Modefication of the drug-induced tolerance induction to large animals

大型动物药物耐受诱导的调节

• 批准号: 10470277
• 负责人: YASUI Hisataka
• 金额: $ 8.06万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470277/
• 关键词: tolerance; graft survival; Post-transplant cardiac allograft vasculopathy; cardiac allograft; 薬剤誘導性特異的免疫寛容; Cyclophosphamide(CP); 頚部異所性心移植; 移植後冠動脈病変; 永久的キメラ状態; 異種移植; 薬剤誘導性免疫寛容系; 混合キメラ

Post-transplant cardiac allograft vasculopathy (CAV) is a key manifestation of chronic rejection in heart transplant recipients and impairs long-term graft outcome. In the present study, we have investigated whether CAB can be prevented by the treatment of cyclophosphamide (CP)-induced tolerance in a murine CAV model of H-2 matched AKR (H-2ィイD2kィエD2 ; Thy1.1, M1s-1ィイD2aィエD2) into C3H (H-2ィイD2kィエD2 ; Thy1.1, M1s-1ィイD2bィエD2) mice. When C3H mice were grafted with H-2 matched AKR heart grafts (HG), most of AKR HG survived over 100 days, but all were rejected within 260 days after grafting. CAV developed in all AKR HG. When C3H mice were primed I.e. with1x10ィイD28ィエD2 AKR(H-2k_) spleen cells (SC) and treated I.p. with 200mg/kg CP, the survival of AKR hearts was prolonged permanently in tolerogen-specific fashion, as observed in that of AKR skins. By this treatment, both minimal degree of mixed chimerism and clonal destruction of M1s-1ィイD2aィエD2-reactive CD4+Vβ6+T cells in the periphery were o … More bserved. Furthermore, post-transplant CAV did not develop in the grafted AKR hearts. When AKR SC and 100mg/kg CP were used as the conditioning, AKR HG were accepted permanently, but survival of AKR skin grafts was mildly prolonged. The clonal destruction of CD4+Vβ6+T cells was induced in the periphery. A minimal degree of mixed chimerism was detective at 4 weeks after AKR SC and 100mg/kg CP treatment, but hardly became detectable at 20 weeks. In the AKR HG of C3H mice treated with AKR SC and 100mg/kg CP, post-transplant CAV did not develop, either. Second set skin grafts from donor AKR mice survived in a tolerogen-specific fashion over 100 days in 10/10 C3H mice treated with AKR SC and 200mg/kg CP and accepting AKR HG over 200 days, and 8/10 C3H mice treated with AKR SC and 100 mg CP and accepting AKR HG over 200 days. In order to further elucidate the nature of tolerance induced with AKR SC and CP, PCR assay was performed. Neither Th1 (IL-2, g-IFN) nor Th2 (IL-4, IL-10) cytokines were accumulated at 4 weeks post-heart grafting in the AKR HG of tolerant C3H mice treated with both AKR SC and 200mg/kg CP and AKR SC and 100mg/kg CP.These results indicate that the suboptimal conditioning (SC+100mg/kg CP) of CP-induced tolerance with 1x10ィイD28ィエD2 SC and 100 mg/kg CP can permit heart allograft without the development of CAV or accumulation of mRNAs for Th1 or Th2 cytokines. Furthermore, the induction of skin allograft tolerance is more difficult than the prevention of post-transplant CAV. Less

同种异体心脏移植后血管病变（CAV）是心脏移植受者慢性排斥反应的主要表现，并损害移植的长期预后。在目前的研究中,我们调查了出租车是否可以预防环磷酰胺(CP)全身治疗的公差2匹配AKR鼠骑兵模型(2ィイD2kィエD2; Thy1.1, M1s-1ィイD2aィエD2)到摘要(2ィイD2kィエD2; Thy1.1, M1s-1ィイD2bィエD2)老鼠。当C3H小鼠移植H-2匹配的AKR心脏移植物（HG）时，大部分AKR HG存活超过100天，但在移植后260天内全部发生排斥反应。CAV在所有AKR HG中都有发生。当C3H小鼠用1x10 μ l - D28 μ l - D2 AKR（H-2k_）脾细胞（SC）进行刺激，并以200mg/kg CP处理时，AKR心脏的存活时间以耐受性特异性的方式永久延长，与AKR皮肤的存活时间相同。通过这种治疗,最小程度的混合嵌合和克隆破坏M1s-1ィイD2aィエD2-reactive CD4 + Vβ6 + T细胞在外围o ... 更多的bserved。此外，移植后的CAV在移植的AKR心脏中没有发生。当AKR SC和100mg/kg CP作为调节作用时，AKR HG被永久接受，但AKR皮肤移植物的存活时间轻度延长。外周血CD4+Vβ6+T细胞克隆性破坏。在AKR SC和100mg/kg CP处理后4周检测到最低程度的混合嵌合，但在20周几乎检测不到。在AKR SC和100mg/kg CP处理的C3H小鼠AKR HG中，移植后CAV也未发生。第二组来自供体AKR小鼠的皮肤移植物在10/10 C3H小鼠中接受AKR SC和200mg/kg CP，并接受AKR HG超过200天，在8/10 C3H小鼠中接受AKR SC和100mg CP，并接受AKR HG超过200天，以耐受性特异性方式存活100天。为了进一步阐明AKR SC和CP诱导耐受性的性质，进行了PCR检测。在移植心脏后4周，接受AKR SC和200mg/kg CP以及AKR SC和100mg/kg CP处理的C3H耐受性小鼠的AKR HG中没有Th1 （IL-2, g-IFN）和Th2 （IL-4, IL-10）细胞因子的积累。这些结果表明，在1 × 10 μ c - D28 μ c - D2 SC和100mg/kg CP诱导的CP耐受性的次优调节（SC+100mg/kg CP）可以使心脏移植不产生CAV或Th1或Th2细胞因子mrna的积累。此外，诱导皮肤异体移植耐受比预防移植后CAV更困难。少

项目成果

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吉川。