Retinoic acid-induced autoantigen-specific type 1 regulatory T cells suppress autoimmunity.

Regulatory T (Treg) cells help to maintain tolerance and prevent the development of autoimmune diseases. Retinoic acid (RA) can promote peripheral conversion of naïve T cells into Foxp3+ Treg cells. Here, we show that RA can act as an adjuvant to induce antigen-specific type 1 Treg (Tr1) cells, which is augmented by co-administration of IL-2. Immunization of mice with the model antigen KLH in the presence of RA and IL-2 induces T cells that secrete IL-10, but not IL-17 or IFN-γ, and express LAG-3, CD49b and PD-1 but not Foxp3, a phenotype typical of Tr1 cells. Furthermore, immunization of mice with the autoantigen MOG in the presence of RA and IL-2 induces Tr1 cells, which suppress pathogenic Th1 and Th17 cells that mediate the development of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease of the CNS. Furthermore, immunization with a surrogate autoantigen, RA and IL-2 prevents development of spontaneous autoimmune uveitis. Our findings demonstrate that the induction of autoantigen-specific Tr1 cells can prevent the development of autoimmunity.

Helminths products directly modulate T cells that mediate experimental autoimmune encephalomyelitis.

Infection with helminths can protect against the development of autoimmune diseases and this has been associated with induction of anti-inflammatory innate immune responses and Tregs. Here, we demonstrate that helminth-derived products can directly target T cells, especially IL-17-secreting γδ T cells that play a key pathogenic role in CNS autoimmune disease.

A new class of 7-deazaguanine agents targeting autoimmune diseases: dramatic reduction of synovial fibroblast IL-6 production from human rheumatoid arthritis patients and improved performance against murine experimental autoimmune encephalomyelitis.

A simple in vitro assay involving the measurement of IL-6 production in human synovial fibroblasts from rheumatoid arthritis patients has been utilised to select candidates from a targeted library of queuine tRNA ribosyltransferase (QTRT) substrates for subsequent in vivo screening in murine experimental autoimmune encephalomyelitis (EAE - a model of multiple sclerosis). The in vitro activity assay discriminated between poor and excellent 7-deazaguanine QTRT substrates and allowed the identification of several structures which subsequently outperformed the previous lead in EAE. Two molecules were of significant promise: one rigidified analogue of the lead, and another considerably simpler structure incorporating an oxime motif which differs structurally from the lead to a considerable extent. These studies provide data from human cells for the first time and have expanded both the chemical space and current understanding of the structure-activity relationship underpinning the remarkable potential of 7-deazguanines in a Multiple Sclerosis disease model.

Evaluation of the safety, efficacy, and mechanism of action of obexelimab for the treatment of patients with IgG4-related disease: an open-label, single-arm, single centre, phase 2 pilot trial.

BACKGROUND: Obexelimab is a bifunctional, non-cytolytic, humanised monoclonal antibody that binds CD19 and Fc gamma receptor IIb to inhibit B cells, plasmablasts, and CD19-expressing plasma cells. We aimed to evaluate the safety, clinical efficacy, and pharmacodynamic effects of obexelimab in patients with active IgG4-related disease. METHODS: We conducted an open-label, single-arm, single centre, phase 2 pilot trial at the Massachusetts General Hospital in Boston, MA, USA. Eligible patients were aged 18-80 years and had active IgG4-related disease confirmed by an IgG4-related disease responder index score of 3 or more. Patients received 5 mg/kg of obexelimab intravenously every 2 weeks for 24 weeks. Patients on glucocorticoids at baseline were expected to discontinue usage within 2 months following enrolment. The primary endpoint was the proportion of patients with a decrease of 2 or more from baseline in the IgG4-related disease responder index at day 169 (ie, primary responders). Patients who achieved a decrease of 2 or more at any visit were designated as responders. Adverse events were graded on a scale of 1-5 (ie, mild, moderate, severe, life-threatening, or death) according to the Common Terminology Criteria for Adverse Events grading scale (version 4.3). Exploratory analyses were quantification of B-cell CD19 receptor occupancy, plasmablast, total B-cell and CD4+ cytotoxic T-cell count by flow cytometry, and immunoglobulin concentrations by nephelometry. This study is registered with ClinicalTrials.gov, NCT02725476. FINDINGS: Between Feb 24, 2016, and Dec 21, 2016, we enrolled 15 patients. The median age was 63 years (IQR 52-65). Ten (67%) of 15 patients were male, five (33%) were female, and 12 (80%) were White. At baseline, 12 (80%) of 15 patients had an elevated median serum IgG4 concentration of 220 mg/dL (IQR 124-441), and the median IgG4-related disease responder index score was 12 (IQR 7-13). 12 (80%) of 15 patients achieved the primary endpoint (ie, primary responders), 14 (93%) were defined as responders. Reductions from baseline in serum B cells and plasmablasts were observed following treatment with obexelimab. However, in most patients with follow-up data, serum B cells recovered to 75% of baseline concentrations within 42 days of the final obexelimab dose. 13 (87%) of 15 patients reported adverse events, one of which (an infusion reaction) resulted in treatment discontinuation. INTERPRETATION: All patients except for one had clinical responses to obexelimab treatment. Both reductions in circulating B cells without evidence of apoptosis during obexelimab treatment and their rapid rebound after treatment discontinuation suggest that obexelimab might lead to B-cell sequestration in lymphoid organs or the bone marrow. These results support the continued development of obexelimab for the treatment of IgG4-related disease. FUNDING: Xencor, Zenas BioPharma, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute of Allergy and Infectious Diseases.

