Gamma/Delta T Cells Surveillance of B Lymphoma in AIDS

艾滋病中 B 淋巴瘤的 Gamma/Delta T 细胞监测

• 批准号: 7002574
• 负责人: C. David Pauza
• 金额: $ 23.46万
• 依托单位: UNIVERSITY OF MD BIOTECHNOLOGY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7002574
• 关键词: AIDS; AIDS therapy; B cell lymphoma; T cell receptor; T lymphocyte; antiviral agents; biomarker; cell population study; clinical research; combination chemotherapy; cytotoxicity; flow cytometry; heat shock proteins; human tissue; leukocyte count; lymphocyte; monocyte; natural killer cells; neoplasm /cancer immunology; neoplastic process; phenotype; protein structure function; toll like receptor; virus cytopathogenic effect; virus related neoplasm /cancer

DESCRIPTION (provided by applicant): B cell Non-Hodgkin's lymphoma (B NHL) affects 5-10% of people with HIV/AIDS, a rate approximately 1,000 times higher than that observed for HIV-negative individuals. Even as the incidence of Kaposi's sarcoma has declined in the U.S. and Europe, B NHL rates have remained high. We postulated that the elevated risk for B NHL reflects HIV-mediated depletion of Vg2/Vd2+ T cells which are important for tumor surveillance of B NHL. The Vg2/Vd2+ T cell population is depleted early during infection and is the only T cell receptor-specific defect common to all individuals with HIV disease. Cell loss is specific for a subset expressing the Vg2-Jg1.2 chain, the same T cell receptor chain needed for recognition of B NHL. The Vg2/Vd2 T cells have strong proliferative responses to B NHL and are potently cytotoxic for tumor cells. However, there is no clear understanding of the mechanism for tumor recognition by Vg2/Vd2 T cells, the tumor effector phenotype remains undefined, and we are limited in our ability to assess the effects of therapy on this important component of tumor immunity. We study the roles for gamma/delta T cell receptor, NK receptors, and Toll-like receptors in B NHL recognition. In particular, we are interested in the recognition of tumor cell HSP60 that is required for Vg2/Vd2 T cell responses. We know from other systems, that HSP60 leader peptide blocks the recognition of HLA-E by the inhibitory receptor NKG2A and this might occur for Vg2/Vd2 T cells. We postulate that an additional pathway involving TLR2 binding to tumor cell HSP60, is needed to explain the data on anti-HSP60 antibody inhibition of tumor responses. Our experimental plan will define the tumor-specific T cell receptor, evaluate the roles for NK receptors and TLR, and utilize these insights to study tumor effector T cells in PBMC from patients with HIV infection that are undergoing long-term HAART. It is important to understand HIV-related defects in tumor immunity that contribute to rising B NHL rates. Assays for Vg2/Vd2 T cells might constitute new biomarkers for B NHL risk during HIV disease. In addition, several efforts are underway to exploit the potential of Vg2/Vd2 T cells for tumor cytotoxicity, by administering already approved and experimental drugs that increase cell counts and activity in vivo. These approaches hold promise for better clinical management of AIDS-related B NHL, to benefit patients with HIV disease.

描述（由申请人提供）：B细胞非霍奇金的淋巴瘤（B NHL）影响5-10％的HIV/AIDS患者，比HIV阴性个体高约1000倍。即使在美国和欧洲，卡波西肉瘤的发病率也有所下降，但B NHL率仍然很高。我们假设B NHL的风险升高反映了HIV介导的VG2/VD2+ T细胞的耗竭，这对于B NHL的肿瘤监测很重要。 VG2/VD2+ T细胞群在感染期间早期耗尽，并且是所有HIV疾病患者常见的T细胞受体特异性缺陷。细胞损失是表达VG2-JG1.2链的子集，这是识别B NHL所需的T细胞受体链。 VG2/VD2 T细胞对B NHL具有强烈的增生反应，并且对肿瘤细胞具有有效的细胞毒性。但是，尚无清楚地了解VG2/VD2 T细胞肿瘤识别的机制，肿瘤效应的表型仍然不确定，并且我们在评估治疗对肿瘤免疫的重要成分的影响的能力方面受到限制。 我们研究了B NHL识别中γ/Delta T细胞受体，NK受体和类似Toll样受体的作用。特别是，我们对VG2/VD2 T细胞反应所需的肿瘤细胞HSP60的识别感兴趣。我们从其他系统中知道，HSP60铅肽可以阻止抑制性受体NKG2A对HLA-E的识别，并且对于VG2/VD2 T细胞可能会发生这种情况。我们假设需要一种涉及与肿瘤细胞HSP60结合的TLR2结合的额外途径，以解释抗HSP60抗体抑制肿瘤反应的数据。我们的实验计划将定义肿瘤特异性T细胞受体，评估NK受体和TLR的作用，并利用这些见解来研究正在经历长期HAART的HIV感染患者的PBMC中的肿瘤效应T细胞。 重要的是要了解肿瘤免疫中与HIV相关的缺陷，这导致B NHL率上升。 VG2/VD2 T细胞的测定可能构成HIV疾病期间B NHL风险的新生物标志物。此外，通过管理已经批准的和实验性药物来增加细胞计数和体内活性的实验药物，从而利用VG2/VD2 T细胞对肿瘤细胞毒性的潜力进行了几项努力。这些方法有望更好地对与艾滋病相关的B NHL进行更好的临床管理，从而使HIV疾病患者受益。