Pathobiology of SAIDS-Associated Lymphomas

描述(申请人提供)：非霍奇金淋巴瘤(NHL)是与艾滋病相关的第二常见癌症。恒河猴体内的猿猴艾滋病(SAID)为这种疾病提供了一个有用和有用的动物模型。SAIDs相关淋巴瘤发生在猕猴身上，其发病率和其他特征与人类AIDS-NHL相似。有效利用SAID-淋巴瘤模型进行活体研究的一个主要障碍是发病率低(约4%)。在之前的资助期间，开发了一个初步的统计模型，该模型确定了一组可能预测SIV感染动物中淋巴瘤的临床和实验室因素。这些因素包括B细胞和T细胞的绝对和相对计数，它们的变化率，明显的周围淋巴肿大的证据和持续性，SIV抗原血症及其变化率。其他变量也可能与此有关，包括接种时的年龄或与其他病毒的混合感染，包括恒河猴淋巴病毒(RhLCV)或恒河猴横纹病毒(RRV)。目标1建议对这些预报器的效用进行严格和系统的测试。将根据对风险标准的遵守来确定淋巴瘤的高危动物。将对这些动物和匹配的对照组进行临床、免疫学和病毒学参数以及疾病结局的监测。预测因素的识别是令人兴奋的，因为它表明了预测哪些感染SIV的动物可能患上淋巴瘤，并可能转化为AIDS-NHL。这项工作的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。针对特定细胞因子相互作用的初步研究表明：(1)肿瘤细胞对转化生长因子-131介导的生长抑制仍然敏感；(2)IL-6治疗可刺激淋巴瘤细胞的生长；(3)IL-6治疗可使淋巴瘤细胞免于受到转化生长因子-131的抑制。在目标2中提出的研究是详细说明转化生长因子-131和白介素6对淋巴瘤来源的细胞系产生独立和交互影响的机制。清楚地了解这些细胞因子影响淋巴瘤细胞正向和负向生长调节的机制可能有助于开发调节其作用的治疗剂。

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.