High-Risk Corneal Graft Rejection in the Setting of Previous Corneal Herpes Simplex Virus (HSV)-1 Infection

Acknowledgments The authors thank M. Robertson and R. Fordyce for technical support during the duration of the study. The work performed in Aberdeen was supported by grant from Action Medical Research UK (SP4328; London, England, UK), NHS Grampian Endowment grant (12/49; Aberdeen, Scotland, UK), and Saving Sight in Grampian (Charity No.SC002938; Aberdeen, Scotland, UK). The work performed in Pittsburgh was supported by a Fight for Sight Post-Doctoral Award (JEK; New York, NY, USA); unrestricted grants from the Western Pennsylvania Medical Eye Bank Foundation (Pittsburgh, PA, USA), Research to Prevent Blindness (New York, NY, USA), and the Eye and Ear Foundation of Pittsburgh (RLH; Pittsburgh, PA, USA); and National Institutes of Health Grants P30EY08098 (RLH; Bethesda, MD, USA) and EY10359 (RLH).Peer reviewedPublisher PD

Low-dose 2-Deoxy Glucose Stabilises Tolerogenic Dendritic Cells and Generates Potent in vivo Immunosuppressive Effects

Open Access via Springer Compact Agreement University of Aberdeen Development Trust Grant number RG14251, RG12663 Acknowledgements: We thank the University of Aberdeen Iain Fraser Flow Cytometry core facility, and the University of Aberdeen Histology and Microscopy core facility for processing of histology slides. The authors thank University of Aberdeen Medical Research Facility for technical assistance with in vivo experiments. We thank Dr. Tian Yu, Dr. Yi-Hsia Liu, Mrs Rosemary Fordyce, and Mrs Elizabeth Muckersie for technical assistance with in vivo and in vitro experiments. Funding: This work was supported by funds from the University of Aberdeen Development Trust Grants RG14251 and RG12663. Maria Christof was the recipient of a University of Aberdeen PhD Studentship. Samantha Le Sommer was funded by a Wellcome Trust ISSF Postdoctoral Fellowship.Peer reviewedPublisher PD

Guidance on Noncorticosteroid Systemic Immunomodulatory Therapy in Noninfectious Uveitis : Fundamentals Of Care for UveitiS (FOCUS) Initiative

Supplemental material available at www.aaojournal.org. Supported by AbbVie, Inc., and the Fundamentals of Care for Uveitis Initiative National Faculty. This manuscript was developed subsequent to an AbbVie-sponsored literature review of noninfectious, nonanterior uveitis. The meeting was conducted to understand the available literature regarding the management of patients with noninfectious, nonanterior uveitis. The program involved a total of 139 experts from 28 countries, who were selected for participation by AbbVie. However, AbbVie was not involved in the development of the manuscript. The authors maintained complete control over the content and this manuscript reflects the opinions of the authors. AbbVie selected the discussion participants and reviewed the final manuscript draft for scientific accuracy, but the authors determined the final content. All authors made substantial contributions to the article or critically revised it for important intellectual content and approved the final manuscript. AbbVie provided funding to invited participants, including honoraria for their attendance at the meetings. Travel to and from the meetings was reimbursed. No payments were made to the authors for the development of this manuscript. Dhinakaran Sambandan, PhD, and Shula Sarner, PhD, of Lucid Partners, Burleighfield House, Buckinghamshire, United Kingdom, provided medical writing and editorial support to the authors in the development of this manuscript; financial support for these services was provided by AbbVie. AbbVie reviewed the manuscript, but was not involved in the methodology, data collection and analysis, or completion of this manuscript.Peer reviewedPublisher PD

Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: fundamentals of care for uveitis (focus) initiative

Topic: An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. Clinical Relevance: The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. Methods: An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic reviewof the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE,CINAHL,SCOPUS,BIOSIS, andWeb of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review.Atotal of 44 globally representativegroupmembersmet in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. Results: In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Conclusions: Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents

