The goal of this project is to develop improved methods for the diagnosis and treatment of ocular inflammatory diseases in human patients of all ages including uveitis, scleritis, inflammatory diseases of the ocular surface, and intraocular malignancies. Over the past year clinical studies have continued to focus on examining the effectiveness of new therapeutic agents with a milder safety profile than that offered by currently available standard immunosuppressive medications. We completed a series of studies to evaluate the long term safety and potential therapeutic activity of humanized anti-IL-2 receptor monoclonal antibody (Daclizumab) therapy in the treatment of patients with severe, sight-threatening, intermediate and posterior non-infectious uveitis. This was based on our initial observations in an animal model for human uveitis. Our initial study in patients was a non-randomized, open-label study to evaluate the long term safety and potential therapeutic activity of daclizumab. In that study, patients with chronic, non-infectious bilateral, sight-threatening uveitiswere weaned off their immunosuppressive agents according to a standardized schedule, while ultimately receiving Daclizumab infusions every 4 weeks. Many patients have now received anti-IL2 receptor therapy for several years. No apparent increase in the infection rate has been seen in these patients. In the course of their therapy some patients were converted to monthly subcutaneous administration of the medication instead of infusions. Patients have tolerated this transition with no problems. Based on these findings we have initiated a second study. : Fifteen study participants with sight-threatening uveitis quiescent on immunosuppressive therapy were enrolled at 3 sites and treated with subcutaneous daclizumab, 2 mg/kg every 2 weeks x2, then maintenance at 1 mg/kg every 2 weeks, with simultaneous tapering of the standard immunosuppressive therapy. Treatments were well tolerated and 11/15 patients reached the preset outcome by eliminating 50% of their standard immunosuppressive medications by 12 weeks without recurrence of their ocular inflammatory disease or reduction in visual acuity. Of the 10 participants that have completed 6 months of followup, 9 were able to reduce or maintain 50% of their baseline medication load without significant loss of vision or increase in disease activity. A study was performed in a small number of patients who had active uveitis in spite of standard immunosuppressive therapy. All the patients'disease responded to the administration of high dose (8mg/kg followed by 4mg/kg) therapy with good results. A pilot study using the high dose regimen of daclizumab in the treatment of juvenile rheumatoid arthritis has been completed with the initial findings suggesting that this approach may have beneficial clinical effects. The company has decided not to produce the medication in spite of what seems to be a good safety profile. We continue our experience with infliximab (Remicade), a chimeric human/murine monoclonal antibody that neutralizes the biologic activity of TNF-alpha for the treatment of scleritis, and posterior segment uveitis including retinal vasculitis. Although infliximab seems to be an effective alternate therapy for the treatment of ocular inflammatory disease the potential for ocular complications may limit the usage of the agent. We evaluated the presence of T -regulatory cells in humans and defined their characteristics. We have seen that uveitis patients resistant to steroid therapy have a group of IL-17 producing cells in the CD4+CD25+ subpopulation. We continue to analyze vitreal cytokine levels from primary intraocular lymphoma (PIOL) and uveitic patients and continue to use the cutoff point in disease diagnosis with an IL-10 to IL-6 ratio greater than 1.0 for PIOL. As well, the MUST (multicenter uveitis steroid treatment study results of the study were made available. The SITE study,in which we participated demonstrated that there was no increased mortality due to long term immunosuppressive therapy for uveitis. SITE 2 will start in the near future. The use of anti-IL-12 and other biologics are planned

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAEY000356-12
Application #
8556820
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2012
Total Cost
$267,859
Indirect Cost
Name
U.S. National Eye Institute
Department
Type
DUNS #
City
State
Country
Zip Code
Kim, Jane S; Jaworski, Laurence; Patel-Donnelly, Dipti et al. (2017) WALDENSTRÖM'S MACROGLOBULINEMIA MASQUERADING AS BIRDSHOT CHORIORETINOPATHY. Retin Cases Brief Rep 11:152-155
Knickelbein, Jared E; Sen, H Nida (2016) Multimodal Imaging of the White Dot Syndromes and Related Diseases. J Clin Exp Ophthalmol 7:
Kim, Jane S; Knickelbein, Jared E; Jaworski, Laurence et al. (2016) Enhanced Depth Imaging Optical Coherence Tomography in Uveitis: An Intravisit and Interobserver Reproducibility Study. Am J Ophthalmol 164:49-56
Chen, Ping; Tucker, William; Hannes, Susan et al. (2015) Levels of blood CD1c+ mDC1 and CD1chi mDC1 subpopulation reflect disease activity in noninfectious uveitis. Invest Ophthalmol Vis Sci 56:346-52
Kim, Jane S; Knickelbein, Jared E; Nussenblatt, Robert B et al. (2015) Clinical trials in noninfectious uveitis. Int Ophthalmol Clin 55:79-110
Liu, Baoying; Dhanda, Ashwin; Hirani, Sima et al. (2015) CD14++CD16+ Monocytes Are Enriched by Glucocorticoid Treatment and Are Functionally Attenuated in Driving Effector T Cell Responses. J Immunol 194:5150-60
Knickelbein, Jared E; Chan, Chi-Chao; Sen, H Nida et al. (2015) Inflammatory Mechanisms of Age-related Macular Degeneration. Int Ophthalmol Clin 55:63-78
Levin, Marc H; Pistilli, Maxwell; Daniel, Ebenezer et al. (2014) Incidence of visual improvement in uveitis cases with visual impairment caused by macular edema. Ophthalmology 121:588-95.e1
Keane, Pearse A; Karampelas, Michael; Sim, Dawn A et al. (2014) Objective measurement of vitreous inflammation using optical coherence tomography. Ophthalmology 121:1706-14
Lima, Breno R; Mandelcorn, Efrem D; Bakshi, Nupura et al. (2014) Syphilitic outer retinopathy. Ocul Immunol Inflamm 22:4-8

Showing the most recent 10 out of 67 publications