Petersson E, Qi Z, Ekberg H, Ostraat O, Dohlsten M, Hedlund G
Department of Tumor Immunology, The Wallenberg Laboratory, Lund University, Sweden.
Transplantation. 1997 Apr 27;63(8):1138-44. doi: 10.1097/00007890-199704270-00014.
We have previously shown that cytotoxic T lymphocytes (CTL) with alloreactivity were induced when Wistar Furth (WF; RT1u) rats were immunized with allogeneic Brown Norway (BN; RT1n) cells. In contrast, when BN rats were immunized with WF cells, the allospecific response was confined to alloreactive natural killer (NK) cells, and no CTL activity was observed. In this study, the effect of cyclosporine (CsA) on the activation of alloreactive NK cells in vivo was analyzed.
Distinct peritoneal effector cells from rats immunized with allogenic cells with or without concomitant CsA and/or interleukin (IL) 2 treatment were tested for specific cytolytic activity. Furthermore, the presumptive role of NK cells in rejection immunity was addressed in a cardiac graft model.
The results showed that doses of CsA that completely inhibited the activation of alloreactive CTL, only marginally affected the activation of alloreactive NK cells. We also showed that CsA treatment failed to prolong graft survival in BN recipients of WF hearts. Treatment of BN rats with CsA/IL-2 during immunization with allogeneic WF cells resulted in concomitant induction of alloreactive NK cells and alloreactive CTL.
We have demonstrated that CsA failed to suppress the activation of alloreactive NK cells. Consequently, the cardiac graft survival in the donor-recipient combination known to activate alloreactive NK cells was not significantly prolonged by CsA treatment, emphasizing the involvement of NK cells as effectors in organ rejection. Furthermore, the parallel emergence of alloreactive NK cells and CTL only in the presence of CsA/IL-2 indicated that CsA interfered with alloreactive NK cell-associated suppression of CTL activated by allogeneic tissue.
我们之前已经表明，用同种异体的布朗挪威（BN；RT1n）大鼠细胞免疫Wistar Furth（WF；RT1u）大鼠时，会诱导出具有同种异体反应性的细胞毒性T淋巴细胞（CTL）。相反，当用WF细胞免疫BN大鼠时，同种异体特异性反应仅限于同种异体反应性自然杀伤（NK）细胞，未观察到CTL活性。在本研究中，分析了环孢素（CsA）对体内同种异体反应性NK细胞活化的影响。
对用同种异体免疫细胞免疫且伴有或不伴有CsA和/或白细胞介素（IL）-2治疗的大鼠的不同腹膜效应细胞进行特异性细胞溶解活性检测。此外，在心脏移植模型中探讨了NK细胞在排斥免疫中的假定作用。
结果表明，完全抑制同种异体反应性CTL活化的CsA剂量，仅对同种异体反应性NK细胞的活化有轻微影响。我们还表明，CsA治疗未能延长WF心脏BN受体的移植物存活时间。在用同种异体WF细胞免疫期间，用CsA/IL-2治疗BN大鼠会同时诱导同种异体反应性NK细胞和同种异体反应性CTL。
我们已经证明CsA未能抑制同种异体反应性NK细胞的活化。因此，已知能激活同种异体反应性NK细胞的供体-受体组合中的心脏移植物存活时间并未因CsA治疗而显著延长，这强调了NK细胞作为器官排斥效应器的参与。此外，仅在存在CsA/IL-2的情况下同种异体反应性NK细胞和CTL同时出现，表明CsA干扰了同种异体组织激活的CTL的同种异体反应性NK细胞相关抑制作用。
