1: Ophthalmic Res. 2008 Apr 29;40(5):221-226 [Epub ahead of print] 

Retinoblastoma: From Disease to Discovery.

Madhavan J, Ganesh A, Kumaramanickavel G.

SN ONGCDepartment of Genetics and Molecular Biology, Vision Research Foundation,
Sankara Nethralaya, Chennai, India.

Retinoblastoma has contributed much to the understanding of cancer. It provided
the classic \'two-hit model\' for oncogenesis and helped to identify the first
tumor suppressor gene RB1. Thirty years since then, the search for additional
events underlying disease progression continues. Phenotypic variations in
retinoblastoma offer numerous clues to disease pathogenesis. Understanding their
molecular biological basis will provide insight into mechanisms underlying tumor
progression. These not fully understood genetic and stochastic events play a
major role in uncontrolled retinal precursor cell proliferation. Comparative
genomic hybridization and gene expression studies have facilitated probing of
genes controlling basic events in cellular development, i.e. proliferation,
differentiation and apoptosis. Research to determine the cell of origin that
underlies the evolution of retinoblastoma can lead to understanding of the
stochastic events underlying the genesis of this cancer, which currently remains
unclear. In this review, we discuss the recent developments in retinoblastoma
and describe how they are beginning to shape a new and revised picture of
retinoblastoma pathogenesis and progression. Copyright (c) 2008 S. Karger AG,
Basel.

PMID: 18446017 [PubMed - as supplied by publisher]

2: Ophthalmic Res. 2008 Apr 25;40(5):273-278 [Epub ahead of print] 

The Role of Nuclear Factor Kappa B in Lens Epithelial Cell Proliferation Using a
Capsular Bag Model.

Lee SJ, Bae S, Seomun Y, Son MJ, Joo CK.

Department of Ophthalmology and Visual Science, College of Medicine, Catholic
University of Korea, Seoul, Korea.

Purpose: This study was performed to elucidate the role of nuclear factor kappaB
(NF-kappaB) in lens epithelial cell proliferation in the capsular bag model for
this study. Methods: Capsular bags were prepared from porcine eyes and cultured
in a 5% CO(2) atmosphere at 37 degrees C. NF-kappaB translocation was confirmed
by immunohistochemistry and Western blot analysis. The effects of sulfasalazine
and SN50 peptide, inhibitors of NF-kappaB activation, were observed by light
microscopy and scanning electron microscopy. Results: NF-kappaB was found in the
cytoplasm of nonproliferated lens epithelial cells. However, NF-kappaB moved to
the nucleus in proliferation cells, proliferating-cell-nuclear-antigen-positive
cells. This translocation was inhibited by treatment with sulfasalazine or
NF-kappaB SN50 peptide. These inhibitors also blocked lens epithelial cell
migration from the equatorial to the posterior capsule. Conclusion: NF-kappaB
controls proliferation and regulates the growth of lens epithelial cells. In
this study, sulfasalazine and NF-kappaB SN50 peptide inhibited cell
proliferation in the capsular bag model. These results suggest that the
regulation of NF-kappaB in lens epithelial cells may modulate posterior capsule
opacification. Copyright (c) 2008 S. Karger AG, Basel.

PMID: 18437038 [PubMed - as supplied by publisher]

3: Ophthalmic Res. 2008 Apr 25;40(5):267-272 [Epub ahead of print] 

Utility of a Biopsy in Suspicious Pigmented Iris Tumors.

Schalenbourg A, Uffer S, Zografos L.

Jules Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland.

Background: In the presence of pigmented iris lesions evocative of malignant
melanoma and implying oncological treatment, a foregoing biopsy to exclude a
benign lesion may seem a reasonable approach. After examining patient files, the
utility of such a diagnostic approach was explored. Material and Methods:
Retrospective, consecutive histopathologic case series of 10 pigmented iris
tumor specimens excised since 1993. Histopathologic diagnosis was compared with
final diagnosis and outcome in the patient\'s medical chart. Results: Five
biopsies had only nevus cells, whereas ulterior clinical data or histopathologic
examinations were compatible with the diagnosis of malignant melanoma. One
biopsy contained insufficient sample tissue. Four biopsies confirmed clinical
suspicion of iris melanoma. Conclusion: In the current case series, 6 out of 10
biopsies provided a falsely reassuring negative or an inconclusive result.
Modern management techniques such as ultrasound biomicroscopy and proton therapy
of the whole anterior segment have equally diminished indications for a biopsy.
In cases clinically evocative of iris melanoma, a biopsy has only a relative
value. Copyright (c) 2008 S. Karger AG, Basel.

PMID: 18437037 [PubMed - as supplied by publisher]

4: Ophthalmic Res. 2008 Apr 25;40(5):257-266 [Epub ahead of print] 

Clinical Evaluation of Succinylated Collagen Bandage Lenses for Ophthalmic
Applications.

Hadassah J, Prakash D, Sehgal PK, Agarwal A, Bhuvaneshwari N.

Bio-Products Laboratory, Central Leather Research Institute, Adyar, Chennai,
India.

