There is no known underlying genetic defect predisposing patients ? to develop primary intraocular lymphoma (PIOL). Discovery of genetic ? factors predisposing to the development of PIOL would be of benefit for ? early diagnosis, prognostic staging, and development of novel treatments ? for PIOL. The interleukins are a specific pathway of interest ? because previous research has demonstrated derangements in the ratios of ? interleukins 10 and 6 in the vitreous humor and spinal fluid of patients ? with PIOL, leading to the hypothesis that altered function or expression ? of these or other interleukins could permit the development of this rare ? malignancy. We investigated the use of a CD-22/pseudomonas construct in order to kill intraocular tumor. Human primary intraocular lymphoma (PIOL) is predominantly a B celloriginated malignant disease with no appropriate animal models and effective therapies available. This study aimed to establish a mouse model to closely mimic human B-cell PIOL and to test the therapeutic potential of a recently developed immunotoxin targeting human B-cell lymphomas. Human B-cell lymphoma cells were intravitreally injected into severe combined immunodeficient mice.The resemblance of this tumor model to human PIOL was examined by fundoscopy, histopathology, immunohistochemistry, and evaluated for molecular markers. The therapeutic effectiveness of immunotoxin HA22 was tested by injecting the drug intravitreally. Results showed that the murine model resembles human PIOL closely. Pathologic examination revealed that the tumor cells initially colonized on the retinal surface, followed by infiltrating through the retinal layers, expanding preferentially in the subretinal space, and eventually penetrating through the retinal pigment epithelium into the choroid. Tumor metastasis into the central nervous system was also observed. A single intravitreal injection of immunotoxin HA22 after the establishment of the PIOL resulted in complete regression of the tumor. This is the first report of a murine model that closely mimics human B-cell PIOL. The results of B cellspecific immunotoxin therapy may have clinical implications in treating human PIOL. We are now evaluating the ocular effects of intravitreal immunotoxin HA22 on twelve New Zealand albino rabbits evaluating toxicity via electroretinography and clinical exam over 12 weeks. Eventually, we hope to do a phase I/II trials to evaluate this immunotoxin as an alternative, localized therapy for PIOL. ? Autofluorescence of intraocular lymphoma of B cell lineage. Uveitis patients with active posterior and intermediate disease have inflammatory cells in their vitreous; those with primary intraocular lymphoma have malignant B-lymphoma cells concomitantly. These cell types cannot be distinguished clinically. The goal of this study was to investigate intrinsic autofluorescence as a non-invasive way of differentiating immune and lymphomatous cell populations. Human T-cells were purified from and cultured with or without anti-CD3 plus anti-CD28 stimulation. A B-lymphoma cell line (CA46) was cultured separately. Five experimental groups were prepared: unstimulated T-cells, stimulated T-cells, CA46 cells, stimulated T-cells mixed with CA46 cells at a ratio of 1:3, or mixed at a ratio of 3:1. Samples were excited with several excitation wavelengths and imaged with a confocal microscope. For each condition, the autofluorescence intensity emitted from the sample was measured over a range of wavelengths. In separate experiments, T-cells or CA46 cells were injected into the anterior chamber of a Balb/C mouse eye and autofluorescence was measured. Pure T-cell and lymphomatous populations were clearly distinguishable based on autofluorescence intensity spectra. Lymphomatous cells were the least fluorescent when excited with 351nm light, but most fluorescent when excited with longer wavelengths like 488nm. Mixed populations of T- and B-lymphoma cells had emission intensities that fell predictably in-between those of the pure populations. Normal activated as well as malignant lymphocyte populations can be distinguished based on their autofluorescent properties.
| Palmer, Douglas C; Chan, Chi-Chao; Gattinoni, Luca et al. (2008) Effective tumor treatment targeting a melanoma/melanocyte-associated antigen triggers severe ocular autoimmunity. Proc Natl Acad Sci U S A 105:8061-6 |
| Cortes, Lizette M; Mattapallil, Mary J; Silver, Phyllis B et al. (2008) Repertoire analysis and new pathogenic epitopes of IRBP in C57BL/6 (H-2b) and B10.RIII (H-2r) mice. Invest Ophthalmol Vis Sci 49:1946-56 |
| Kurup, Shree K; Levy-Clarke, Grace; Calvo, Katherine R et al. (2007) Primary diffuse large B-cell lymphoma of the spleen with coincident serous retinal detachments responsive to corticosteroids. Clin Experiment Ophthalmol 35:468-72 |
| O'Mahony, Deirdre; Morris, John C; Quinn, Cate et al. (2007) A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy. Clin Cancer Res 13:958-64 |
| Wallace, Dana J; Altemare, Chandra R; Shen, De Fen et al. (2006) Primary testicular and intraocular lymphomas: two case reports and a review of the literature. Surv Ophthalmol 51:41-50 |
| Nussenblatt, Robert B; Chan, Chi-Chao; Wilson, Wyndham H et al. (2006) International Central Nervous System and Ocular Lymphoma Workshop: recommendations for the future. Ocul Immunol Inflamm 14:139-44 |
| Li, Zhuqing; Mahesh, Sankaranarayana P; Shen, De Fen et al. (2006) Eradication of tumor colonization and invasion by a B cell-specific immunotoxin in a murine model for human primary intraocular lymphoma. Cancer Res 66:10586-93 |
| Wallace, Dana J; Shen, DeFen; Reed, George F et al. (2006) Detection of the bcl-2 t(14;18) translocation and proto-oncogene expression in primary intraocular lymphoma. Invest Ophthalmol Vis Sci 47:2750-6 |
| Levy-Clarke, Grace A; Chan, Chi-Chao; Nussenblatt, Robert B (2005) Diagnosis and management of primary intraocular lymphoma. Hematol Oncol Clin North Am 19:739-49, viii |
| Wolf, Lesley A; Reed, George F; Buggage, Ronald R et al. (2003) Vitreous cytokine levels. Ophthalmology 110:1671-2 |
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