MACULAR HOLE FORMATION AFTER PARS PLANA VITRECTOMY FOR PRIMARY VITREORETINAL LYMPHOMA.

PURPOSE: To report a case of primary vitreoretinal lymphoma in which a macular hole developed after a diagnostic pars plana vitrectomy. METHODS: A retrospective interventional case report. RESULTS: A 65-year-old woman presented with worsening vision in the left eye. Fundus examination showed vitreous haze and multifocal, yellow-white infiltrates in the retina and under the retinal pigment epithelium in the left eye. She underwent a diagnostic pars plana vitrectomy in that eye. Undiluted vitreous specimen showed an increased interleukin-10 level (1,470 pg/mL) with an elevated interleukin-10 to interleukin-6 ratio of 15.1; cytologic analysis of the vitreous showed atypical lymphoid cells with large irregular nuclei and scanty cytoplasm. The retinal and sub-retinal pigment epithelial infiltrates responded well to intravitreal methotrexate injections, but a macular hole developed in the left eye. The second pars plana vitrectomy with internal limiting membrane peeling and 20% sulfur hexafluoride gas tamponade successfully closed the macular hole. CONCLUSION: Macular hole closure can be accomplished in eyes receiving intravitreal methotrexate injections for treating primary vitreoretinal lymphoma.

The role of soluble TNF receptors for TNF-alpha in uveitis.

PURPOSE: To investigate the presence of soluble tumor necrosis factor receptors (sTNF-Rs) and TNF-alpha in the ocular fluids of patients with uveitis and the capacity of sTNF-Rs to affect TNF-alpha production by intraocular T cells. METHODS: Ocular fluid samples were collected from patients with active and inactive uveitis, as well as from control subjects without uveitis. The sTNF-Rs and TNF-alpha levels were measured by enzyme-linked immunosorbent assay (ELISA). T-cell clones (TCCs) were established from intraocular infiltrating cells, and the TCCs were cocultured with recombinant sTNF-Rs or TNF-alpha. The supernatants were measured by ELISA. The neutralization of sTNF-R production by TCCs was evaluated with an anti-human TNF-R antibody. RESULTS: Significantly higher amounts of sTNF-R1 and -R2 were present in the ocular fluids of patients with active uveitis than in the ocular fluids of those with inactive uveitis and in control subjects. Significantly higher amounts of TNF-alpha were present in the ocular fluids of patients with active uveitis than in those with inactive uveitis. Recombinant sTNF-Rs enhanced TNF-alpha production by TCCs in a dose-dependent manner. Similarly, recombinant TNF-alpha enhanced sTNF-Rs production by the TCCs, and production was neutralized with anti-human TNF-R antibody. CONCLUSIONS: sTNF-Rs are present in the ocular fluids of patients with uveitis. Intraocular levels of sTNF-Rs are significantly increased in patients with uveitis, particularly in those with active uveitis. The data suggest that intraocular sTNF-Rs may play a regulatory role in ocular inflammation such as occurs in uveitis.

Ocular infiltrating CD4+ T cells from patients with Vogt-Koyanagi-Harada disease recognize human melanocyte antigens.

PURPOSE: To determine whether patients with Vogt-Koyanagi-Harada (VKH) disease have immune responses specific to the melanocyte antigens tyrosinase and gp100. METHODS: T-cell clones (TCCs) were established from cells infiltrating the aqueous humor and from peripheral blood mononuclear cells (PBMCs) of patients with VKH. The target cells were LDR4-transfected cells (HLA-DRB1*0405). The TCCs were cocultured with LDR4 in the presence of tyrosinase (tyrosinase450-462: SYLQDSDPDSFQD), gp100 (gp100(44-59): WNRQLYPEWTEAQRLD), or a control peptide. The immune response was evaluated by cytokine production. The responding melanocyte peptide-specific VKH-TCCs were characterized by an immunofluorescence method with flow cytometry. A search was made for molecular mimicry among tyrosinase450-462, gp100(44-59), and exogenous antigens, such as viruses, by database screening. RESULTS: Cells infiltrating the eye and PBMCs in HLA-DR4+ (HLA-DRB1*0405, 0410) patients with VKH contained a population of CD4+ T lymphocytes that recognized tyrosinase and gp100 peptides and produced RANTES and IFN-gamma in response to the two peptides. The T cells were active memory Th1-type lymphocytes, and they recognized the tyrosinase peptide and produced IFN-gamma in response to HLA-DRB1*0405+ melanoma cells. Cytomegalovirus envelope glycoprotein H (CMV-egH290-302) had high amino acid homology with the tyrosinase peptide. In addition, some of the VKH-TCCs recognized CMV-egH290-302 peptide, as well as the tyrosinase peptides. CONCLUSIONS: In VKH there are tyrosinase and gp100 peptide-specific T cells that can mediate an inflammatory response. Such melanocyte antigen-specific T cells could be associated with the cause and pathology of VKH disease.

The presence of macrophage migration inhibitory factor in human trabecular meshwork and its upregulatory effects on the T helper 1 cytokine.

