GROWTH REGULATION IN AIDS RELATED LYMPHOMAS

艾滋病相关淋巴瘤（ARL）是一组免疫缺陷相关的， 侵袭性B细胞、非霍奇金淋巴瘤（NHL-B）。 ARL的发病率 在美国，随着艾滋病患者的寿命延长， 对于免疫妥协的后期后果变得更大的风险。 ARL的生物学，主要导致小无裂细胞 (SNCC伯基特（BL））或大细胞（免疫母细胞）组织型，似乎 涉及许多与侵袭性NHL-B相关的致病程序， 在HIV阴性患者人群中， ARL的发育和巨大的细胞生长潜力，表明， 可能涉及其他遗传、生物或免疫因素。的 恶性B细胞侵袭性生长的生物学或分子学基础 ARL未知。 ARL产生于B淋巴样细胞谱系， 不同数量的特定致癌基因、病毒或肿瘤的积累 抑制基因异常导致细胞永生化， NHL-B前体细胞。 研究将继续我们的初步结果， 提示永生化NHL前体B细胞异常表达 一个或多个BCGF（IL 14，LMW-BCGF）细胞因子基因，可能作为 恶性转化的过程。不适当表达的BCGF ARL中的基因成为淋巴瘤细胞的自分泌生长因子（AGF）， 也组成性表达IL-I4 R。 共刺激因子 正常的B细胞增殖，如CD 4 O配体（CD 4 OL）gp 39，也将 在ARL中评估生长刺激潜力。 其它细胞因子 具有推定的B细胞刺激活性的细胞，如IL 6或IL 10，也将 研究其介导或共刺激ARL细胞的可能作用 体外生长 由于ARL的自分泌生长似乎是由 通过BCGF分子，我们将探索抑制细胞生长的方法， 生长因子剥夺，通过抑制这些细胞因子生长因子 ARL中的基因，用细胞因子抑制药物，如环孢菌素A (CsA)和反义寡核苷酸（阿索）。 ARL的发病机制 将在体外实验B细胞模型中进行探索， 转染的癌基因和生长因子基因，这将扩大到在 体内研究，利用免疫缺陷。SCID小鼠。最后，我们将寻求 以确定额外的（或不同的）遗传病变的ARL，可能 考虑到加速开发和/或积极的临床 行为，使用比较基因组杂交（CGH），用于识别 染色体异常，常规细胞遗传学无法识别 技术.

AIDS-related lymphomas (ARL) are a group of immune deficiency-associated, aggressive B cell, non-Hodgkin's lymphomas (NHL-B). The incidence of ARL in the US is currently increasing, as AIDS patients live longer, and become at greater risk for the later consequences of immune compromise. The biology of ARL, that primarily results in the small non-cleaved cell (SNCC; Burkitt's (BL)) or Large cell (Immunoblastic) histo-types, seems to involve a number of the pathogenetic programs involved in aggressive NHL-B in the HIV negative patient population, However, the rapidity of development and the prodigious cell growth potential of ARL, suggests that additional genetic, biologic, or immune factors may be involved. The biologic or molecular basis of the aggressive malignant B cell growth in the ARL is unknown. ARL arises in the B lymphoid cell lineage, after the accumulation of a variable number of specific oncogene, viral, or tumor suppressor gene abnormalities that lead to cellular immortalization in NHL-B precursor cells. Studies will pursue our preliminary results that suggest that the immortalized, NHL precursor B cells, aberrantly express one or more of the BCGF (IL14, LMW-BCGF) cytokine genes, probably as part of the malignant transformation process. inappropriately expressed BCGF genes in ARL become autocrine growth factors (AGF) for the lymphoma cells, that also constitutively express the IL-I4R. Co-stimulatory factors for normal B cell proliferation, such the CD4O ligand (CD4OL) gp39, will also be evaluated for growth stimulatory potential in the ARL. Other cytokines with putative B cell stimulatory activity, such as IL6 or lL1O, will also be studied for a possible role in mediating or co-stimulating ARL cell growth in vitro. Since autocrine growth in the ARL appears to be mediated by BCGF molecules, we will explore methods for inhibiting cell growth thru growth factor deprivation, by inhibiting these cytokine growth factor genes in the ARL, with cytokine inhibitory drugs, such as cyclosporin A (CsA), and anti-sense oligonucleotides (ASO). Pathogenesis of the ARL will be explored in vitro, in experimental B cell models, containing transfected oncogenes and growth factor genes, that will be extended to in vivo studies, utilizing immune deficient. SCID mice. Finally, we will seek to identify additional (or different) genetic lesions in the ARL, possibly accounting for the accelerated development and/or aggressive clinical behavior, using comparative genomic hybridization (CGH), for identifying chromosomal abnormalities, not identifiable using conventional cytogenetic techniques.