异种周围神经移植免疫耐受的实验研究
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摘要
周围神经缺损是临床上常见的病症,有许多学者进行了同种异体神经和异种神经移植的实验及临床研究,异种移植排斥反应的类型与同种移植相似,但其反应的严重程度和发生频率却更为严重。有研究表明,T细胞疫苗免疫受体动物能够显著延长同种心脏移植物的存活时间。T细胞疫苗作为一种新技术为在不需预先清除机体成熟T淋巴细胞的情况下诱导移植免疫耐受提供了新的途径。FK506是一种新型免疫抑制剂,降低了IL-2基因转录,减少了IL-2的分泌,从而抑制T细胞增生,活化发挥免疫抑制作用。
本实验首先在小鼠到大鼠的神经移植基础上,从几个方面探讨异种神经移植后的一些变化。然后在12周时间里采用T细胞疫苗接种联合应用FK506来抑制大鼠的异种神经移植排斥反应,以观察该方法抑制大鼠异种神经移植排斥反应的效应。结果表明T细胞疫苗作为预处理手段可预先清除体内的T细胞克隆,可以对异种神经移植后产生有效的免疫耐受。而且T细胞疫苗联合FK506未能诱导异种移植后的完全免疫耐受,但较之其他对照组,对大鼠神经移植排斥反应具有明显抑制作用。
Xenotransplantation offers a potentially unlimited source for tissues and organs for transplantation,but the strong xenoimmune responses pose a major obstacle to its application in the clinic.In this study,we investigate the rejection of mouse peripheral nerve xenografts in rats.Severe intragraft mononuclear cell infiltration,and graft distension and necrosis were detected in the recipients as early as 2 weeks after mouse nerve xenotransplantation.The number of axons in xenografts reduced progressively and became almost undetectable at week 8. However,mouse nerve xenotransplantation only led to a transient and moderate increase in the production of Th1 cytokines,including IL-2,IFN-γand TNF-α. The data implicate that cellular immune responses play a critical role in nerve xenograft rejection,but that further identification of the major effector cells mediating the rejection is required for developing effective means to prevent peripheral nerve xenograft rejection.
Objective To investigate the alteration of the immunological cytokine level and histological changes of nerves.To investigate the anti-rejection effect of T cell vaccination combined with FK506 of heterogenic transplantation on rat nerve.
Methods The change of nerves in general,using microscopy and electron microscope and the concentration of serum IL-2、IL-4、IFN-γ、TNF-αwere observed after 4,8 and 12weeks of transplantation,respectively.SD rats were vaccinated by the spleen cells of BABL/c mice;T cell vaccines were activated and vaccinated in the spleen cells of these SD rats.The SD rats of nerve transplantation recipient were vaccinated with T cells combined with FK506. The mixture lymphocytes culture,microcytotoxicity assay,histological alteration of nerves,humid weights of tibial anterior muscle were observed to confirm the anti-rejection effect of T cell vaccination combined with FK506 treatment.
Results Inflammatory cells infiltrated after 4 weeks of transplantation, the myelin sheath structure could be seen after 4 weeks and disaggregated in 8 weeks;the concentrations of Th1 cytokine increased and Th2 decreased after 4 weeks,which statistically different from those in control group(P＜0.05).The humid weights of tibial anterior muscle of the vaccinated rats combined with FK506 treatment were statistically different from those in control group (P＜0.05),and so as the index of rejection(e.g.lymphocytes transformation efficiency)(P＜0.05).
Conclusion The immunological rejection after heterogenic transplantation was mainly mediated by cellular immunity,and the level of cytokines and histological changes were most significant.T cell vaccination combined with FK506 treatment can inhibit the rejection of heterogenic transplantation on rat peripheral nerve.
本实验首先在小鼠到大鼠的神经移植基础上,从几个方面探讨异种神经移植后的一些变化。然后在12周时间里采用T细胞疫苗接种联合应用FK506来抑制大鼠的异种神经移植排斥反应,以观察该方法抑制大鼠异种神经移植排斥反应的效应。结果表明T细胞疫苗作为预处理手段可预先清除体内的T细胞克隆,可以对异种神经移植后产生有效的免疫耐受。而且T细胞疫苗联合FK506未能诱导异种移植后的完全免疫耐受,但较之其他对照组,对大鼠神经移植排斥反应具有明显抑制作用。
Xenotransplantation offers a potentially unlimited source for tissues and organs for transplantation,but the strong xenoimmune responses pose a major obstacle to its application in the clinic.In this study,we investigate the rejection of mouse peripheral nerve xenografts in rats.Severe intragraft mononuclear cell infiltration,and graft distension and necrosis were detected in the recipients as early as 2 weeks after mouse nerve xenotransplantation.The number of axons in xenografts reduced progressively and became almost undetectable at week 8. However,mouse nerve xenotransplantation only led to a transient and moderate increase in the production of Th1 cytokines,including IL-2,IFN-γand TNF-α. The data implicate that cellular immune responses play a critical role in nerve xenograft rejection,but that further identification of the major effector cells mediating the rejection is required for developing effective means to prevent peripheral nerve xenograft rejection.
Objective To investigate the alteration of the immunological cytokine level and histological changes of nerves.To investigate the anti-rejection effect of T cell vaccination combined with FK506 of heterogenic transplantation on rat nerve.
Methods The change of nerves in general,using microscopy and electron microscope and the concentration of serum IL-2、IL-4、IFN-γ、TNF-αwere observed after 4,8 and 12weeks of transplantation,respectively.SD rats were vaccinated by the spleen cells of BABL/c mice;T cell vaccines were activated and vaccinated in the spleen cells of these SD rats.The SD rats of nerve transplantation recipient were vaccinated with T cells combined with FK506. The mixture lymphocytes culture,microcytotoxicity assay,histological alteration of nerves,humid weights of tibial anterior muscle were observed to confirm the anti-rejection effect of T cell vaccination combined with FK506 treatment.
Results Inflammatory cells infiltrated after 4 weeks of transplantation, the myelin sheath structure could be seen after 4 weeks and disaggregated in 8 weeks;the concentrations of Th1 cytokine increased and Th2 decreased after 4 weeks,which statistically different from those in control group(P＜0.05).The humid weights of tibial anterior muscle of the vaccinated rats combined with FK506 treatment were statistically different from those in control group (P＜0.05),and so as the index of rejection(e.g.lymphocytes transformation efficiency)(P＜0.05).
Conclusion The immunological rejection after heterogenic transplantation was mainly mediated by cellular immunity,and the level of cytokines and histological changes were most significant.T cell vaccination combined with FK506 treatment can inhibit the rejection of heterogenic transplantation on rat peripheral nerve.
引文
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