Aim: To study whether succinylated collagen bandage lenses (SCBL) prepared from
modified bovine collagen (succinylated collagen) can replace other bandage
lenses presently employed to treat various corneal conditions like filamentary
keratitis, dry eyes, recurrent corneal erosions, foreign body removal and
epithelial trauma. Methods: This observational case study included 32 patients
(22 female and 10 male): 8 patients for filamentary keratitis (25%), 10 patients
for dry eyes (31%), 4 patients for recurrent corneal erosions (13%), 7 patients
for foreign body removal (22%) and 3 patients for epithelial trauma (9%). Their
eyes were evaluated for biocompatibility, in vivo transparency, patient comfort,
corneal fit, best corrected visual acuity (BCVA), tear fluid level and
dissolution rate of SCBL. This was carried out over a 24-hour period of time.
Results: SCBL exhibited good transparency and remained transparent throughout
the period of study (between 0 and 24 h) in the eyes of patients. SCBL did not
cause any irritation, discomfort and foreign body sensation in the eye and eyes
remained comfortable throughout the experiment. BCVA in the control group of
patients was 1.00 (20/20). Mean (+/-SD) BCVA before inserting SCBL (in decimal
equivalent) was 0.31 (20/60) +/- 0.18 (range 0.1- 0.66). BCVA (+/-SD) changed to
0.25 (20/80) +/- 0.18 4 h after the application of SCBL and 0.27 (20/70) +/-
0.18 24 h after the application of SCBL, with a safety index of 1.20. The mean
(+/-SD) tear fluid level before application of SCBL was 11.9 +/- 5.39 h (range
3-24 mm) and changed to 13.9 +/- 5.68 h (range 5-28 mm) after 4 h of application
of SCBL and 15.9 +/- 5.72 h (range 7-30 mm) after 24 h with a safety index of 13
mm. The mean (+/-SD) dissolution rate of SCBL in the control group of patients
was 17.8 +/- 8.65 h (range 10-24 h) and the mean (+/-SD) dissolution rate in the
experimental group was 22.2 +/- 9.29 h (range 10-24 h). We report the use of
SCBL in various corneal conditions. Conclusion: The present study showed that
SCBL has complete corneal fit and good comfort in human eyes. Transparency was
maintained for a longer period along with fair visual acuity and improvement in
tear fluid levels. The disadvantages of other bandage lenses presently used to
treat various corneal conditions could be overcome by the use of SCBL lenses.
Copyright (c) 2008 S. Karger AG, Basel.

PMID: 18437036 [PubMed - as supplied by publisher]

5: Ophthalmic Res. 2008 Apr 25;40(5):249-256 [Epub ahead of print] 

Increased Homocysteine Levels in Tear Fluid of Patients with Primary Open-Angle
Glaucoma.

Roedl JB, Bleich S, Schlotzer-Schrehardt U, von Ahsen N, Kornhuber J, Naumann
GO, Kruse FE, Junemann AG.

Department of Ophthalmology, University Eye Hospital, Erlangen-Nuremberg,
Germany.

Aims: We assessed homocysteine (Hcy) levels in tear fluid and plasma of patients
with primary open-angle glaucoma (POAG). We determined the association between
Hcy levels, dry eye syndrome and B vitamin status. Methods: This prospective
case-control study included 36 patients with POAG and 36 controls. Hcy
concentrations were measured by high-performance liquid chromatography. Results:
Patients with POAG had significantly higher mean Hcy levels both in tear fluid
(205 +/- 84 nmol/l; p < 0.001, t test) and in plasma (13.43 +/- 3.53 mumol/l; p
= 0.001, t test) than control subjects (130 +/- 53 nmol/l and 10.50 +/- 3.33
mumol/l, respectively). Hcy in tear fluid was significantly correlated with
plasma Hcy in POAG patients (r = 0.459; p = 0.005, Pearson\'s correlation), but
not in controls (r = 0.068; p = 0.695). POAG patients with dry eye disease had
significantly higher Hcy levels both in tear fluid and plasma than POAG patients
without dry eye disease. There was no association between Hcy levels and B
vitamin status in subjects with POAG. Conclusions: The study suggests increased
Hcy levels in tear fluid and plasma of patients with POAG. Elevated Hcy levels
might be a risk factor for POAG and dry eye syndrome in subjects with glaucoma.
Copyright (c) 2008 S. Karger AG, Basel.

PMID: 18437035 [PubMed - as supplied by publisher]

6: Ophthalmic Res. 2008 Apr 25;40(5):241-248 [Epub ahead of print] 

Involvement of Retinal Neurons and Pigment Epithelial Cells in a Murine Model of
Sandhoff Disease.

Sango K, Yamanaka S, Ajiki K, Arai N, Takano M.

Department of Developmental Morphology, Tokyo Metropolitan Institute for
Neuroscience, Fuchu, Japan.

Background/Aims: To investigate the effects of deficient degradation of
glycolipids on the morphological appearance of all retinal cells in a murine
model of G(M2) gangliosidosis (Sandhoff disease). Methods: The morphological
appearance of the retina in Sandhoff mice at symptomatic stages (3 and 4 months
of age) was examined by immunohistochemistry, lectin histochemistry and electron
microscopy. Results: Under a light microscope, intense immunoreactivity for
G(M2) ganglioside was observed in the ganglion cell, inner plexiform, and inner
nuclear layers in the Sandhoff mice. The ganglion cell layers and retinal
pigment epithelium in the Sandhoff mice were stained intensely withconcanavalin
A agglutinin and succinylated wheat germ agglutinin. Ultrastructural studies
revealed numerous inclusions in the cytoplasm of retinal ganglion cells and
other neuronal cells (particularly amacrine cells), whereas we failed to detect
apparent involvement of photoreceptor cells. In addition to the cytoplasmic
inclusions in the retinal neurons, vacuolation was evident in the retinal
pigment epithelium. Conclusion: These findings suggest that neuronal cells and
pigment epithelial cells are more vulnerable to the deficient ganglioside
degradation than other retinal cells in Sandhoff mice. Copyright (c) 2008 S.
Karger AG, Basel.

PMID: 18437034 [PubMed - as supplied by publisher]

7: Ophthalmic Res. 2008 Apr 25;40(5):235-240 [Epub ahead of print] 

Optical Coherence Tomography Fast versus Regular Macular Thickness Mapping in
Diabetic Retinopathy.

Ceklic L, Maar N, Neubauer AS.

