Gamma/Delta T Cells Surveillance of B Lymphoma in AIDS

描述(申请人提供)：B细胞性非霍奇金淋巴瘤(B NHL)影响5-10%的艾滋病毒/艾滋病患者，其发病率大约是艾滋病毒阴性患者的1,000倍。尽管卡波西肉瘤在美国和欧洲的发病率有所下降，但B非霍奇金淋巴瘤的发病率仍然很高。我们推测，B NHL风险的增加反映了HIV介导的Vg2/Vd2+T细胞的耗尽，这对B NHL的肿瘤监测是重要的。Vg2/Vd2+T细胞群在感染早期就被耗尽，这是所有HIV疾病患者共同的唯一T细胞受体特异性缺陷。细胞丢失是表达Vg2-Jg1.2链的亚群所特有的，该链与识别B NHL所需的T细胞受体链相同。Vg2/Vd2T细胞对B-NHL有较强的增殖反应，对肿瘤细胞具有较强的细胞毒作用。然而，Vg2/Vd2T细胞识别肿瘤的机制尚不清楚，肿瘤效应表型仍不明确，我们评估治疗对这一肿瘤免疫重要组成部分的影响的能力有限。 我们研究了γ/Delta T细胞受体、NK受体和Toll样受体在识别B NHL中的作用。特别是，我们感兴趣的是肿瘤细胞HSP60的识别，这是Vg2/Vd2T细胞反应所必需的。我们从其他系统得知，HSP60先导肽可以阻断抑制性受体NKG2A对人类白细胞抗原-E的识别，这种作用可能发生在Vg2/Vd2T细胞上。我们推测，需要TLR2与肿瘤细胞HSP60结合的额外途径来解释抗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接受长期HAART的HIV感染患者PBMC中的肿瘤效应T细胞。 了解导致B-NHL发病率上升的肿瘤免疫中与HIV相关的缺陷是很重要的。 Vg2/Vd2T细胞检测可能成为HIV疾病中B-NHL风险的新的生物标志物。此外，为了开发Vg2/Vd2 T细胞对肿瘤细胞的毒性作用，目前正在进行几项工作，方法是使用已经批准的和实验药物，增加体内细胞数量和活性。这些方法有望更好地对艾滋病相关的B非霍奇金淋巴瘤进行临床治疗，使艾滋病毒患者受益。

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.