Primary Intraocular Lymphoma and Animal Models

原发性眼内淋巴瘤和动物模型

• 批准号: 8938307
• 负责人: Robert Nussenblatt
• 金额: $ 4.12万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8938307
• 关键词: Animal Model; B-Cell Lymphomas; B-Lymphocytes; Cells; Cerebrospinal Fluid; Choroid; Clinic; Clinical; Development; Disease; Disease model; Early Diagnosis; Eye; Genetic; Histopathology; Human; Immunohistochemistry; Immunotoxin Therapy; Immunotoxins; Interleukin-10; Interleukins; Intraocular Lymphoma; Local Therapy; Malignant - descriptor; Malignant Neoplasms; Methods; Modeling; Mus; Mutation; Neoplasm Metastasis; Neuraxis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I/II Trial; Predisposing Factor; Pseudomonas; Reporting; Research; Retinal; SCID Mice; Staging; Structure of retinal pigment epithelium; Surface; Techniques; Testing; Therapeutic; Vitreous humor; effective therapy; human tissue; interest; intravitreal injection; killings; molecular marker; mouse model; neoplastic cell; novel; prognostic; therapeutic effectiveness; tumor

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 hoping to develop new methods to visualize the tumor in the human eye using techniques available in the clinic, such as OCT. The long term plan is to do a phase I/II trials to evaluate this immunotoxin as an alternative, localized therapy for PIOL.

没有已知的潜在遗传缺陷使患者易患原发性眼内淋巴瘤（PIOL）。发现易致PIOL发展的遗传因素将有利于PIOL的早期诊断、预后分期和开发新的治疗方法。白细胞介素是一种特殊的途径，因为先前的研究表明，PIOL患者的玻璃体体液和脊髓液中白细胞介素10和6的比例失调，导致这些或其他白细胞介素的功能或表达改变可能导致这种罕见疾病的发展