Disruption of Intestinal Homeostasis and Intestinal Microbiota During Experimental Autoimmune Uveitis.

Purpose: We determine the changes in intestinal microbiota and/or disruptions in intestinal homeostasis during uveitis. Methods: Experimental autoimmune uveitis (EAU) was induced in B10.RIII mice with coadministration of interphotoreceptor retinoid-binding protein peptide (IRBP) and killed mycobacterial antigen (MTB) as an adjuvant. Using 16S rRNA gene sequencing, we looked at intestinal microbial differences during the course of uveitis, as well as intestinal morphologic changes, changes in intestinal permeability by FITC-dextran leakage, antimicrobial peptide expression in the gastrointstinal tract, and T lymphocyte prevalence before and at peak intraocular inflammation. Results: We demonstrate that increased intestinal permeability and antimicrobial peptide expression in the intestinal tract coincide in timing with increased effector T cells in the mesenteric lymph nodes, during the early stages of uveitis, before peak inflammation. Morphologic changes in the intestine were most prominent during this phase, but also occurred with adjuvant MTB alone, whereas increased intestinal permeability was found only in IRBP-immunized mice that develop uveitis. We also demonstrate that the intestinal microbiota were altered during the course of uveitis, and that some of these changes are specific to uveitic animals, whereas others are influenced by adjuvant MTB alone. Intestinal permeability peaked at 2 weeks, coincident with an increase in intestinal bacterial strain differences, peak lipocalin production, and peak uveitis. Conclusions: An intestinal dysbiosis accompanies a disruption in intestinal homeostasis in autoimmune uveitis, although adjuvant MTB alone promotes intestinal disruption as well. This may indicate a novel axis for future therapeutic targeting experimentally or clinically.

Targeting Interleukin-23 in the Treatment of Noninfectious Uveitis.

The interleukin (IL)-23/IL-17 axis plays a central role in the pathogenesis of immune-mediated diseases such as psoriasis, psoriatic arthritis, Crohn's disease, and uveitis. Therefore, targeting the IL-23/IL-17 axis has become the focus of multiple clinical trials for drug development in patients with autoimmune diseases. We briefly describe the biology of the IL-23/IL-17 axis and its relevance to the pathogenesis of experimental and clinical uveitis, and review the monoclonal antibody therapies targeting this pathway. Finally, 2 ongoing phase 2 trials of the anti-IL-23 biologic therapy ustekinumab (STELARA, Janssen Biotech Inc, Horsham, PA) in patients with noninfectious uveitis are introduced.

Frontiers in the management of retinoblastoma.

PURPOSE: To provide an overview of the current clinical management of retinoblastoma by discussing the trends in the categorization, treatment, and recent advances in molecular diagnostics as well as therapy for retinoblastoma. DESIGN: Literature review and commentary. METHODS: Selected articles from the medical literature and the authors' clinical and research experience were reviewed critically. RESULTS: Retinoblastoma has evolved from a deadly childhood cancer to a largely curable cancer within the past 40 years. Current treatment strategies aim to salvage the eye and provide the best visual outcome possible. Using the international classification system to stratify intraocular retinoblastoma into treatment groups, the multicenter Children's Oncology Group treatment protocols use 2- to 3-drug chemoreduction with focal consolidative therapy for most categories of disease. Furthermore, collaborative efforts are being directed toward a better understanding of genotype-phenotype relationships in retinoblastoma that will be useful in the multidisciplinary management of this disease. Molecular targeting therapy is emerging as a potential strategy to individualize therapy. Finally, improvements in local drug delivery methods and vehicles are providing solutions for the problem of systemic toxicity from existing chemotherapy regimens. CONCLUSIONS: The management of retinoblastoma has become a prototype for other ophthalmic diseases and systemic cancers in which genetic information and molecular targets are being used to design more elegant treatment strategies.

The lysophospholipid receptor G2A activates a specific combination of G proteins and promotes apoptosis.

G2A, a G protein-coupled receptor for which lysophosphatidylcholine (LPC) is a high affinity ligand, belongs to a newly defined lysophospholipid receptor subfamily. Expression of G2A is transcriptionally up-regulated by stress-inducing and cell-damaging agents, and ectopic expression of G2A leads to growth inhibition. However, the G proteins that functionally couple to G2A have not been elucidated in detail. We report here that G2A ligand independently stimulates the accumulation of both inositol phosphates and cAMP. LPC does not further enhance inositol phosphate accumulation but dose-dependently augments intracellular cAMP concentration. Expression of G alpha(q) and G alpha(13) with G2A potentiates G2A-mediated activation of a NF-kappa B-luciferase reporter. These results demonstrate that G2A differentially couples to multiple G proteins including G alpha(s), G alpha(q), and G alpha(13), depending on whether it is bound to ligand. G2A-transfected HeLa cells display apoptotic signs including membrane blebbing, nuclear condensation, and reduction of mitochondrial membrane potential. Furthermore, G2A-induced apoptosis can be rescued by the caspase inhibitors, z-vad-fmk and CrmA. Although apoptosis occurs without LPC stimulation, LPC further enhances G2A-mediated apoptosis and correlates with its ability to induce cAMP elevation in both HeLa cells and primary lymphocytes. Rescue from G2A-induced apoptosis was achieved by co-expression of a G alpha(12/13)-specific inhibitor, p115RGS (regulator of G protein signaling), in combination with 2',5'-dideoxyadenosine treatment. These results demonstrate the ability of G2A to activate a specific combination of G proteins, and that G2A/LPC-induced apoptosis involves both G alpha(13)- and G alpha(s)-mediated pathways.