrated description of the immunological processes triggered by TBI in both humans and animal models, in particular considering the interplay between the innate immune system, danger-associated molecular patterns and loss of self-tolerance leading to adaptive autoimmunity.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 13-05-2022
Abstract: Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing.
Publisher: Springer Science and Business Media LLC
Date: 17-02-2020
Publisher: Springer Science and Business Media LLC
Date: 09-10-2020
Publisher: BMJ
Date: 21-05-2014
Abstract: Alemtuzumab is a newly licensed treatment of active relapsing-remitting multiple sclerosis (RRMS) in Europe, which in phase II and III studies demonstrated superior efficacy over β-interferon in reducing disability progression over 2-3 years. In this observational cohort study, we sought to describe our longer-term experience of the efficacy and safety of alemtuzumab in active RRMS. Clinical and laboratory data including serial Expanded Disability Status Scale (EDSS) assessments, from all 87 patients treated with alemtuzumab on investigator-led studies in Cambridge, UK, from 1999 to 2012, were collected. The occurrence of adverse events including secondary autoimmunity, malignancy and death, and pregnancy outcomes was recorded. Baseline variables including age, disease duration and relapse rate were compared in univariate and logistic regression analyses between groups with different disability outcomes. Over a median 7-year follow-up (range 33-144 months), most patients (52%) required just two cycles of alemtuzumab. In the remaining patients, relapses triggered re-treatment to a total of three cycles (36%), four cycles (8%) or five cycles (1%). Using a 6-month sustained accumulation of disability definition, 59/87 (67.8%) of patients had an improved or unchanged disability compared with baseline. By an area under the curve analysis, 52/87 (59.8%) patients had an overall improvement or stabilisation of disability. Higher baseline relapse rate was associated with worse long-term disability outcomes, with trends for longer disease duration and older age at first treatment. Secondary autoimmunity was the most frequent adverse event occurring in 41/86 (47.7%) patients, most commonly involving the thyroid gland. Alemtuzumab is associated with disease stabilisation in the majority of patients with highly active RRMS over an average seven-year follow-up. No new safety concerns arose over this extended follow-up.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Joanne Jones.