(PQ 6) New Models of KSHV Oncogenesis and KS Immune Environment

项目 总结 卡波西 共同 (KSHV, 卡斯尔曼氏 KSHV相关 细胞 相关 的 许多 被 表面上 ex 将 肉瘤（KS）是全球艾滋病毒感染者中最常见的癌症，也是最常见的癌症之一。 撒哈拉以南非洲的癌症，由卡波西肉瘤疱疹病毒感染引起 也称为HHV-8）。这种病毒也会引起原发性渗出性淋巴瘤（PEL）和多中心淋巴瘤。 疾病（MCD）。虽然PEL是罕见的，但它是一种侵袭性恶性肿瘤，治疗选择很少。 疾病很难建模，因为这种病毒是物种特异性的， 在培养物中，体外感染经常导致潜伏性和裂解性病毒基因表达的混合， 动物病毒不会引起相同的病理。此外，KS病变由混合物组成， 包括潜伏性KSHV感染的梭形细胞和混合炎性浸润，包括 CD 8+和CD 4 + T细胞、浆细胞、巨噬细胞和肥大细胞。虽然大量的注意力 考虑到梭形细胞的组织发生，KS病变中的免疫浸润仅是 不完整的描述。总体目标是该应用程序是在体外开发临床前， KSHV相关疾病的体内和体内模型，包括KS、MCD和淋巴瘤。为了建立KS模型，我们 应用从人类病变的观察，并包括这种疾病的免疫因素。这将是 通过以下具体目标来实现：1）在大肠杆菌中条件性表达主要的潜伏转录物基因， 免疫活性小鼠; 2）检查 体外和离体卡波西肉瘤样组织工程 用于健康和患病的原代内皮细胞的受控生长的小生境。我们将研究 在这些模型中的一线治疗方法，靶向治疗和免疫治疗，以验证它们的 临床前使用。 主要 免疫 子集 在 小鼠; 肿瘤免疫环境在KS患者皮损中的作用及检测 和3）

PROJECT SUMMARY Kaposi's common (KSHV, Castleman's KSHV-associated cells related of numerous been superficially ex will sarcoma (KS) is the most common cancer globally in people living with HIV, and among the most cancers in Sub-Saharan Africa, and is caused by infection by the Kaposi sarcoma herpesvirus also called HHV-8). This virus also causes primary effusion lymphoma (PEL) and multicentric disease (MCD). While PEL is rare, it is an aggressive malignancy with few therapeutic options. diseases are difficult to model because this virus is species-specific, it does not transform in in culture, in vitro infection frequently leads to a mixture of latent and lytic viral gene expression, and animal viruses do not cause the same pathologies. Furthermore, KS lesions are composed of a mixture cells that include latently KSHV-infected spindle cells and a mixed inflammatory infiltrate that includes CD8+ and CD4+ T cells, plasma cells, macrophages, and mast cells. While substantial attention has given to the histogenesis of the spindle cells, the immune infiltrates in KS lesions have only been and incompletely described. The overarching goal is this application is develop preclinical in vitro, vivo and in vivo models of KSHV-associated diseases, including KS, MCD and lymphoma. To model KS, we applyobservations from human lesions, and include the immune elements of this disease. This will be accomplished through the following specific aims: 1) conditional expression of major latency transcript genes in immunocompetent mice; 2) examine of engineer synthetic, in vitro and ex vivo Kaposi sarcoma-like tissue niches for controlled growth of healthy and diseased primary endothelial cells. We will examine the effects of first line therapeutic approaches, targeted therapy and immunotherapy in these models to validate them for preclinical use. major immune subsets in mice; the tumor immune environment in KS lesions in patients and test the role and 3)