Atorvastatin Fails to Prevent the Development of Autoimmune Diabetes Despite Inhibition of Pathogenic β-Cell–Specific CD8
T-Cells
Biliana Lozanoska-Ochser 1 ,
Francesca Barone 2 ,
Costantino Pitzalis ...2 and
Mark Peakman 1
1 Department of Immunobiology, King’s College London, School of Medicine, London, U.K
2 Department of Rheumatology, King’s College London, School of Medicine, London, U.K
Address correspondence and reprint requests to Professor Mark Peakman, Department of Immunobiology, King’s College London,
School of Medicine, 2nd Floor, New Guy’s House, Guy’s Hospital, London, SE1 9RT, U.K. E-mail: mark.peakman{at}kcl.ac.uk
Abstract
Statins, the widely used inhibitors of cholesterol biosynthesis, also have immunomodulatory properties. Statins have recently
been shown to have beneficial prophylactic and therapeutic effects in actively induced, short-term animal models of the autoimmune
diseases multiple sclerosis and rheumatoid arthritis, leading to clinical trials. We therefore investigated whether statins’
protective effects could be reproduced in the nonobese diabetic (NOD) mouse, a spontaneous, chronic model of autoimmune diabetes.
Mice were treated with 0, 1, 10, or 50 mg · kg −1 · day −1 oral atorvastatin from 6 or 12 weeks of age, without effect on the rate or prevalence of diabetes development, islet infiltration,
or islet major histocompatibility complex class II expression. However, there was clear evidence of a disease-relevant immunological
effect of statins in vivo, since short-term (12-day) treatment significantly reduced the number of proinflammatory (γ-interferon–producing)
CD8 cells recognizing a dominant pathogenic epitope. This effect was absent in mice treated for longer periods, suggesting
that atorvastatin loses efficiency in inhibiting autoantigen-specific T-cells over time. This observation may explain the
discrepancy between the reported success of statins in acutely induced models and the lack of it in a chronic, spontaneous
model of autoimmune disease and has implications for the adoption of such therapy in humans.
CIA, collagen-induced arthritis
CTL, cytotoxic T-lymphocyte
EAE, experimental encephalomyelitis
FITC, fluorescein isothiocyanate
IEC, islet endothelial cell
IFN-γ, γ-interferon
IGRP, islet-specific glucose 6-phosphatase catalytic subunit–related protein
IL, interleukin
MHC, major histocompatibility complex
Th1, T-helper 1
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted January 4, 2006.
Received September 27, 2005.
DIABETES
Abstract
Objectives
Primary SS (pSS) is a chronic autoimmune disorder characterized by mucosal dryness and systemic symptoms. We tested the effects of inhibition of cathepsin S using the potent and ...selective inhibitor RO5459072 on disease activity and symptoms of pSS.
Methods
This was a randomized, double-blind, placebo-controlled, parallel-group, Phase IIA study to investigate the effects of RO5459072 (100 mg twice daily; 200 mg per day). Seventy-five patients with pSS were randomized 1:1 to receive either RO5459072 or placebo for 12 weeks. The primary outcome was the proportion of patients with a ≥3 point reduction from baseline in EULAR SS Disease Activity Index (ESSDAI) score. We also investigated the effects of RO5459072 on quality of life, exocrine gland function, biomarkers related to SS, and safety and tolerability.
Results
The proportion of patients showing an improvement in ESSDAI score was not significantly different between the RO5459072 and placebo arms. No clinically meaningful treatment effects were observed in favour of RO5459072 for all secondary outcomes. Analysis of soluble biomarkers indicated target engagement between RO5459072 and cathepsin S. There were modest decreases in the number of circulating B cells and T cells in the RO5459072 group, although these did not reach significance. RO5459072 was safe and well-tolerated.
Conclusions
There was no clinically relevant improvement in ESSDAI score (primary endpoint), and no apparent benefit in favour of RO5459072 in any of the secondary clinical endpoints. Further work is needed in order to understand the mechanisms of MHC-II-mediated immune stimulation in pSS.
Trial registration
ClinicalTrials.gov; NCT02701985.
Salivary gland changes, characterised by a focal lymphocytic sialadenitits, play an important role in the diagnosis of primary Sjögren's syndrome (PSS) and were first described over 40 years ago. ...Recent evidence suggests that minor salivary gland biopsy may also provide information useful for prognostication and stratification, yet difficulties may arise in the histopathological interpretation and scoring, and evidence exists that reporting is variable. With the increasing number of actual and proposed clinical trials in PSS, we review the evidence that might support the role of histopathology as a biomarker for stratification and response to therapy and highlight areas where further validation work is required.
