Evidence for kidney rejection after combined bone marrow and renal transplantation despite ongoing whole-blood chimerism in rhesus macaques.
Evidence for kidney rejection after combined bone marrow and renal transplantation despite ongoing whole-blood chimerism in rhesus macaques.
复制标题
DOI：
10.1111/j.1600-6143.2012.04045.x
复制
发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
Kean LS
中科院分区：
文献类型：
--
作者：
Ramakrishnan SK;Page A;Farris AB 3rd;Singh K;Leopardi F;Hamby K;Sen S;Polnett A;Deane T;Song M;Stempora L;Strobert E;Kirk AD;Larsen CP;Kean LS
尽管有证据表明造血嵌合诱导与实体器官移植耐受有关，但嵌合诱导耐受的机制要求尚不清楚。为了解决这个问题，我们使用MHC定义的灵长类动物模型来确定非永久性、T细胞缺乏、混合嵌合体对移植肾存活的影响。我们比较了两组：一组接受骨髓+肾移植(“BMT/肾”)，另一组只接受肾移植。两组患者均接受CD28/CD40共刺激阻断和西罗莫司维持免疫抑制治疗。正如先前证明的那样，这种移植策略持续地诱导分区供者嵌合体(显著的全血嵌合体，缺乏T细胞嵌合体)。这种嵌合体不足以延长移植肾的接受度：骨髓移植/肾移植的平均存活时间(MST，76天)与单独进行肾移植的MST(85天，p=0)没有显著差异。46)，组织病理学记录T细胞介导的排斥反应。流式细胞仪分析显示排斥肾中CD28-/CD95+CD4+和CD8+Tem细胞显著丰富，提示CD28阴性Tem与共刺激阻断抵抗排斥反应之间存在联系。这些结果表明，在某些情况下，短暂的T细胞缺乏嵌合体不足以诱导对同时放置的肾移植的耐受性，并且这种嵌合体的存在本身并不是识别耐受性的独立生物标记物。
Although there is evidence linking hematopoietic chimerism-induction and solid organ transplant tolerance, the mechanistic requirements for chimerism-induced tolerance are not clearly elucidated. To address this, we used an MHC-defined primate model to determine the impact of impermanent, T cell-poor, mixed-chimerism on renal allograft survival. We compared two cohorts: one receiving a bone marrow + renal transplant (“BMT/renal”) and one receiving only a renal transplant. Both cohorts received maintenance immunosuppression with CD28/CD40-directed costimulation blockade and sirolimus. As previously demonstrated, this transplant strategy consistently induced compartmentalized donor chimerism, (significant whole-blood chimerism, lacking T cell chimerism). This chimerism was not sufficient to prolong renal allograft acceptance: the BMT/renal mean survival time (MST, 76 days) was not significantly different than the renal transplant alone MST (85 days, p= 0. 46), with histopathology documenting T-cell mediated rejection. Flow cytometric analysis revealed significant enrichment for CD28-/CD95+ CD4+ and CD8+ Tem cells in the rejected kidney, suggesting a link between CD28-negative Tem and costimulation blockade-resistant rejection. These results suggest that in some settings, transient T cell-poor chimerism is not sufficient to induce tolerance to a concurrently placed renal allograft and that the presence of this chimerism per se is not an independent biomarker to identify tolerance.
登录
查看更多内容
影响因子：
4.4
作者：
Adams, AB;Durham, MM;Larsen, CP
通讯作者：
Larsen, CP
影响因子：
0.9
作者：
Kawai, T;Abrahamian, G;Cosimi, A
通讯作者：
Cosimi, A
影响因子：
--
作者：
Lobashevsky, A;Smith, JP;Thomas, J
通讯作者：
Thomas, J
影响因子：
8.8
作者：
Kean, L. S.;Adams, A. B.;Larsen, C. P.
通讯作者：
Larsen, C. P.
影响因子：
--
作者：
Knapp, LA;Lehmann, E;Watkins, DI
通讯作者：
Watkins, DI