Pathobiology of SAIDS-Associated Lymphomas

描述（由申请人提供）：非霍奇金淋巴瘤（NHL）是第二个最常见的与艾滋病相关的癌症。猴艾滋病（SAIDS）在恒河猴提供了一个有用的和信息丰富的动物模型，这种疾病。SAIDS相关淋巴瘤发生在猕猴中，其发病率和其他特征与人类AIDS-NHL相当。有效使用SAIDS-淋巴瘤模型进行体内研究的一个主要障碍是发病率低（约4%）。在上一个资助期间，开发了一个初步的统计模型，确定了一组临床和实验室因素，有可能预测SIV感染动物的淋巴瘤。这些因素包括绝对和相对B-和T-细胞计数，它们的变化率，明显的外周淋巴结肿大的证据和持续性，SIV抗原血症及其变化率。其他变量也可能存在关联，包括接种时的年龄或与其他病毒（包括恒河猴淋巴隐病毒（RhLCV）或恒河猴脊灰病毒（RRV））的合并感染。在目标1中提出的是对这些预测因子的效用进行严格和系统的测试。根据对风险标准的依从性，识别淋巴瘤高风险动物。将监测这些动物和匹配对照的临床、免疫学和病毒学参数以及疾病结局。预测因子的识别是令人兴奋的，因为它表明预测哪些SIV感染的动物可能发展为淋巴瘤的潜力，并且可能转化为AIDS-NHL。这项工作的一个长期目标是利用动物模型开发新的治疗方法，特别是那些基于调节淋巴瘤细胞生长的生理机制的方法。集中于特异性细胞因子相互作用的初步研究表明，（i）肿瘤细胞对TGF-131介导的生长抑制保持敏感，（ii）IL-6处理刺激淋巴瘤细胞的生长，和（iii）IL-6处理从TGF-131介导的抑制中拯救淋巴瘤细胞。目的2中提出的研究是详细说明TGF-131和IL-6对淋巴瘤衍生细胞系发挥独立和相互作用影响的机制。对这些细胞因子影响1）淋巴瘤细胞的正性和负性生长调节的机制的清楚理解可以有助于调节其作用的治疗剂的开发。

DESCRIPTION (provided by applicant): Non-Hodgkin's lymphoma (NHL) is the second most frequent cancer associated with AIDS. Simian AIDS (SAIDS) in the rhesus macaque offers a useful and informative animal model for this disease. SAIDS-associated lymphoma occurs in the macaque with an incidence and other features comparable to human AIDS-NHL. A major obstacle to the effective use of the SAIDS-lymphoma model for in vivo studies is the low incidence (approximately 4%). During the previous funding period, an initial statistical model was developed that identified a set of clinical and laboratory factors with the potential to predict lymphoma in SIV-infected animals. Those factors include absolute and relative B- and T-cell counts, their rates of change, evidence and persistence of marked peripheral lymph node enlargement, SIV antigenemia and its rate of change. Other variables may also be linked, including age at inoculation or co-infections with other viruses including rhesus lymphocryptovirus (RhLCV) or rhesus rhadinovirus (RRV). Proposed in Aim 1 is a rigorous and systematic test of the utility of those predictors. Animals at high risk for lymphoma will be identified based on adherence to the risk criteria. Those animals and matched controls will be monitored for clinical, immunologic and virologic parameters as well as for disease outcome. The identification of predictive factors is exciting because it indicates the potential to forecast which SIV-infected animals are likely to develop lymphoma, and may be translatable to AIDS-NHL. A long-term objective of the work is to use the animal model for development of novel therapeutic approaches, especially those based on physiologic mechanisms that regulate the growth of lymphoma cells. Preliminary studies focused on specific cytokine interactions indicated that (i) tumor cells remain sensitive to TGF-131- mediated growth inhibition, (ii) IL-6 treatment stimulates growth of lymphoma cells, and (iii) IL-6 treatment rescues lymphoma cells from TGF-131-mediated inhibition. Proposed in Aim 2 are studies to detail the mechanisms by which TGF-131and IL-6 exert independent and interacting influences on lymphoma-derived cell lines. A clear understanding of the mechanisms by which these cytokines effect positive and negative growth regulation of 1) lymphoma cells could contribute to the development of therapeutic agents that modulate their action.