Abstract
A “first-in-human” phase 1 trial of intralesional injection of CAN-3110, an immunotherapeutic oncolytic based on herpes simplex virus 1 (HSV1), was conducted in 41 subjects with recurrent ...high-grade glioma (rHGG). The impact of CAN-3110 on the tumor immune microenvironment was assessed using immunohistochemistry, multiplexed immunofluorescence, TCR-beta DNA sequencing, and bulk RNA sequencing of paired pre- and post-treatment samples. These analyses were combined with patient features to identify potential biomarkers of therapy response in rHGG. In IDH wild type recurrent glioblastoma (IDHwt rGBM) patients, post-treatment survival times were positively associated with positive pre-treatment HSV1 serology after controlling for additional covariates such as tumor volume, age, gender, CAN-3110 dose, etc. (HR = 0.16, p < 0.001, n = 32, CoxPH). Positive HSV1 serology was also significantly associated with clearance of CAN-3110 from injected tumors. Interestingly, increased intratumoral CD8 and CD4 T cell numbers following treatment were positively associated with prolonged survival in HSV1 seropositive patients (p = 0.017 and 0.026, respectively), but not when analyses were conducted including HSV1 seronegative patients. Likewise, post-treatment immune expression signatures (such as for antitumor cytokines, T cell traffic, etc.) were more strongly associated with prolonged survival for HSV1 seropositive patients than for seronegative patients, and most assessed immune signatures only became associated with survival after CAN-3110 treatment. Extended survival was also associated with increased TCR-beta diversity following therapy in both the tumor and in PBMCs. Combined with a lack of observed dose-limiting toxicities and a median post-treatment survival of 14.2 months (95% CI: 9.5-15.7) in IDHwt rGBM patients with positive HSV1 serology, these data provide evidence that intralesional CAN-3110 treatment can instigate immune activation in a traditionally immunologically cold tumor and that this immune activation may influence survival time—particularly when patients have had prior exposure to HSV1. (clinicaltrials.gov NCT03152318).
To evaluate whether fat quality, in the context of meals with high- (HGI) or low-glycemic index (LGI), influences postprandial blood glucose (PPG) response in patients with type 1 diabetes.
According ...to a randomized crossover design, 13 patients with type 1 diabetes on insulin pump consumed two series (HGI or LGI) of meals with the same carbohydrate quantity while differing for amount and quality of fat: 1) low in fat ("low fat"), 2) high in saturated fat (butter), or 3) high in monounsaturated fat (extra-virgin olive oil) (EVOO). Premeal insulin doses were based on insulin-to-glycemic load ratios. Continuous glucose monitoring was performed and 6-h PPG evaluated.
PPG was significantly different between HGI and LGI meals (P = 0.005 for time × glycemic index interaction by repeated-measures analysis RMA), being significantly higher during the first 3 h after the HGI meals with a later tendency to an opposite pattern. In the context of HGI meals, PPG was significantly lower after EVOO than after low fat or butter (P < 0.0001 for time × meal interaction by RMA), with a marked difference in the 0- to 3-h glucose incremental area under the curve between EVOO (mean ± SD 198 ± 274 mmol/L × 180 min) and either low fat (416 ± 329) or butter (398 ± 355) (P < 0.05). No significant differences were observed in PPG between the three LGI meals.
Carbohydrate quality of a mixed meal influences shape and extent of PPG. Besides, using EVOO in a HGI meal attenuates the early postprandial glucose response observed when this meal is consumed with either low fat or butter. Therefore, an optimal prandial insulin administration would require considering, in addition to the quantity of carbohydrates, the quality of both carbohydrate and fat.
Objective
To assess the safety and efficacy of RSLV‐132, an RNase Fc fusion protein, in a phase II randomized, double‐blind, placebo‐controlled clinical trial in patients with primary Sjögren’s ...syndrome (SS).
Methods
Thirty patients with primary SS were randomized to receive treatment with RSLV‐132 or placebo intravenously once per week for 2 weeks, and then every 2 weeks for 12 weeks. Eight patients received placebo and 20 patients received RSLV‐132 at a dose of 10 mg/kg. Clinical efficacy measures included the European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index, EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI), Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT‐F), Profile of Fatigue (ProF), and the Digit Symbol Substitution Test (DSST).
Results
Patients randomized to receive RSLV‐132 experienced clinically meaningful improvements in the ESSPRI score (P = 0.27), FACIT‐F score (P = 0.05), ProF score (P = 0.07), and DSST (P = 0.02) from baseline to day 99, whereas patients who received placebo showed no changes in any of these clinical efficacy measures. This improvement was significantly correlated with increased expression of selected interferon‐inducible genes (Pearson’s correlations, each P < 0.05).