Department of Ophthalmology, Clinical Center of Eastern Sarajevo, RS-Bosnia and
Herzegovina University of Sarajevo, Sarajevo, RS-Bosnia.

Objective: The purpose of the study was to investigate if absolute values and
reproducibility of thickness maps obtained from 2 optical coherence tomography
(OCT) scanning protocols, regular high-resolution and fast low-density mode,
differ in patients with diabetic macular edema. Methods: A total of 26
consecutive patients undergoing fluorescein angiography and Stratus OCT scanning
for the evaluation of diabetic macular edema at the Departments of Ophthalmology
in Munich and Vienna were included. Results: Retinal thickness of the central
field of the thickness map measured by fast retinal thickness protocol was 287
+/- 97 and 290 +/- 113 mum by the regular protocol. This difference as well as
that for all other fields was not statistically significant. Three times
repeated measurements applying both OCT scanning modes in 10 patients yielded
very good intrasession correlation coefficients between 0.70 and 0.99, with
corresponding intrasession standard deviations ranging between 6 and 16 mum. The
fast mode yielded slightly less reproducible values than the regular mode.
Visual acuity did not influence the results. Conclusion: In practice both
scanning modes can be interchanged and absolute values can be compared directly.
Best reproducibility is obtained with higher sampling density even in patients
with reduced visual acuity due to diabetic macular edema. Copyright (c) 2008 S.
Karger AG, Basel.

PMID: 18437033 [PubMed - as supplied by publisher]

8: Ophthalmic Res. 2008 Apr 25;40(5):227-234 [Epub ahead of print] 

Two Autocrine Pathways to Regulate Cyclic GMP Synthesis in Cultured Human
Retinal Pigment Epithelial Cells.

Diederen RM, La Heij EC, Markerink-van Ittersum M, Hendrikse F, de Vente J.

Eye Research Institute Maastricht, Department of Ophthalmology, University of
Maastricht, Maastricht, The Netherlands.

Aim: To investigate the role of two separate enzymatic pathways [soluble (sGC)
vs. particulate (pGC) guanylyl cyclase] in the synthesis of cyclic GMP (cGMP) in
cultured human retinal pigment epithelial (RPE) cells. Methods: cGMP
accumulation was evaluated by quantitative analysis of cGMP immunoreactivity.
RPE cells were also stained for inducible nitric oxide synthase (iNOS), ANP and
beta(1)- and alpha(2)-subunits of sGC. Results: We showed nicotinamide adenine
dinucleotide phosphate (NADPH) diaphorase activity and iNOS immunoreactivity in
RPE cells. Incubation of the cells in the presence of 1 mM IBMX to inhibit
phosphodiesterase activity, and the simultaneous inhibition of NOS activity with
L-NAME suggested the involvement of sGC in maintaining a low level of cGMP in
the RPE cells. The involvement of sGC was further supported by detection of the
beta(1)- and alpha(2)-subunits of sGC. Incubation of the cells in the presence
of atrial natriuretic peptide (ANP) to stimulate pGC strongly increased cGMP
immunoreactivity. We also demonstrated the presence of ANP in all RPE cells.
Conclusion: Cultured human RPE cells are capable of producing cGMP after
stimulation of sGC or pGC. The presence of iNOS and ANP in all cells suggests
two different autocrine pathways of stimulating cGMP production in these cells.
The possible role of cGMP in the regulation iNOS gene expression and in the
regulation of ANP is discussed. Copyright (c) 2008 S. Karger AG, Basel.

PMID: 18437032 [PubMed - as supplied by publisher]

9: Ophthalmic Res. 2008;40(3-4):212-6. Epub 2008 Apr 18. 

Optic nerve degeneration in experimental autoimmune encephalomyelitis.

Guy J.

Department of Ophthalmology , University of Florida, College of Medicine,
Gainesville, FL 32610-0284, USA. johnguy@eye.ufl.edu

The mechanisms of axonal and neuronal degeneration causing disability in optic
neuritis and multiple sclerosis are poorly understood. Here we describe the role
of mitochondria, oxidative stress and the effects of modulating antioxidant gene
expression in the optic nerves of mice induced with experimental autoimmune
encephalomyelitis, with a focus on long-term neuroprotection. Oxidative injury
to the mitochondrion began prior to inflammatory cell infiltration and
continued. It affected subunits of the respiratory chain, glycolysis and a
chaperone critical to the stabilization and import of proteins. Oxidative
products were associated with loss of membrane potential, mitochondrial
degeneration and severe axonal loss. Reductions in ATP synthesis were even
greater than those associated with mitochondrial diseases. Increasing SOD2
levels by viral mediated gene transfer rescued ATP synthesis, suppressed myelin
fiber injury and increased retinal ganglion cell survival 1 year later. 2008 S.
Karger AG, Basel.

PMID: 18421242 [PubMed - in process]

10: Ophthalmic Res. 2008;40(3-4):208-11. Epub 2008 Apr 18. 

Animal models of intraocular lymphomas.

Touitou V, Bodaghi B, de Kozak Y, Lehoang P, Sautes-Fridman C, Fisson S.

Institut National de la Sante et de la Recherche Medicale (INSERM), UMRS 872,
Centre de Recherche des Cordeliers, Paris, France.

Primary intraocular lymphoma is a high-grade non-Hodgkin lymphoma whose
pathogenesis is still unclear. Few animal models exist in order to study this
condition. Although intraocular lymphomas in humans are usually B cell
lymphomas, most of these models are T cell lymphomas. Recently, a major step
forward has been realized with the development of new models of intraocular B
cell lymphoma. New therapeutic tools are being evaluated in these models of B
cell lymphoma. We evaluate the contribution of the different animal models
available to study intraocular lymphomas, and we discuss the new therapeutic
strategies and their various targets in the tumor as well as in the environment,
which are currently investigated through the development of these models. 2008
S. Karger AG, Basel.

