Primary Intraocular Lymphoma and Animal Models

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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. Until recently, genetic approaches to investigate the etiology of cancer have relied upon methods utilizing linkage based on traditional Mendelian inheritance patterns. It is probable that many diseases are a consequence of multiple genetic factors, and are therefore less amenable to study using traditional methods of linkage analysis and positional cloning to isolate single genes. Single nucleotide polymorphisms (SNPs) are the most common sources of variation in the human genome. SNPs are single-base differences in the DNA sequence that can be observed among individuals in a population. A SNP is defined on the basis of a frequency of at least 1% prevalence in one or more populations. SNPs are present throughout the genome at an average frequency of 1/1000 base pairs. We propose to analyze the frequency of SNPs specifically within the coding frames of biologically plausible genes responsible for function of the innate immune system. 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. Samples continue to be collected, but as no results have yet been obtained. We hosted a workshop on this subject at the NIH this past fiscal year with the results recently published. Since recruitment for this study was very slow we have made the decision to suspend this study. However, we received a Bench to Bedside award to begin to investigate the use of a CD-22/pseudomonas construct in order to kill intraocular tumor. Initial studies have been promising with our plan to carry these further in animal studies and ultimately to the treatment of patients. From 2005 to 2007, we have made substantial progress in establishing a murine model to mimic human PIOL as well as searching for novel and effective therapy for this disease. We have established a mouse model that resembles human PIOL at the level of histopathology and molecular pathogenesis. We demonstrated that the model shares several hall mark characteristics of human PIOL and is ideal for further studying the molecular mechanisms of human PIOL. Furthermore, in collaboration with NCI, we found that a recently developed immunotoxin (HA22) can eradicate the tumor with minimal toxicity and is potentially a novel therapeutic agent for treating human PIOL. Currently, we are investigating the toxicity of HA22 to ocular tissues using a rabbit model.