短期运用免疫抑制药物对非去髓异基因骨髓移植方案诱导的混合嵌合体和移植耐受的影响  

Effects of short-course immunosuppression on chimerism and tolerance indhuced by bone marrow transplantation without cytoreductive conditioning

作　　者：奉友刚[1] 曾甫清[1] 王光明[2] 李爱玲[2] 郝杰[2] 李翀[2] 袁国红[2] 高翔[2] 谢蜀生[2] 

机构地区：[1]华中科技大学同济医学院附属协和医院泌尿外科研究所,武汉430022 [2]北京大学医学部免疫学系

出　　处：《中华微生物学和免疫学杂志》2006年第10期879-882,共4页Chinese Journal of Microbiology and Immunology

基　　金：国家自然科学基金重点项目(批准号:39830340)

摘　　要：目的探讨免疫抑制药物对CTLA4-FasL重组腺病毒和供者骨髓移植联合方案诱导的混合嵌合耐受的影响。方法将BALB/c(H-2~d)小鼠皮肤移植于C57BL/6(H-2~b,B6)小鼠,同时经尾静脉给B6小鼠注射BALB/c小鼠骨髓细胞和腺病毒AdCTLA4-FasL,B6小鼠接受皮肤移植术后4周内每天注射环孢素A(CsA)或霉酚酸酯(MMF)或这两种药物同时注射；然后观察移植皮肤存活情况,通过流式细胞仪测定受体外周血Vβ11^+的T细胞的水平和供体来源细胞的嵌合水平,通过单向混合淋巴细胞反应了解对供体抗原的耐受状态。结果在CTLA4-FasL重组腺病毒和供者骨髓移植联合方案诱导的混合嵌合耐受模型中,短期运用免疫抑制药物均促进早期供体骨髓细胞植入,但注射CsA或CsA与MMF联用的受体小鼠在皮肤移植后140d时混合嵌合降低到很低水平,且单用CsA或CsA与MMF联用的受体小鼠中供体皮肤平均生存时间显著低于不用免疫抑制药物或用MMF的受体小鼠(P＜0．05)；皮肤移植后21d时单用CsA或CsA与MMF联用的受体小鼠V∞11^+的T细胞水平显著高于不用免疫抑制药物或用MMF的受体小鼠(P＜0．05)；皮肤移植后150d时单用CsA或CsA与MMF联用的受体小鼠脾细胞未显示对同种抗原特异性耐受。结论CsA或含CsA的免疫抑制方案对CTLA4- FasL重组腺病毒和供者骨髓移植联合方案诱导的混合嵌合耐受有抑制作用,其机理可能与早期外周供体特异性T细胞删除减少有关；而MMF与该嵌合耐受方案兼容。Objective To analyse the effects of conventional immunosuppressive drugs on ehimerism and tolerance induced by allogeneie bone marrow transplantation （BMT） in combination with CTLA4-FasL gene transfer mediated by adenovints. Methods C57BL/6（H-2^b, B6） mice received BALB/c（H-2^d ） mice skin transplantation, followed by combined injection of adenovirus vector encoding CTLA4-FasL gene and bone marrow cells （BMC） via tail vein. Cyelosporin A （CsA） or mycophenolate mofetil （MMF） or both was administered daily from day 0 to day 28 post-transplantation. Then, survival of the skin grafts were observed, the level of Vβ11^＋ T cells and donor cells in peripheral blood leucocyte （PBL） of recipient were tested by flow cytometry, the tolerance to donor antigen was evaluated through one-way MLR. Results In our non-cytoreductive model using BMT and CTLA4-FasL gene transfer, short-couse immunosuppression facilitated early engraftment of donor bone marrow, while the mixed chimerism in peripheral blood of B6 recipients treated with CsA or both CsA and MMF were reduced to very low level on day 140 after skin transplantation; when compared with B6 recipients treated with MMF or without immunosuppressive drugs, the mean survival time （MST） of skin allografts of those mice treated with CsA or both CsA and MMF was significantly reduced, and the levels of Vβ11^＋ T cells were higher; furthermore, B6 recipients treated with CsA or both CsA and MMF showed no tolerance to donor antigen. Conclusion Immunosuppressive regime containing CsA could abrogate the induction of long-lasting mixed chimerism and the development of tolerance in non-cytoreductive model using BMT and CTLA4-FasL gene transfer, owing to negative effect of CsA on Peripheral deletion of donor-specific T cells. However, MMF was compatible with our non-cytoreductive protocol.

关 键 词：移植耐受 混合嵌合体 免疫抑制 皮肤移植 

分 类 号：R96[医药卫生—药理学] R617[医药卫生—药学]