Okura Y, Tanaka R, Ono K, Yoshida S, Tanuma N, Matsumoto Y
Department of Neurosurgery, Brain Research Institute, Niigata University, Japan.
J Neurosci Res. 1997 Jun 1;48(5):385-96.
To obtain basic knowledge for the application of xenogeneic neural transplantation to patients with Parkinson's disease, the rejection process of xenogeneic neural grafts in rats was examined and a therapy to control it was developed. Tissues including the ventral mesencephalon were taken from mouse embryos and transplanted into the right lateral ventricle of mature male rats. Transplanted xenografts were usually rejected by day 15. To prevent the graft rejection, host rats were treated with anti-T-cell receptor alphabeta (anti-TCR alphabeta) or anti-CD2 monoclonal antibody (mAb) or by a combination of the two. Anti-TCR alphabeta (1 mg/kg) and anti-CD2 (7 mg/kg) mAb were administered for 3 consecutive days (day -2, -1, and 0 of transplantation). Although the administration of mAb against either CD2 or TCR alphabeta did not induce tolerance, the combination therapy with anti-CD2 and anti-TCR alphabeta mAb produced graft survival for more than 100 days. The tolerance induced by this combined antibody therapy is antigen specific because rats with long-term surviving neural xenograft accepted a second neural graft from the same donor strain C3H/He mouse, but not from a third-party strain BALB/c mouse, without additional treatment. In addition, T cells isolated from these rats did not respond to cultured C3H/He brain cells, but did respond vigorously to BALB/c brain cells in mixed lymphocyte reaction. More importantly, the finding that xenograft transplantation with the proper treatment reduced the rotation rate of 6-OHDA-lesioned rats confirmed that surviving grafts functioned properly. The results of the present study suggest that xenogeneic neural transplantation in combination with T-cell-targeted immunotherapy is an effective approach for treatment of Parkinson's disease.
为获取将异种神经移植应用于帕金森病患者的基础知识，研究了大鼠异种神经移植物的排斥过程，并开发了一种控制排斥的疗法。从小鼠胚胎中获取包括腹侧中脑在内的组织，移植到成年雄性大鼠的右侧脑室。移植的异种移植物通常在第15天被排斥。为防止移植物排斥，给宿主大鼠注射抗T细胞受体αβ（抗TCRαβ）或抗CD2单克隆抗体（mAb），或两者联合使用。抗TCRαβ（1mg/kg）和抗CD2（7mg/kg）mAb连续给药3天（移植的第-2、-1和0天）。尽管单独给予抗CD2或抗TCRαβ的mAb不会诱导耐受，但抗CD2和抗TCRαβmAb联合治疗可使移植物存活超过100天。这种联合抗体疗法诱导的耐受具有抗原特异性，因为长期存活神经异种移植物的大鼠在未进行额外治疗的情况下，接受了来自同一供体品系C3H/He小鼠的第二次神经移植，但不接受第三方品系BALB/c小鼠的移植。此外，从这些大鼠分离的T细胞在混合淋巴细胞反应中对培养的C3H/He脑细胞无反应，但对BALB/c脑细胞有强烈反应。更重要的是，适当治疗的异种移植降低了6-OHDA损伤大鼠的旋转率，这一发现证实存活的移植物功能正常。本研究结果表明，异种神经移植联合靶向T细胞的免疫疗法是治疗帕金森病的有效方法。