Conclusion
Administration of RSLV‐132 improved severe fatigue, as determined by 4 independent patient‐reported measures of fatigue, in patients with primary SS.
Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ ...localization across three cohorts of patients with IBD (total n = 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total n = 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease.
The aim of this preliminary study was to determine the microbiological quality of pastry products and gastronomic preparations served in food service establishments in Benevento province, Southern ...Italy. A total of 125 samples were collected from food service establishments. Parameters investigated were: aerobic plate counts (APCs), total Coliform bacteria counts, beta-glucuronidase-positive Escherichia (E.) coli counts, Enterobacteriaceae counts, coagulase-positive Staphylococci counts, isolation of Salmonella spp., Bacillus (B.) cereus counts, and isolation of Listeria (L.) monocytogenes. The microbiological quality was good, with absence of the pathogens L. monocytogenes and Salmonella spp. and extremely rare presence of E. coli. The fresh pastry and the uncooked gastronomy products were the most contaminated groups; also, cooked cold-served gastronomy products were susceptible to microbiological risk, as a result of the inadequate reheating and the interruption of the warm chain. On the contrary, dried pastry and cooked warm-served gastronomy products showed an excellent hygienic profile. In fact, the amount of compliant samples was 74.4%.
B-cell expansion is a key feature of Sjögren's syndrome (SS). Accordingly, several studies have reported the benefits of B-cell depletion with anti-CD20 monoclonal antibody (Rituximab) in the ...treatment of glandular and extraglandular manifestations of SS. Patients with SS are at increased risk of lymphoma development. B-lymphocyte stimulator (BAFF) is an essential cytokine for the control of B-cell maturation and survival, and high levels of BAFF were described in the serum and salivary glands of SS patients, strongly suggesting a crucial role in the proliferation of B cells in SS.
We describe the treatments employed, with particular regards to rituximab therapy, and the histopathologic and biologic studies, in particular BAFF levels in serum and in pathologic tissues before and after B-cell depletion therapy, and the characterization of the cultured epithelial cells obtained by the parotid gland MALT-lymphoma, in a case of a 51-year old woman with primary SS and mixed cryoglobulinaemia type II with features of systemic vasculitis, who developed a bilateral parotid MALT-type lymphoma. Rheumatoid factor (RF), cryoglobulins, BAFF levels were assessed monthly up to month +6, then at the end of follow-up (month +12), as well as peripheral blood CD19-positive B-cell level
A significant systemic effect of rituximab on B-cell biomarkers was documented, however, the cryoglobulinemic syndrome did not improve and the parotid enlargement did not decrease confirming the failure of B-cell depletion to affect the parotid lymphoma. BAFF levels decreased only under B-cell depletion associated with high-dose steroids. Tissue studies further documented the persistent overexpression of BAFF in the salivary gland pathologic tissue during the disease course.
Tissue and systemic overexpression of BAFF may have contributed to resistance to rituximab therapy, in MALT lymphoproliferation associated with SS. Thus, alternative treatment strategies should be then considered, possibly including BAFF-targeted approaches.
Labial salivary gland (LSG) biopsy is used in the classification of primary Sjögren's syndrome (PSS) and in patient stratification in clinical trials. It may also function as a biomarker. The ...acquisition of tissue and histological interpretation is variable and needs to be standardised for use in clinical trials. A modified European League Against Rheumatism consensus guideline development strategy was used. The steering committee of the ad hoc working group identified key outstanding points of variability in LSG acquisition and analysis. A 2-day workshop was held to develop consensus where possible and identify points where further discussion/data was needed. These points were reviewed by a subgroup of experts on PSS histopathology and then circulated via an online survey to 50 stakeholder experts consisting of rheumatologists, histopathologists and oral medicine specialists, to assess level of agreement (0–10 scale) and comments. Criteria for agreement were a mean score ≥6/10 and 75% of respondents scoring ≥6/10. Thirty-nine (78%) experts responded and 16 points met criteria for agreement. These points are focused on tissue requirements, identification of the characteristic focal lymphocytic sialadenitis, calculation of the focus score, identification of germinal centres, assessment of the area of leucocyte infiltration, reporting standards and use of prestudy samples for clinical trials. We provide standardised consensus guidance for the use of labial salivary gland histopathology in the classification of PSS and in clinical trials and identify areas where further research is required to achieve evidence-based consensus.
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