Dry-eye syndrome (DES) is a multifactorial disease affecting millions of individuals worldwide. Various factors, including age, hormonal status, genetics, sex, immune status, innervation status, nutrition, pathogens, and environmental stress, can alter the cellular and molecular structure or function of components of the ocular surface system. The resulting imbalance increases susceptibility to desiccation and epithelial damage, leading to a vicious circle in which inflammation amplifies and sustains further damage by chronic deregulation of the system. Lubricating agents and steroids have been used as treatment options. However, as the causes of the disease become better elucidated, the more chemically complex cyclosporine A has become an increasingly useful treatment option and in the United States is currently the only Food and Drug Administration (FDA)-approved prescription drug for the treatment of dry eye. The safety and efficacy of cyclosporine have been shown in numerous studies.

SUMMARY Epidemiologic studies discovered an inverse association between Immunoglobulin E (IgE)-mediated allergies and cancer, implying tumor-protective properties of IgE. The underlying immunologic mechanisms remain, however, poorly understood. Antigen cross-presentation by dendritic cells (DCs) is key for anti-tumor immunity because of the generation of cytotoxic CD8+ T lymphocytes (CTLs) with specificity for tumor antigens. We demonstrate that DCs use IgE and FcεRI, the high affinity IgE receptor, for cross-presentation and priming of CTLs in response to free soluble antigen at low doses. Importantly, IgE/FcεRI-mediated cross-presentation is a distinct, novel receptor-mediated pathway as it does not require MyD88 signals or IL-12 induction in DCs. Using passive immunization with tumor antigen-specific IgE and DC-based vaccination experiments, we demonstrate that IgE-mediated cross-presentation significantly improves anti-tumor immunity and induces memory responses in vivo. Our findings suggest a cellular mechanism for the tumor-protective features of IgE and expand the known physiological functions of this immunoglobulin.

BackgroundNitration of proteins on tyrosine residues, which can occur due to polluted air under “summer smog” conditions, has been shown to increase the allergic potential of allergens. Since nitration of tyrosine residues is also observed during inflammatory responses, this modification could directly influence protein immunogenicity and might therefore contribute to food allergy induction. In the current study we have analyzed the impact of protein nitration on sensitization via the oral route.Methodology/Principal FindingsBALB/c mice were immunized intragastrically by feeding untreated ovalbumin (OVA), sham-nitrated ovalbumin (snOVA) or nitrated ovalbumin (nOVA) with or without concomitant acid-suppression. To analyze the impact of the sensitization route, the allergens were also injected intraperitoneally. Animals being fed OVA or snOVA under acid-suppressive medication developed significantly elevated levels of IgE, and increased titers of specific IgG1 and IgG2a antibodies. Interestingly, oral immunizations of nOVA under anti-acid treatment did not result in IgG and IgE formation. In contrast, intraperitoneal immunization induced high levels of OVA specific IgE, which were significantly increased in the group that received nOVA by injection. Furthermore, nOVA triggered significantly enhanced mediator release from RBL cells passively sensitized with sera from allergic mice. Gastric digestion experiments demonstrated protein nitration to interfere with protein stability as nOVA was easily degraded, whereas OVA and snOVA remained stable up to 120 min. Additionally, HPLC-chip-MS/MS analysis showed that one tyrosine residue (Y107) being very efficiently nitrated is part of an ovalbumin epitope recognized exclusively after oral sensitization.Conclusions/SignificanceThese data indicated that despite the enhanced triggering capacity in existing allergy, nitration of OVA may be associated with a reduced de novo sensitizing capability via the oral route due to enhanced protein digestibility and/or changes in antibody epitopes.

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Background:The aim of this study was to investigate the uptake and release kinetics of two common glaucoma drugs delivered onto hydrogel contact lenses using analytical chemistry and to evaluate this device's ability to control intraocular pressure in a limited number of volunteers. Methods: Contact lenses were incubated in a source solution containing timolol maleate or brimonidine tartrate to determine uptake kinetics. The lenses were then immersed in fresh saline to determine release kinetics. Analysis was performed by high-pressure liquid chromatography (HPLC). HPLC column retention times were determined for drugs released from the lens individually and under co-elution conditions. To evaluate clinical feasibility and toxicity, three volunteers (patients being treated for glaucoma) were provided with contact lenses that had been passively impregnated with either drug. After a three-week wash-out period, the volunteers were instructed to wear the lenses for 30 minutes per day for two weeks. Results: HPLC analysis showed that maximum uptake and release of both drugs had occurred by approximately 60 minutes, with the slopes tending to flatten after this point. The retention time on the HPLC column was 8.08 minutes for timolol maleate and 2.16 minutes for brimonidine tartrate after incubation for one hour, with no changes after seven hours. Patient data showed that use of the lenses maintained IOP at levels equivalent to those obtained with previous treatment. No ocular toxicity was observed. Conclusion: Drugs commonly used for glaucoma treatment can be passively transferred to a hydrogel contact lens and then eluted from the polymer. Data obtained from a limited number of patients suggest that this contact lens/drug delivery system may be a feasible means of controlling IOP.

