CD40 blockade combines with CTLA4Ig and sirolimus to produce mixed chimerism in an MHC-defined rhesus macaque transplant model.
CD40 blockade combines with CTLA4Ig and sirolimus to produce mixed chimerism in an MHC-defined rhesus macaque transplant model.
复制标题
DOI：
10.1111/j.1600-6143.2011.03737.x
复制
发表时间：
2012-01
期刊：
影响因子：
--
通讯作者：
Kean LS
中科院分区：
文献类型：
--
作者：
Page A;Srinivasan S;Singh K;Russell M;Hamby K;Deane T;Sen S;Stempora L;Leopardi F;Price AA;Strobert E;Reimann KA;Kirk AD;Larsen CP;Kean LS
在小鼠模型中，T细胞共刺激阻断CD 28：B7和CD 154：CD 40通路协同促进移植后的免疫耐受。虽然CD 28阻断已成功地应用于临床，但CD 154：CD 40通路阻断的转化不太成功，这在很大程度上是由于与抗CD 154抗体相关的血栓栓塞并发症。CD 40阻断的转化也很慢，部分原因是CD 40阻断和CD 28阻断之间的协同作用尚未在灵长类动物模型或人类中得到证实。在这里，我们表明，一种新的，非消耗性的CD 40单克隆抗体，3A 8，可以结合联合收割机与组合CTLA 4 Ig和西罗莫司在一个完善的灵长类动物骨髓嵌合体诱导模型。长期植入需要在维持治疗期间存在所有三种药物，并导致在免疫抑制治疗期间移植物接受，在免疫抑制剂停药后导致排斥反应。流式细胞术分析显示，CD 4+和CD 8 + T细胞上CD 95表达的上调与排斥反应相关，表明CD 95可能是移植物丢失的可靠生物标志物。这些结果首次证明了用CD 28/mTOR阻断和非耗竭性CD 40阻断治疗的灵长类动物中的嵌合状态延长，并支持进一步研究靶向CD 28和CD 40通路的联合共刺激阻断。
In murine models, T-cell costimulation blockade of the CD28:B7 and CD154:CD40 pathways synergistically promotes immune tolerance after transplantation. While CD28 blockade has been successfully translated to the clinic, translation of blockade of the CD154:CD40 pathway has been less successful, in large part due to thromboembolic complications associated with anti-CD154 antibodies. Translation of CD40 blockade has also been slow, in part due to the fact that synergy between CD40 blockade and CD28 blockade had not yet been demonstrated in either primate models or humans. Here we show that a novel, non-depleting CD40 monoclonal antibody, 3A8, can combine with combined CTLA4Ig and sirolimus in a well-established primate bone marrow chimerism-induction model. Prolonged engraftment required the presence of all three agents during maintenance therapy, and resulted in graft acceptance for the duration of immunosuppressive treatment, with rejection resulting upon immunosuppression withdrawal. Flow cytometric analysis revealed that upregulation of CD95 expression on both CD4+ and CD8+ T-cells correlated with rejection, suggesting that CD95 may be a robust biomarker of graft loss. These results are the first to demonstrate prolonged chimerism in primates treated with CD28/mTOR blockade and non-depletional CD40 blockade, and support further investigation of combined costimulation blockade targeting the CD28 and CD40 pathways.
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：
6.2
作者：
Imai, Atsushi;Suzuki, Tomomi;Todo, Satoru
通讯作者：
Todo, Satoru
影响因子：
5.4
作者：
de Vos, AF;Melief, MJ;Larman, JD
通讯作者：
Larman, JD
影响因子：
8.8
作者：
Kean, L. S.;Adams, A. B.;Larsen, C. P.
通讯作者：
Larsen, C. P.
DOI：
10.1111/j.1600-6143.2011.03736.x
发表时间：
2012-01
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Badell IR;Thompson PW;Turner AP;Russell MC;Avila JG;Cano JA;Robertson JM;Leopardi FV;Strobert EA;Iwakoshi NN;Reimann KA;Ford ML;Kirk AD;Larsen CP
通讯作者：
Larsen CP