Gamma/Delta T Cells Surveillance of B Lymphoma in AIDS

描述（由申请人提供）：B细胞非霍奇金淋巴瘤（B NHL）影响5-10%的艾滋病毒/艾滋病患者，这一比例比艾滋病毒阴性个体观察到的比例高出约1，000倍。即使卡波西肉瘤的发病率在美国和欧洲已经下降，B NHL的发病率仍然很高。我们推测，B NHL的风险升高反映了HIV介导的Vg 2/Vd 2 + T细胞耗竭，这对B NHL的肿瘤监测很重要。Vg 2/Vd 2 + T细胞群在感染早期被耗尽，是所有HIV疾病个体共有的唯一T细胞受体特异性缺陷。细胞损失对于表达Vg 2-Jg1.2链的亚群是特异性的，Vg 2-Jg1.2链是识别B NHL所需的相同T细胞受体链。Vg 2/Vd 2 T细胞对B NHL具有强的增殖反应，并且对肿瘤细胞具有强的细胞毒性。然而，对于Vg 2/Vd 2 T细胞识别肿瘤的机制还没有明确的理解，肿瘤效应表型仍然不确定，并且我们评估治疗对肿瘤免疫的这一重要组分的影响的能力有限。 我们研究了γ/δ T细胞受体、NK受体和Toll样受体在B NHL识别中的作用。特别是，我们感兴趣的是识别肿瘤细胞HSP 60所需的Vg 2/Vd 2 T细胞反应。我们从其他系统中知道，HSP 60前导肽阻断抑制性受体NKG 2A对HLA-E的识别，这可能发生在Vg 2/Vd 2 T细胞中。我们推测，需要一个额外的途径，涉及TLR 2结合肿瘤细胞HSP 60，解释抗HSP 60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接受长期HAART的HIV感染患者PBMC中的肿瘤效应T细胞。 重要的是要了解艾滋病毒相关的肿瘤免疫缺陷，导致B NHL率上升。 Vg 2/Vd 2 T细胞的检测可能构成HIV疾病期间B NHL风险的新生物标志物。此外，正在进行几项努力，以利用Vg 2/Vd 2 T细胞对肿瘤细胞毒性的潜力，通过施用已经批准的和实验性的药物，增加体内细胞计数和活性。这些方法有望更好地临床管理艾滋病相关的B NHL，使艾滋病患者受益。

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.