Gallagher Sandra, Turman Sean, Lekstrom Kristen, Wilson Susan, Herbst Ronald, Wang Yue
Department of Oncology Research, MedImmune, One MedImmune Way, Gaithersburg, MD 20878, USA.
Department of Protein Science, MedImmune, One MedImmune Way, Gaithersburg, MD 20878, USA.
Mol Immunol. 2017 May;85:57-65. doi: 10.1016/j.molimm.2017.01.022. Epub 2017 Feb 14.
Recent studies have demonstrated the importance of CD47 in protecting malignant B cells from antibody dependent cellular phagocytosis (ADCP). Combined treatment of anti-CD47 and -CD20 antibodies synergistically augment elimination of tumor B cells in xenograft mouse models. This has led to the development of novel reagents that can potentially enhance killing of malignant B cells in patients. B cell depleting therapy is also a promising treatment for autoimmune patients. In the current study, we aimed to investigate whether or not CD47 protects non-malignant B cells from ADCP. We show that CD47 is expressed on all B cells in mice, with the highest level on plasma cells in bone marrow and spleen. Although its expression is dispensable for B cell development in mice, CD47 on B cells limits antibody mediated phagocytosis. B cell depletion following in vivo anti-CD19 treatment is more efficient in CD47-/- mice than in wild type mice. In vitro, both naïve and activated B cells from CD47-/- mice are more sensitive to ADCP than wild type B cells. Lastly, we show in an ADCP assay that blocking CD47 can enhance anti-CD19 antibody mediated phagocytosis of wild type B cells. These results suggest that in addition to its already demonstrated benefit in cancer, targeting CD47 may be used as an adjunct in combination with B cell depletion antibodies for treatment of autoimmune diseases.
最近的研究已经证明了CD47在保护恶性B细胞免受抗体依赖性细胞吞噬作用（ADCP）中的重要性。在异种移植小鼠模型中，联合使用抗CD47和抗CD20抗体可协同增强肿瘤B细胞的清除。这导致了新型试剂的开发，这些试剂有可能增强对患者体内恶性B细胞的杀伤。B细胞清除疗法对自身免疫性疾病患者也是一种有前景的治疗方法。在本研究中，我们旨在调查CD47是否能保护非恶性B细胞免受ADCP。我们发现CD47在小鼠所有B细胞上均有表达，在骨髓和脾脏中的浆细胞上表达水平最高。虽然其表达对于小鼠B细胞发育并非必需，但B细胞上的CD47会限制抗体介导的吞噬作用。体内抗CD19治疗后，CD47基因敲除小鼠的B细胞清除效率高于野生型小鼠。在体外，来自CD47基因敲除小鼠的幼稚B细胞和活化B细胞比野生型B细胞对ADCP更敏感。最后，我们在ADCP试验中表明，阻断CD47可增强抗CD19抗体介导的野生型B细胞吞噬作用。这些结果表明，除了已证明的在癌症治疗中的益处外，靶向CD47还可作为辅助手段与B细胞清除抗体联合用于治疗自身免疫性疾病。