Publication Types:
    Research Support, Non-U.S. Gov\'t

PMID: 18421241 [PubMed - in process]

11: Ophthalmic Res. 2008;40(3-4):203-7. Epub 2008 Apr 18. 

PlGF-1 and VEGFR-1 pathway regulation of the external epithelial hemato-ocular
barrier. A model for retinal edema.

Miyamoto N, de Kozak Y, Normand N, Courtois Y, Jeanny JC, Benezra D, Behar-Cohen
F.

INSERM, UMRS 872, Equipe 17, Centre de Recherche des Cordeliers, Paris, France.

VEGF is considered as an important factor in the pathogenesis of macular edema.
VEGF induces the rupture of the blood retinal barrier and may also influence the
retinal pigment epithelial (RPE) outer retinal barrier. The aim of this work was
to analyze the influence of the VEGF receptor pathways in the modulation of the
RPE barrier breakdown in vitro and in vivo. The ARPE19 human junctions in
culture are modulated by VEGF through VEGFR-1 but not through VEGFR-2. PlGF-1,
that is a pure agonist of VEGFR-1, is produced in ARPE-19 cells under hypoxic
conditions and mimics VEGF effects on the external retinal barrier as measured
by TER and inulin flux. In vivo, the intravitreous injection of PlGF-1 induces a
rupture of the external retinal barrier together with a retinal edema. This
effect is reversible within 4 days. VEGF-E, that is a pure agonist of VEGFR-2,
does not induce any acute effect on the RPE barrier. These results demonstrate
that PlGF-1 can reproduce alterations of the RPE barrier occurring during
diabetic retinopathy. 2008 S. Karger AG, Basel.

PMID: 18421240 [PubMed - in process]

12: Ophthalmic Res. 2008;40(3-4):200-2. Epub 2008 Apr 18. 

Relevance of animal models to human uveitis.

Bodaghi B, Rao N.

Department of Ophthalmology, Pitie-Salpetriere Hospital, Paris, France.
bahram.bodaghi@psl.aphp.fr

Uveitis represents a wide spectrum of intraocular inflammatory conditions and
includes various autoimmune and infectious etiologies. The relevance of animal
models of uveitis to human diseases remains a key issue with major implications
for the translational research and development of therapeutic strategies.
Histopathological findings in patients with Vogt-Koyanagi-Harada disease,
birdshot retinochoroidopathy and anterior uveitis are correlated to those
observed in different animal models. Even though evidence based on
histopathology is usually irrefutable, similar features may be due to different
disease mechanisms. Analysis of triggering factors, determination of cellular
populations and immune microenvironment should prevail over clinical phenotype
evaluation. There is a controversy in correlating the clinical finding of
nummular chorioretinal scars, commonly referred to as Dalen-Fuchs nodules, seen
in the periphery of fundus in patients with chronic Vogt-Koyanagi-Harada disease
with histologic observations made on such enucleated eyes. Although
histopathology of the lesions consisted of focal chorioretinal scars with loss
of RPE, there was no consensus about the histologic nature of the nummular
chorioretinal scars, particularly whether they represent Dalen-Fuchs nodules.
Based on the immunogenetic background, there may be different forms of one
specific disease with variable phenotypic expression. This review discusses the
importance of experimental models in the light of immunologic alterations and
histopathological features in human uveitic entities. 2008 S. Karger AG, Basel.

PMID: 18421239 [PubMed - in process]

13: Ophthalmic Res. 2008;40(3-4):193-9. Epub 2008 Apr 18. 

Microbial products trigger autoimmune ocular inflammation.

Fujimoto C, Shi G, Gery I.

Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892-1857,
USA.

PURPOSE: Microbial products stimulate the immune system by interacting with
Toll-like receptors (TLR) on antigen-presenting cells. This study examined the
hypothesis that microbial products, which function as TLR ligands, are playing a
major role in triggering pathogenic autoimmunity. METHODS: An experimental
system was developed in which microbial TLR ligands were tested in vivo for
their capacity to stimulate naive CD4 cells specific against hen egg lysozyme
(HEL) to become effector cells capable of inducing inflammation in eyes in which
HEL is expressed. The ligands\' mode of action was analyzed by determining their
effects on the proliferation, acquisition of tissue-invading capacity, i.e.
elevated CD49d and decreased CD62L expression, and production of
interferon-gamma by the HEL-specific cells. RESULTS: All the 7 tested TLR
ligands triggered ocular inflammation in the experimental system used here, with
pertussis toxin surpassing all other ligands in its activities. A correlation
was found between the capacity of the ligands to trigger pathogenic immunity and
to stimulate the proliferation, modification of cell surface and
interferon-gamma production by T cells. CONCLUSIONS: This study provides direct
evidence to support the notion that microbial products are capable of triggering
pathogenic autoimmunity. 2008 S. Karger AG, Basel.

PMID: 18421238 [PubMed - in process]

14: Ophthalmic Res. 2008;40(3-4):189-92. Epub 2008 Apr 18. 

Anterior uveitis accompanies joint disease in a murine model resembling
ankylosing spondylitis.

Rosenzweig HL, Martin TM, Planck SR, Jann MM, Smith JR, Glant TT, van Eden W,
Davey MP, Rosenbaum JT.

Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA.
rosenzwh@ohsu.edu

BACKGROUND: Uveitis is often associated with a systemic inflammatory disease
such as ankylosing spondylitis. Our understanding of the eye\'s susceptibility to
immune-mediated uveitis as in the apparent absence of infection has been limited
by a relative lack of experimental models. Here we sought to assess whether
ocular inflammation occurs in a previously described murine model of
proteoglycan-induced spondylitis, wherein mice develop progressive spondylitis,
sacroiliitis and peripheral arthritis--features common to the clinical
presentations of ankylosing spondylitis. METHODS: Using intravital microscopy we
examined the ocular inflammatory response after the onset of arthritis in mice
that overexpressed the T cell receptor (TCR) specific for a dominant
arthritogenic epitope of cartilage proteoglycan [TCR-Tg (transgenic) mice] or
BALB/c controls. RESULTS: Immunized TCR-Tg mice showed a significant increase in
the number of rolling and adhering cells within the iris vasculature compared to
adjuvant control mice. Cellular infiltration within the iris tissue, as assessed
by intravital microscopy and histology, was also increased. Our initial temporal
analysis has revealed that immunized TCR-Tg mice show a significant increase in
intravascular inflammation by 2 weeks after immunization, but it diminishes at 4
weeks after immunization. CONCLUSIONS: Although these data are preliminary, this
model has the potential to clarify the mechanisms accounting for the coexistence
of eye and sacroiliac inflammation as occurs in patients with ankylosing
spondylitis. 2008 S. Karger AG, Basel.

Publication Types:
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov\'t
    Research Support, U.S. Gov\'t, Non-P.H.S.

PMID: 18421237 [PubMed - in process]

15: Ophthalmic Res. 2008;40(3-4):181-8. Epub 2008 Apr 18. 

Primate model of uveoretinitis and vasculitis/experimental autoimmune
uveoretinitis induced in cynomolgus monkeys by retinal s antigen.

LeHoang P, Sterkers M, Thillaye B, de Kozak Y, Coscas G, Faure JP.

Department of Ophthalmology, University Pierre et Marie Curie, Pitie-Salpetriere
Medical School, Assistance Publique, Hopitaux de Paris, Paris, France.
phuc.lehoang@psl.aphp.fr

PURPOSE: We aimed to describe the clinical and angiographic changes in an
experimental model of autoimmune uveoretinitis and vasculitis in primates.
METHODS: Six cynomolgus monkeys received a single subcutaneous immunization with
100 microg of human S antigen with complete Freund\'s adjuvant. RESULTS: All the
animals had a bilateral long-term disease occurring usually in 1 eye
approximately 4 weeks after immunization, the second eye being involved 1-5
weeks later. A cyclic course of the disease could be demonstrated by repeated
fundus fluorescein angiograms. The initial and principal manifestation consisted
in retinal vascular sheathing affecting veins and venules. The more severe forms
showed areas of posterior uveoretinitis, dense vitritis and anterior uveitis.
CONCLUSION: A single systemic injection of pure human retinal S antigen could
induce a chronic and recurrent ocular disease similar to human retinal
vasculitis. 2008 S. Karger AG, Basel.

PMID: 18421236 [PubMed - in process]

16: Ophthalmic Res. 2008;40(3-4):175-80. Epub 2008 Apr 18. 

Pathological aspects of spontaneous uveitis and retinopathy in HLA-A29
transgenic mice and in animal models of retinal autoimmunity: relevance to human
pathologies.

de Kozak Y, Camelo S, Pla M.

Institut National de la Sante et de la Recherche Medicale U872, Paris, France.
ydekozak@ccr.jussieu.fr

PURPOSE: A major increased risk of developing birdshot chorioretinopathy is
reported in humans who are HLA-A29-positive. To better characterize this
disease, an animal model of HLA-A29-associated disease was developed and the
pathology arising spontaneously in these transgenic mice was compared to animal
models of autoimmune uveoretinitis and to human pathology. MATERIALS AND
METHODS: HLA-A2902 cDNA (A29c) was obtained from a patient suffering from
birdshot retinochoroidopathy and used for transgene construct to generate
HLA-A29 transgenic mice. Histopathological examination of the animal cohort was
performed up to 15 months of age. It was compared with the ocular pathology
developed in C57BL/6 mice and in Lewis rats immunized with retinal autoantigens.
RESULTS: Aging HLA-A29 transgenic mice spontaneously developed an ocular disease
with resemblance to experimental retinal-Ag-induced autoimmune ocular disease
and to human pathologies shown in birdshot retinochoroidopathy,
Vogt-Koyanagi-Harada and sympathetic ophthalmia. Pathogenic mechanisms could
possibly be shared by these conditions. CONCLUSION: Humanized models of ocular
inflammation developed in HLA class I and class II transgenic mice will help
better understand the mechanisms responsible for ocular inflammation. Local
control of autoimmunity in HLA-A29-positive individuals would be an important
option for new therapeutic strategies. 2008 S. Karger AG, Basel.

PMID: 18421235 [PubMed - in process]

17: Ophthalmic Res. 2008;40(3-4):169-74. Epub 2008 Apr 18. 

Mouse models of experimental autoimmune uveitis.

Caspi RR, Silver PB, Luger D, Tang J, Cortes LM, Pennesi G, Mattapallil MJ, Chan
CC.

Laboratory of Immunology, NEI, NIH, Bethesda, MD 20892-1857, USA.

The mouse model of experimental autoimmune uveitis, induced by immunization of
mice with the retinal protein IRBP, was developed in our laboratory 20 years ago
and published in 1988. Since that time it has been adopted by many investigators
and has given rise to many studies that helped elucidate genetic influences,
dissect the basic mechanisms of pathogenesis and test novel immunotherapeutic
paradigms. The current overview will summarize the salient features of the
experimental autoimmune uveitis model and discuss its mechanisms. 2008 S. Karger
AG, Basel.

Publication Types:
    Research Support, N.I.H., Intramural
    Research Support, Non-U.S. Gov\'t

PMID: 18421234 [PubMed - in process]

18: Ophthalmic Res. 2008;40(3-4):165-8. Epub 2008 Apr 18. 

