Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Cancer Res. 2012 Oct 1;72(19):4931-43. doi: 10.1158/0008-5472.CAN-12-1390. Epub 2012 Aug 8.
CD200 is a transmembrane molecule with an important immunoregulatory role that is overexpressed on most chronic lymphocytic leukemia (CLL) cells. In this study, we characterized a previously unknown soluble form of this molecule in human plasma termed sCD200. Levels of sCD200 were elevated in the plasma of patients with CLL as compared with healthy controls, and there was a significant correlation with CLL disease stage. Infusion of sCD200(hi) CLL plasma into severely immunocompromised NOD.SCIDγ(c)(null) (NSG) mice enhanced the engraftment of CLL splenocytes as compared with mice receiving sCD200(lo) normal plasma. CLL cells were detected in both the spleen and peritoneal cavity of animals for up to 75 days. Engraftment of CLL cells did not occur after infusion of CLL plasma depleted of sCD200 and was abolished in mice treated with anti-CD200 or OKT3 monoclonal antibody (mAb), suggesting a role for both sCD200 and T cells in CLL engraftment. Notably, anti-CD200 mAb was as effective as rituximab in eliminating engrafted CLL cells when administered 21 days after engraftment. Taken together, our findings point to sCD200 as a novel prognostic marker and therapeutic target for CLL. Furthermore, the humanized mouse model described here may prove valuable to preclinically assess new treatment regimens for CLL.
CD200 是一种跨膜分子，具有重要的免疫调节作用，在大多数慢性淋巴细胞白血病 (CLL) 细胞上过度表达。在这项研究中，我们在人血浆中鉴定了这种分子的一种以前未知的可溶性形式，称为 sCD200。与健康对照相比，CLL 患者的血浆中 sCD200 水平升高，并且与 CLL 疾病阶段有显著相关性。与接受 sCD200(lo)正常血浆的小鼠相比，将 sCD200(hi) CLL 血浆输注到严重免疫缺陷的 NOD.SCIDγ(c)(null) (NSG) 小鼠中，增强了 CLL 脾细胞的植入。动物的脾脏和腹腔中可检测到 CLL 细胞长达 75 天。输注 CLL 血浆耗尽 sCD200 后不会发生 CLL 细胞的植入，并且在用抗 CD200 或 OKT3 单克隆抗体 (mAb) 处理的小鼠中被废除，这表明 sCD200 和 T 细胞在 CLL 植入中都起作用。值得注意的是，抗 CD200 mAb 在植入后 21 天给药时与利妥昔单抗一样有效，可消除植入的 CLL 细胞。总之，我们的发现表明 sCD200 是 CLL 的一种新的预后标志物和治疗靶标。此外，这里描述的人源化小鼠模型可能对临床前评估 CLL 的新治疗方案具有重要价值。
