Wang Zhaohui, Navarro-Alvarez Nalu, Shah Jigesh A, Zhang Huiping, Huang Qi, Zheng Qian, Madsen Joren C, Sachs David H, Huang Christene A, Wang Zhirui
Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Division of Cardiac Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Vet Immunol Immunopathol. 2016 Dec;182:150-158. doi: 10.1016/j.vetimm.2016.10.014. Epub 2016 Oct 29.
Regulatory T cells (Tregs) are known to play an important role in immunoregulation and have been shown to facilitate induction of transplantation tolerance. Chemokine (C-C motif) receptor 4 (CCR4) is expressed on the surface of effector Tregs involved in controlling alloimmune and autoimmune responses. Recently we have developed a novel diphtheria-toxin based anti-human CCR4 immunotoxin for depleting CCR4 cells in vivo. In this study, we have demonstrated that the anti-human CCR4 immunotoxin bound to porcine lymphocytes including CD4FoxP3 Tregs. Anti-human CCR4 immunotoxin effectively depleted CCR4 Foxp3 porcine Tregs in vivo. We observed depletion of up to 70-85% of the CCR4Foxp3 porcine Tregs in the peripheral blood and 85-91% in the lymph nodes following the anti-human CCR4 immunotoxin treatment in Massachusetts General Hospital (MGH) miniature swine. The depletion lasted for about one week with no significant reduction observed within CCR4 cell populations including CD8α T cells, CCR4CD4 T cells and B cells. In summary, anti-human CCR4 immunotoxin effectively depleted CCR4Foxp3 porcine Tregs in both peripheral blood and lymph nodes.
调节性T细胞（Tregs）在免疫调节中发挥重要作用，且已被证明有助于诱导移植耐受。趋化因子（C-C基序）受体4（CCR4）表达于参与控制同种异体免疫和自身免疫反应的效应性Tregs表面。最近，我们开发了一种基于白喉毒素的新型抗人CCR4免疫毒素，用于在体内清除CCR4细胞。在本研究中，我们证明抗人CCR4免疫毒素可与包括CD4FoxP3 Tregs在内的猪淋巴细胞结合。抗人CCR4免疫毒素在体内有效清除CCR4 Foxp3猪Tregs。在麻省总医院（MGH）小型猪中，经抗人CCR4免疫毒素治疗后，我们观察到外周血中CCR4Foxp3猪Tregs的清除率高达70 - 85%，淋巴结中的清除率为85 - 91%。这种清除持续约一周，在包括CD8α T细胞、CCR4CD4 T细胞和B细胞在内的CCR4细胞群体中未观察到显著减少。总之，抗人CCR4免疫毒素可有效清除外周血和淋巴结中的CCR4Foxp3猪Tregs。