Uveitis secondary to bacterial products.

Rosenbaum JT, Rosenzweig HL, Smith JR, Martin TM, Planck SR.

Oregon Health and Science University, Portland, OR 97239, USA. rosenbaj@ohsu.edu

Bacteria are suspected contributors to several forms of immune-mediated,
noninfectious forms of uveitis including that associated with ankylosing
spondylitis, sarcoidosis, Behcet\'s disease and inflammatory bowel disease.
Endotoxin (lipopolysaccharide)-induced uveitis has been a widely used model for
more than 2 decades. Both rats and mice develop a transient, bilateral anterior
uveitis after a systemic injection of endotoxin. Inflammation posterior to the
lens is generally milder than anterior segment inflammation. The uveitis is
severer if the lipopolysaccharides are injected intraocularly. The model has
been invaluable in helping to identify mediators induced in the inflamed eye and
in testing pharmacologic approaches to reduce eye inflammation. Muramyl
dipeptide is another bacterial cell component that can induce uveitis in
laboratory animals. Muramyl dipeptide is especially intriguing as a cause of
uveitis because it activates the intracellular protein, Nod2, and mutations in
the NOD2 gene are the cause of the autosomal dominant form of uveitis that is
characteristic of Blau syndrome. Since a mutation in a gene that codes for a
protein which senses a bacterial product consistently results in uveitis, it is
critical to understand more fully the mechanisms by which bacterial products
cause uveitis in laboratory animals. 2008 S. Karger AG, Basel.

Publication Types:
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov\'t

PMID: 18421233 [PubMed - in process]

19: Ophthalmic Res. 2008;40(3-4):160-4. Epub 2008 Apr 18. 

Photoreceptor mitochondrial oxidative stress in experimental autoimmune uveitis.

Saraswathy S, Rao NA.

Doheny Eye Institute, University of Southern California, Los Angeles, CA 90033,
USA.

In experimental autoimmune uveitis (EAU), the macrophages infiltrate the retina
during the late phase, 10-14 days after immunization with uveitogenic antigen,
causing photoreceptor damage. However, prior to inflammatory cell infiltration,
during the early phase (5-7 days after immunization), increased generation of
reactive oxygen and nitric oxide species was observed in the photoreceptor
mitochondria indicating oxidative stress. The oxidative-stress-induced nitration
of photoreceptor mitochondrial proteins and peroxidation of membrane lipids led
to activation and migration of microglia toward the photoreceptors. These
observations suggest oxidative stress could be an initial pathologic event
leading to amplification of inflammation inducing photoreceptor damage, thereby
causing clinical and histologic expression of uveitis in the form of
inflammatory cell infiltration. 2008 S. Karger AG, Basel.

Publication Types:
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov\'t

PMID: 18421232 [PubMed - in process]

20: Ophthalmic Res. 2008;40(3-4):154-9. Epub 2008 Apr 18. 

Evidence for extrathymic generation of regulatory T cells specific for a retinal
antigen.

Gregerson DS, Heuss ND, Lehmann U, McPherson SW.

Department of Ophthalmology, University of Minnesota, Minnesota, MN 55455-3007,
USA. grege001@umn.edu

BACKGROUND: Thymic expression of a photoreceptor cell antigen,
interphotoreceptor retinoid-binding protein, is known to generate regulatory T
cells (T(reg)) that prevent spontaneous autoimmune disease of the retina.
However, the contribution of other endogenous, tissue-specific antigens (Ags)
expressed in the retina to the generation of T(reg) is uncertain. METHODS:
Transgenic mice that express beta-galactosidase (beta-gal) in photoreceptor
cells, together with beta-gal-specific T cell receptor transgenic mice, were
used to study the induction of T(reg) in vivo. RESULTS: Transgenic expression of
beta-gal on the arrestin promoter led to a spontaneous immunoregulatory response
that inhibited the development of immune responses to beta-gal. The regulation
was transferred by CD3+4+25+ T(reg). Several strategies were then used to show
that beta-gal expressed in the retina supported spontaneous, thymus-independent
T(reg) development. The endogenous T(reg) also differed from the T(reg) induced
by Ag inoculation into the anterior chamber of the eye. CONCLUSION: These
results demonstrate that retinal expression of very small amounts of a
tissue-specific Ag can generate T(reg) in the periphery. 2008 S. Karger AG,
Basel.

Publication Types:
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov\'t

PMID: 18421231 [PubMed - in process]

21: Ophthalmic Res. 2008;40(3-4):151-3. Epub 2008 Apr 18. 

Equine recurrent uveitis--a spontaneous horse model of uveitis.

Deeg CA, Hauck SM, Amann B, Pompetzki D, Altmann F, Raith A, Schmalzl T,
Stangassinger M, Ueffing M.

Institute of Animal Physiology, LMU Munich, Munich, Germany.
deeg@tiph.vetmed.uni-muenchen.de

Equine recurrent uveitis (ERU) is an autoimmune disease that occurs with a high
prevalence (10%) in horses. ERU represents the only reliable spontaneous model
for human autoimmune uveitis. We already identified and characterized novel
autoantigens (malate dehydrogenase, recoverin, CRALBP) by analyzing the
autoantibody-binding pattern of horses affected by spontaneous recurrent uveitis
(ERU) to the retinal proteome. CRALBP also seems to be relevant to human
autoimmune uveitis. Proteomic screening of vitreous and retinal samples from ERU
diseased cases in comparison to healthy controls has led to the identification
of a series of differentially regulated proteins, which are functionally linked
to the immune system and the maintenance of the blood-retinal barrier. 2008 S.
Karger AG, Basel.

Publication Types:
    Research Support, Non-U.S. Gov\'t

PMID: 18421230 [PubMed - in process]

22: Ophthalmic Res. 2008;40(3-4):145-50. Epub 2008 Apr 18. 