Anti-inflammatory Trained Immunity Mediated by Helminth Products Attenuates the Induction of T Cell-Mediated Autoimmune Disease.

Recent studies have suggested that the innate immune system can display characteristics of immunological memory and this has been called "innate immune memory" or "trained immunity." Certain fungal products have been shown to induce epigenetic imprinting on monocytes/macrophages that results in heightened inflammatory responses to subsequent stimuli. Here we report that innate immune cells can be trained to be more anti-inflammatory following exposure to products of a helminth pathogen. Macrophages trained in vitro with Fasciola hepatica total extract (FHTE) had enhanced IL-10 and IL-1RA, but reduced TNF production upon re-stimulation with FHTE or TLR ligands and this was reversed by inhibitors of DNA methylation. In contrast, macrophages trained with ß-glucan or Bacillus Calmette-Guérin had enhanced TNF production upon re-stimulation with Pam3cys or LPS. Furthermore, FHTE-trained macrophages had enhanced expression of markers of alternative activated macrophages (AAM). Macrophages from mice treated with FHTE expressed markers of AAM and had heightened IL-10 and IL-1RA production in response to FHTE or TLR ligands and had suppressed TNF and IL-12p40 production. Macrophages from mice treated with FHTE had reduced APC function and inhibited IL-17 production and the encephalitogenic activity of T cells in the experimental autoimmune encephalomyelitis (EAE) model. In addition, mice pre-treated with FHTE were resistant to induction of EAE and this was associated with a significant reduction in IL-17-producing γδ and CD4 T cells infiltrating the CNS. Our findings reveal that cells of the innate immune system can be trained in vitro or in vivo to be more anti-inflammatory by exposure to helminth products and this protects mice against the induction of a T cell-mediated autoimmune disease.

Aflibercept in Diabetic Macular Oedema Previously Refractory to Standard Intravitreal Therapy: An Irish Retrospective Study.

INTRODUCTION: To determine visual and anatomical outcomes of diabetic macular oedema (DMO) patients in a tertiary centre following conversion to aflibercept having been refractory to previous treatment with bevacizumab/ranibizumab. METHODS: A retrospective case series of patients with a diagnosis of DMO undergoing aflibercept intravitreal therapy for at least 6 months who had previous treatment with three consecutive bevacizumab/ranibizumab injections pre-switch. Exclusion criteria included other procedures affecting visual outcome performed within the treatment period. Outcomes measured included visual acuity (VA), central macular thickness (CMT) and injection frequency. RESULTS: Eighteen eyes of 13 patients were included. Mean VA pre-switch was 61.5 ± 13.8 letters and CMT was 433.2 ± 101.4. Mean number of prior bevacizumab/ranibizumab treatments was 11.3 ± 7.2. Mean follow-up post-switch was 22.5 months (SD 7.9). Mean VA improved from baseline by 4.8 letters at 6 months (p = 0.005), by 6.1 letters at 12 months (p = 0.006), by 7.9 letters (p = 0.004) at 18 months and by 6.4 letters (p = 0.1) at 24 months. Mean CMT decreased from baseline by 108.6 µm at 6 months (p = 0.01), 117.7 µm at 12 months (p = 0.0003), 158.0 µm at 18 months (p = 0.005) and by 123.3 µm at 24 months (p = 0.02). CONCLUSION: Switching to aflibercept in treatment-resistant DMO produces significant improvements in visual and anatomical outcomes, with eventual maintenance of VA levels.

Telangiectasis as a cause of intra-schitic haemorrhage in optic disc pit maculopathy.

PURPOSE: To present a patient with the novel finding of vascular telangiectasis as a cause of intra-schitic haemorrhage, occurring in optic disc pit-associated maculopathy. METHODS: A clinical history was detailed. Clinical examination included visual acuity assessment and slit-lamp microscopy. Fluorescein angiography was performed. RESULTS: A temporal optic disc pit, macular retinoschisis and a circumscribed detachment of the outer retinal layer and inner leaf holes were noted. A retinal haemorrhage extending into the schitic cavity was present, along with an associated vitreous haemorrhage. Fluorescein angiography showed telangiectatic vessels in association with the haemorrhage. CONCLUSION: This is the first reported case of vascular telangiectasis as a cause of intra-schitic haemorrhage occurring in optic disc pit-associated maculopathy.

Assessment of delays in presentation of patients with retinal detachment to a tertiary referral centre.

The referral pathway of patients with retinal detachment from primary care providers to a tertiary care ophthalmic unit was examined, in order to determine the length and source of any delays between the onset of symptoms and arrival at the hospital. A prospective survey of all symptomatic patients (n = 60) admitted for primary rhegmatogenous retinal detachment surgery was carried out over an 8 week period. Twenty-one patients were referred by their optometrists and 18 by their general practitioners. The remainder were referred by local accident and emergency and ophthalmic departments or presented directly to the tertiary referral centre. Patients who presented to their optometrists were symptomatic for an average of four times longer. More than half the patients thought that the time to initial presentation was the most significant delay. Referral from optometrists via general practitioners and local ophthalmic clinics was considerably longer. Increased awareness of symptoms, necessity of urgent referral and knowledge of available services locally may reduce delay for those who require emergency sight-saving surgery.