Guidance on Noncorticosteroid Systemic Immunomodulatory Therapy in Noninfectious Uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative

Topic: An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. Clinical Relevance: The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. Methods: An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic review of the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE, CINAHL, SCOPUS, BIOSIS, and Web of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review. A total of 44 globally representative group members met in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. Results: In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Conclusions: Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents

Quantitative evaluation of the corneal endothelium in the mouse after grafting

Background/aim: Corneal graft survival depends critically on the quality of the endothelium. In this study the authors aimed to evaluate corneal endothelium in mice at different times after transplantation and to correlate endothelial integrity with corneal graft survival. Methods: Syngeneic and allogeneic corneal grafts at various times (days 0–60) after engraftment were examined in flat mount preparation by confocal microscopy, by evaluating the hexagonal pattern of the endothelial monolayer using actin staining of the cell cortex. Corneas from untreated mice and from mice, who were grafted after removal of draining lymph nodes served as controls. Results: In control corneas, more than 90% of the posterior surface was covered by endothelium. Syngeneic grafts were always covered by 54–99% of endothelium. In contrast, the posterior surface of corneal allografts showed great variation in the degree of endothelial cell coverage (0–98%). In addition, clinical opacity grading measure was not a reliable predictor of endothelial coverage. Conclusion: In corneal allografts there is progressive loss of endothelium over time, unlike with syngeneic grafts. However, in the early stages of allograft rejection, the grade of graft opacity does not accurately reflect the degree of endothelial cell coverage. Although corneal opacity grade is considered the main determinant of graft rejection, the data suggest that both the grade of corneal opacity plus a sufficient post-graft time duration (>8 weeks in the mouse) are required for the diagnosis of irreversible graft rejection

The effect of local and systemic administration of soluble IL-15 receptor alpha-chain in experimental corneal transplantation [Abstract]

Purpose: To investigate and compare the effects of local and systemic administration of sIL-15 receptor {alpha}-chain (sIL-15R{alpha}) in a mouse model of corneal transplantation. Method: In a model of murine allografting [C57BL10 mice (H2b) to BALB/c mice (H2d)] we treated recipients of the grafts as follows: (1) topical treatment with sIL-15R{alpha} (3x per day for 20 days); (2) systemic treatment i.p. using 3 different schedules: (a) sIL-15R{alpha} or control non-sense M4 protein or PBS from day 0-20 post-graft at a dose of 60{gamma}g/day/animal; (b) sIL-15R{alpha} or M4 protein from day 0 –10 post-graft; and (c) sIL-15R{alpha} or M4 protein from day 5-15 after corneal grafting. Immunohistochemistry of donor corneas after local treatment and CBA from the DLN was performed at 3, 6 and 9d post-graft. Results: Systemic treatment with sIL-15R{alpha} using both the 0-20 and 0-10 days post-graft protocol significantly prolonged corneal graft survival. Control administration of non-sense M4 protein had no effect on prolongation of corneal graft survival compared to untreated (PBS) controls. In contrast, administration of sIL-15R{alpha} using the 5-15 days post graft protocol led to an accelerated tempo of corneal graft rejection. Local treatment with sIL-15R{alpha} significantly prolonged graft survival in comparison with non-treated or M4 protein treated graft recipients. Immunohistochemistry showed reduced F4/80+, CD11b+, MoMa-2+ and mannose receptor positive macrophage infiltration of corneal grafts topically treated with sIL-15R{alpha}. No statistically significant difference was found in production of IFN-{gamma}, TNF-{alpha} and IL-6 by cells from DLN between groups treated with sIL-15R{alpha} and M4 protein. However, the production of IL-12p70, IL-10 and MCP-1 was significantly higher in the group treated with sIL-15R{alpha} than treated with M4 protein. Conclusions: These results indicate that IL-15-IL-15R blockade is effective in delaying corneal graft rejection when used both systematically and topically. In both cases, the effect was observed only when blockage was in place from the time of grafting