Drainage of fluorescent liposomes from the vitreous to cervical lymph nodes via
conjunctival lymphatics.

Camelo S, Lajavardi L, Bochot A, Goldenberg B, Naud MC, Fattal E, Behar-Cohen F,
de Kozak Y.

Centre de Recherche des Cordeliers, Universite Pierre et Marie Curie-Paris 6,
France. serge.camelo@inserm.idf.fr

The use of liposomes as carriers for the delivery of biologically active
molecules into the eye is of major interest. Indeed, encapsulation of
biologically active molecules in liposomes may increase their bioavailability
and may induce a sustained release, thus avoiding repeated intraocular
injections and reducing side effects. We describe here the fate of
rhodamine-conjugated liposomes (Rh-Lip) injected into the vitreous of normal
Lewis rats. Twenty-four hours after intravitreal injection fluorescent liposomes
were detected in the vitreous, the inner layer of the retina and to a lesser
extent in the anterior segment of the eye. In addition, numerous Rh-Lip were
also observed in the episclera and conjunctival stroma, in conjunctival
lymphatic vessels and cervical lymph nodes (LN) draining the conjunctiva and the
eye. In the LN, Rh-Lip were taken up by resident macrophages adjacent to CD4+
and CD8+ T cells. Thus, intravitreal injection of anti-inflammatory drugs loaded
in liposomes could modulate the ocular immune microenvironment. In addition the
passage of drugs into the cervical LN could alter the immune status of these LN
and contribute to the regulation of intraocular inflammation. Our results
suggest that this phenomenon should be taken into account to design new
therapies based on intraocular drug administration. 2008 S. Karger AG, Basel.

Publication Types:
    Research Support, Non-U.S. Gov\'t

PMID: 18421229 [PubMed - in process]

23: Ophthalmic Res. 2008;40(3-4):141-4. Epub 2008 Apr 18. 

Rat models of autoimmune uveitis.

Wildner G, Diedrichs-Mohring M, Thurau SR.

Section of Immunobiology, Department of Ophthalmology, Medical Center of the
University of Munich, Ludwig-Maximilians-University, Munich, Germany.
Gerhild.Wildner@med.uni-muenchen.de

Experimental autoimmune uveitis (EAU) in Lewis rats is a well-established model
for human uveitis. During the last years we used this model to demonstrate
extraocular induction of uveitis by antigenic mimicry of environmental antigens
with retinal autoantigen and investigated the migration and intraocular
reactivation of autoreactive green fluorescent protein (GFP)+ T cells. We could
also elaborate several differences between EAU induced with S-antigen peptide
PDSAg or R14, a peptide derived from interphotoreceptor retinoid-binding
protein, suggesting two differently regulated diseases in the same rat strain.
R14-mediated EAU in Lewis rats has been shown to relapse, thus we have a new
model to test therapeutic approaches in an ongoing immune response instead of
just preventing disease. Finally, we show antigenic mimicry of PDSAg and an
HLA-B peptide for oral tolerance induction. After the successful first
therapeutic trial this approach will now proceed with international multicenter
clinical trials. 2008 S. Karger AG, Basel.

PMID: 18421228 [PubMed - in process]

24: Ophthalmic Res. 2008;40(3-4):136-40. Epub 2008 Apr 18. 

Experimental melanin-induced uveitis: experimental model of human acute anterior
uveitis.

Smith JR, Rosenbaum JT, Williams KA.

Department of Cell and Developmental Biology, Casey Eye Institute, Oregon Health
and Science University, Portland, OR 97239, USA. smithjus@ohsu.edu

Experimental melanin-protein-induced uveitis (EMIU), which is also known as
experimental autoimmune anterior uveitis, was first described in 1993 by
Broekhuyse et al. This experimental uveitis may be induced in certain inbred and
outbred rat strains by immunization with bovine ocular melanin. The inflammation
shares clinical features with human acute anterior uveitis. The duration of the
first episode is approximately 1 month. Spontaneous recovery to a near normal
clinical state is the rule, but multiple recurrences are common. Slit-lamp
biomicroscopic examination reveals a florid anterior-chamber reaction, with
formation of a retro-iridal empyema, fibrin clots and posterior synechiae. At a
microscopic level, leukocytic infiltration is first observed in the anterior
uvea. Although this tissue remains the site of maximum inflammation throughout
an attack, in severe cases, limbitis, vitritis and choroiditis are also
observed. Abrogation of EMIU occurs after treatment with anti-CD4 antibody,
indicating that the uveitis is controlled by CD4-positive T cells. Several
research groups have used EMIU to investigate various aspects of the
pathogenesis of acute anterior uveal inflammation, including the participation
of different leukocyte subsets, the expression of cell adhesion molecules,
cytokines, chemokines and nitric oxide, the role of complement and the impact of
apoptosis. In addition, EMIU has also been used to evaluate various biologic
interventions with potential implications for the treatment of human disease.
2008 S. Karger AG, Basel.

Publication Types:
    Research Support, Non-U.S. Gov\'t

PMID: 18421227 [PubMed - in process]

25: Ophthalmic Res. 2008;40(3-4):129-35. Epub 2008 Apr 18. 

Animal models of Vogt-Koyanagi-Harada disease (sympathetic ophthalmia).

Yamaki K, Ohono S.