The purpose of this study was to evaluate the presence of interleukin-6 (IL-6) in basal tears of contact lens wearers (n = 18) and nonlens wearers (n = 25). Samples (5 microl) were collected with a microcapillary pipette and evaluated using PAGE electrophoresis and immunoblot analysis. Contact lens-wearing patients had a mean IL-6 level of 43.8 +/- 5.3 pg/5 microl compared with nondetectable IL-6 levels throughout the noncontact lens-wearing population. IL-6 in several patients removed from contact lens wear for 6 days became nondetectable. When these patients were returned to wearing lenses, IL-6 levels increased to their original levels within 24 h. The data presented indicate that an ocular medical device may stimulate IL-6 production.

Purpose: Despite pharmacological advances, delivery of drugs to the posterior segment of the eye remains problematic. We investigated the ability of hydrogel contact lenses to deliver small-molecule steroids, as well as larger biological molecules to the posterior segment. Methods: Release characteristics of steroid-instilled lenses were studied in vitro. Drug delivery to the posterior segment of the eye was evaluated in a rabbit model, in which hydrogel contact lenses treated with diluted steroids (prednisolone or beclomethasone) were placed on rabbit corneas for four hours on days 1, 2, 5, 8 and 10. The amount of drug in plasma, posterior segment tissue and vitreous humour was measured with highperformance liquid chromatography-tandem mass spectrometry. In a further preliminary investigation, two rabbits were treated with ranibizumab. Results: The lenses released prednisolone and beclomethasone in saline over a six-hour period at a declining rate. Prednisolone was found in posterior segment tissue from six of six rabbits at concentrations ranging from 26.8 to 166 ng/g and in vitreous humour from two of six rabbits. Beclomethasone was detected in posterior segment tissue from three rabbits but was not found in the vitreous humour. Ranibizumab was detected in posterior segment tissue in a range from 0.19 ng/mL to 0.5183 ng/mL. Conclusions: Hydrogel contact lenses are a non-invasive, periocular drug delivery device capable of achieving measurable drug levels in posterior segment tissue.Submitted: 17 May 2010 Revised: 9 July 2010 Accepted for publication: 6 September 2010Key words: contact lens, drug delivery systems, high-performance liquid chromatography, hydrogels, mass spectrometry, passive diffusion/transport, ranibizumab Recent pharmacological advances have resulted in new drugs for the treatment of posterior segment ocular diseases. For example, inhibitors of vascular endothelial growth factor, a biological molecule closely linked to neovascularisation in the human eye, slow or stop the progression of age-related macular degeneration; [1][2][3] however, delivery of such drugs to the posterior segment of the eye remains problematic. To date, most have been delivered by intravitreal injection. This method provides rapid delivery of the drug to the vitreous humour and can achieve immediate therapeutic 212Clinical and Experimental Optometry © 2010 Optometrists Association Australia concentrations while avoiding systemic exposure; however, drugs are eliminated via first-order diffusion within a short time and thus, in most cases, repeated injections are necessary to maintain sustained delivery of the drug. 4,5 There are many risks associated with repeated intravitreal injections, including endophthalmitis, cataract formation, retinal detachment, haemorrhage and infection. 4,6 Less invasive approaches than intraocular drug delivery for the treatment of ocular diseases include topical application by means of eye drops or ointments, systemic delivery and periocular delivery through various sustained release device...

The development of a small-animal model to test the protective efficacy and immunogenicity of a vaccine strain against shigellosis would greatly facilitate the evaluation of potential vaccine candidates. In guinea pigs, the ability of shigellae to invade and multiply within the corneal epithelium, causing keratoconjunctivitis, closely mimics the invasion process in the intestinal epithelium (B. Sereny, Acta Microbiol. Acad. Sci. Hung. 4:367-376, 1957). The serum response of animals recovering from a Shigella keratoconjunctival infection was determined and found to be consistent with that shown by convalescent humans and primates. This model was used to test the efficacy of two vaccine candidates, and the immune response of the guinea pigs to the vaccine strains was examined. Both vaccine strains demonstrated significant protection against challenge by homologous virulent Shigella strains, and the results were comparable with results obtained in trials with monkeys. The guinea pig model also provides a rapid and inexpensive means of evaluating different immunization regimens as well as of testing other variables such as length of protection against disease.