A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease
A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease
复制标题
DOI：
10.1182/blood-2010-12-324210
复制
发表时间：
2011-05-19
期刊：
影响因子：
20.3
通讯作者：
Chiorazzi, Nicholas
中科院分区：
文献类型：
--
作者：
Bagnara, Davide;Kaufman, Matthew S.;Chiorazzi, Nicholas
慢性淋巴细胞白血病（CLL）是一种无法治愈的成人疾病，病因不明。了解CLL细胞的生物学，特别是细胞在体内的成熟和生长，由于缺乏可重复的过继转移模型而受到阻碍。我们报道了一个简单的、可重复的系统，在激活的CLL来源的T淋巴细胞的影响下，原发性CLL细胞在非肥胖糖尿病/严重联合免疫缺陷/ γ c（null）小鼠中增殖。通过在体内被同种异体抗原激活的自体T淋巴细胞共转移，实现了cfse标记的CLL细胞在体内的存活和生长，并对其进行了量化。使用这种方法，我们已经确定了CD4(+) T细胞在CLL扩增中的关键作用，白血病B细胞CD38表达与其激活之间的直接联系，以及支持CLL细胞在继发性淋巴组织中优先增殖。该模型应简化体内CLL细胞动力学分析，破译促进CLL细胞生长的非白血病因素和非遗传因素的参与，识别和表征潜在的白血病干细胞，并允许临床前研究新的治疗方法。由于自体活化的T淋巴细胞是一把双刃剑，会产生不必要的抗宿主反应和可能的自体抗肿瘤反应，该模型还可以促进与造血移植和肿瘤细胞毒性相关的免疫监视相关的T细胞群的分析。(血。2011;117 (20):5463 - 5472)
Chronic lymphocytic leukemia (CLL) is an incurable adult disease of unknown etiology. Understanding the biology of CLL cells, particularly cell maturation and growth in vivo, has been impeded by lack of a reproducible adoptive transfer model. We report a simple, reproducible system in which primary CLL cells proliferate in nonobese diabetes/severe combined immunodeficiency/gamma c(null) mice under the influence of activated CLL-derived T lymphocytes. By cotransferring autologous T lymphocytes, activated in vivo by alloantigens, the survival and growth of primary CFSE-labeled CLL cells in vivo is achieved and quantified. Using this approach, we have identified key roles for CD4(+) T cells in CLL expansion, a direct link between CD38 expression by leukemic B cells and their activation, and support for CLL cells preferentially proliferating in secondary lymphoid tissues. The model should simplify analyzing kinetics of CLL cells in vivo, deciphering involvement of nonleukemic elements and nongenetic factors promoting CLL cell growth, identifying and characterizing potential leukemic stem cells, and permitting preclinical studies of novel therapeutics. Because autologous activated T lymphocytes are 2-edged swords, generating unwanted graph-versus-host and possibly autologous antitumor reactions, the model may also facilitate analyses of T-cell populations involved in immune surveillance relevant to hematopoietic transplantation and tumor cytoxicity. (Blood. 2011;117(20):5463-5472)