Department of Ophthalmology, Chiba Hokusoh Hospital, Nippon Medical School,
Chiba, Japan. kyamaki@nms.ac.jp

BACKGROUND/AIMS: We aimed to establish the animal model of Vogt-Koyanagi-Harada
disease (VKH). METHODS: Rats, Akita dogs and monkeys were immunized with the
peptides derived from tyrosinase-related protein 1. Each experimental animal was
examined clinically and histologically. RESULTS AND CONCLUSION: The rats
developed ocular and extraocular inflammation homologous to human VKH by
immunization of tyrosinase-related protein 1. The Akita dogs also developed the
autoimmune disease almost similar to the spontaneously emerging dog VKH
equivalent to human VKH. The monkeys developed similar clinical findings as
human VKH. These models may serve as human VKH models. 2008 S. Karger AG, Basel.

PMID: 18421226 [PubMed - in process]

26: Ophthalmic Res. 2008;40(3-4):124-8. Epub 2008 Apr 18. 

Ccl2/Cx3cr1-deficient mice: an animal model for age-related macular
degeneration.

Chan CC, Ross RJ, Shen D, Ding X, Majumdar Z, Bojanowski CM, Zhou M, Salem N Jr,
Bonner R, Tuo J.

Section of Immunopathology, Laboratory of Immunology, National Eye Institute,
Bethesda, MD 20892-1857, USA. chanc@nei.nih.gov

BACKGROUND/AIMS: Senescent Ccl2-/- mice develop cardinal features of human
age-related macular degeneration (AMD). Loss-of-function single-nucleotide
polymorphisms within CX3CR1 are associated with AMD. METHODS: We generated
Ccl2-/-/Cx3cr1-/- [double-knockout (DKO)] mice and evaluated the eyes using
fundoscopy routine histology, immunochemistry, biochemistry and proteomics.
RESULTS: At 6 weeks old, all DKO mice developed AMD-like retinal lesions such as
abnormal retinal pigment epithelium cells, drusen, photoreceptor atrophy and
choroidal neovascularization, which progressed with age and reversed with high
omega-3 long-chain polyunsaturated fatty acid diet.
N-retinylidene-N-retinylethanolamine (A2E), a major lipofuscin fluorophore,
illustrated by an emission peak at approximately 600 nm, was significantly
higher in DKO retinal pigment epithelium. Decreased ERp29 was found in the
retina of DKO mice. CONCLUSION: A broad spectrum of AMD pathologies with early
onset and high penetrance in these mice implicate certain chemokines, A2E and
endoplasmic reticulum proteins in AMD pathogenesis. 2008 S. Karger AG, Basel.

PMID: 18421225 [PubMed - in process]

27: Ophthalmic Res. 2008;40(3-4):120-3. Epub 2008 Apr 18. 

Lack of alphavbeta5 integrin receptor or its ligand MFG-E8: distinct effects on
retinal function.

Nandrot EF, Finnemann SC.

Department of Ophthalmology, Dyson Vision Research Institute, New York, NY
10065, USA.

BACKGROUND/AIMS: Diurnal phagocytosis of spent photoreceptor outer segment
fragments by the retinal pigment epithelium (RPE) is critical for vision. We
recently identified an important role for alphavbeta5 integrin receptors and
their ligand Milk fat globule-EGF factor 8 (MFG-E8) in RPE phagocytosis.
METHODS: We compared RPE phagocytosis and retinal function between mice
deficient in alphavbeta5 integrin receptors and mice deficient in the secreted
integrin ligand MFG-E8. RESULTS: Both beta5-/- and MFG-E8-/- mice exhibit the
same phagocytic defect: RPE cells retain basal uptake activity but completely
lack the burst of phagocytic activity as well as the rhythmic activation of Mer
tyrosine kinase that follow circadian photoreceptor shedding in wild-type RPE.
Strikingly, electroretinogram photoresponses decline with age only in beta5 -/-
but not in MFG-E8-/- retina. CONCLUSION: These results identify a critical role
of alphavbeta5 integrin receptors and their ligand MFG-E8 in synchronizing
retinal phagocytosis. Additionally, we show that lack of alphavbeta5 receptors
and MFG-E8 ligand have distinct consequences for retinal function. These
intriguing results suggest that loss of phagocytic rhythm is not solely
responsible for the age-related blindness of beta5-/- mice. 2008 S. Karger AG,
Basel.

Publication Types:
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov\'t

PMID: 18421224 [PubMed - in process]

28: Ophthalmic Res. 2008;40(3-4):115-9. Epub 2008 Apr 18. 

Lipid-bloated subretinal microglial cells are at the origin of drusen appearance
in CX3CR1-deficient mice.

Raoul W, Feumi C, Keller N, Lavalette S, Houssier M, Behar-Cohen F, Combadiere
C, Sennlaub F.

Inserm, UMR S 872, Centre de Recherche des Cordeliers, Paris, France.

Drusen, the white yellowish deposits that can be seen in funduscopy, are a
hallmark of age-related macular degeneration. Histologically, drusen are
believed to be dome-shaped or more confluent lipid accumulations between the
retinal pigment epithelium and the choriocapillaries. Recent advances in mouse
funduscopy have revealed the presence of drusen-like structures in chemokine
knockout animals in the absence of sizeable dome-shaped material below the
retinal pigment epithelium. We show that aged CX3CR1-/- mice present with
drusen-like appearance in funduscopy that is associated with a progressive
age-related microglial cell accumulation in the subretinal space. We demonstrate
that the anatomical equivalent of the drusen-like appearance in these mice are
lipid-bloated subretinal microglial cells rather than subretinal pigment
epithelium deposits [Combadiere C, et al: J Clin Invest 2007;117:2920-2928].
2008 S. Karger AG, Basel.

Publication Types:
    Research Support, Non-U.S. Gov\'t

PMID: 18421223 [PubMed - in process]

29: Ophthalmic Res. 2008;40(3-4):113-4. Epub 2008 Apr 18. 

Editorial.

Bodaghi B, de Kozak Y, Lehoang P, Rao NA.

Publication Types:
    Editorial
    Introductory Journal Article

PMID: 18421222 [PubMed - in process]