PURPOSE: To investigate the expression and secretion of macrophage migration inhibitory factor (MIF) in human trabecular meshwork (HTM) and evaluate its role in ocular inflammation. METHODS: Tissue samples of HTM cells were isolated from donor human eyes or corneoscleral buttons, and the HTM cells were cultured. The expression of MIF on HTM cells was evaluated by RT-PCR, Western blot analysis, and ELISA. T-cell clones (TCCs) were established from ocular infiltrating cells of patients with uveitis. ELISA was used to evaluate the pathologic role of MIF, in relation to regulatory effects on cytokine production by T cells. RESULTS: MIF was detected in the HTM by RT-PCR and Western blot analysis. MIF was also shown by ELISA to be secreted by the HTM cells in culture. The HTM supernatant enhanced IFN-gamma production by TCCs, but not IL-10; and these effects were neutralized by anti-MIF antibodies. Similarly, recombinant MIF enhanced the IFN-gamma production by the TCCs. CONCLUSIONS: MIF is expressed and secreted in the HTM, and MIF has the capacity to enhance T helper 1 cytokines and may play a role as an inflammatory cytokine in the eye.

Spectral-domain optical coherence tomography of the choroid in choroidal osteoma.

The authors report spectral-domain optical coherence tomography (SD-OCT) findings in a patient with decalcifying choroidal osteoma accompanied by a choroidal neovascular membrane and serous retinal detachment. A 13-year-old girl was found to have a choroidal osteoma in the left eye. The clinical diagnosis was confirmed by B-scan ultrasonography, computed tomography, and fluorescein and indocyanine green angiography. The SD-OCT findings over the decalcified portion included serous retinal detachment, photoreceptor outer segment disorganization, retinal pigment epithelial atrophy, deformed Bruch's membrane, and choroidal neovascular membrane. In contrast, the retinal structures over the calcified portion appeared to be preserved. SD-OCT showed loss of a vascular appearance and increased thickness in the affected choroid, especially in the decalcified portion. Choroidal thickening may be associated not only with choroidal osteomas, but also with tumor decalcification. These unique features on SD-OCT may be important in understanding poor visual prognosis when decalcification involves the fovea.

Phase I clinical study of NMK36: a new PET tracer with the synthetic amino acid analogue anti-[18F]FACBC.

OBJECTIVE: NMK36 is a novel PET tracer containing a synthetic amino acid analogue anti-[(18)F]FACBC as the active ingredient, and is under development for the use of tumor diagnosis. A Phase I clinical study of NMK36 was conducted to evaluate its safety, biodistribution, and radiation dosimetry in healthy volunteers. METHODS: Six healthy volunteers (Japanese male) received a bolus injection of NMK36 (174.4-201.4 MBq) intravenously. The safety of NMK36 was evaluated by monitoring signs/symptoms, electrocardiography, recording vital signs, and laboratory examinations at baseline and several time points in 6 days after injection. A total of 11 whole-body PET-CT scans were acquired up to 4 h post-injection, and venous blood and urine samples were also collected for 6 and 24 h post-injection, respectively. Based on the results of the biodistribution study, absorbed radiation dose was estimated by the MIRD method. RESULTS: Although two adverse events occurred after the injection of NMK36, they were mild and disappeared without any specific treatment. NMK36 preferentially accumulated in the pancreas and liver early after injection, followed by rapid clearance from the pancreas. Persistent uptake was observed in the skeletal muscle. NMK36 showed low uptake in the brain, and its urinary excretion was limited (5.40 ± 1.43% of the injected dose at 24 h post-injection). The liver was the critical organ, with a mean absorbed dose of 40.6 µGy/MBq. The estimated effective dose of NMK36 was 13.8 µSv/MBq, which was similar to or lower than those of radiotracers approved for clinical use including [(18)F]FDG. CONCLUSIONS: The findings of this study indicate that NMK36 is well tolerated. NMK36 has favorable characteristics for imaging brain and pelvic tumors, such as low brain uptake, slow urinary excretion, and high in vivo stability.

Cross-reaction between tyrosinase peptides and cytomegalovirus antigen by T cells from patients with Vogt-Koyanagi-Harada disease.

AIM: To determine whether T lymphocytes of patients with Vogt-Koyanagi-Harada (VKH) disease cross-react with peptides of melanocytes and with exogenous antigens. METHODS: Cross-reactivity with melanocyte peptides, tyrosinase (tyrosinase(450-462): SYLQDSDPDSFQD) and the mimic virus peptide, i.e., cytomegalovirus envelope glycoprotein H (CMV-egH(290-302): SYLKDSDFLDAAL) was examined by a lymphocyte proliferation assay or cytokine production. The seroprevalence of various viruses was examined by a complement fixation test. To examine if the virus infections in VKH patients were latent, we measured genomic DNA of the virus using real-time polymerase chain reaction (PCR). RESULT: Some of the T cells established from VKH recognized melanocyte peptides including the tyrosinase peptide as well as the CMV-egH(290-302) peptide, which had a high amino acid homology to the tyrosinase peptide. Cytomegalovirus (CMV) peptide-specific T cells showed a significant proliferation not only to CMV-egH(290-302) but also to tyrosinase(450-462). The seroprevalence of CMV was significantly higher in VKH patients. In addition, all tested samples of VKH patients were negative for CMV-DNA. CONCLUSIONS: These results indicate that CMV infection may stimulate the production of T cells that cross-react with tyrosinase by a mechanism of molecular mimicry. These events may be responsible for the onset of VKH disease.