Allo-reactivity of mesenchymal stem cells in rhesus macaques is dose and haplotype dependent and limits durable cell engraftment in vivo.
Allo-reactivity of mesenchymal stem cells in rhesus macaques is dose and haplotype dependent and limits durable cell engraftment in vivo.
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DOI：
10.1371/journal.pone.0087238
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Phinney DG
中科院分区：
文献类型：
--
作者：
Isakova IA;Lanclos C;Bruhn J;Kuroda MJ;Baker KC;Krishnappa V;Phinney DG
MSC免疫豁免的新兴范例促进了在人类临床试验中使用“现成的”基于同种异体MSC的疗法。然而，这种方法忽略了在实验动物中的研究，其中跨MHC边界移植MSC引起可测量的同种免疫应答。为了确定MSC是否是低免疫原性的，我们表征了恒河猴颅内施用同种异体与自体MSC后的免疫应答。该分析揭示了基于外周血中NK、B和T细胞亚群的扩增和施用同种异体而非自体MSC的动物中同种特异性抗体的检测的生产性同种异体识别的明确证据。此外，MSC供体和受体之间的MHC I类和II类错配的程度显着影响同种免疫应答的程度和性质。与这些发现一致，对给予不同剂量雄性同种异体MSC的女性受体的脑组织进行实时PCR分析，显示MSC植入水平与细胞剂量之间存在显着的负相关性。移植后中性粒细胞和淋巴细胞计数的变化也与剂量相关，并可预测总体MSC植入水平。然而，二次抗原激发未能在同种异体受体中引起可测量的免疫应答。最后，对动物的广泛行为测试显示，细胞剂量对运动技能、社会发展或气质没有主要影响。总的来说，这些数据表明，同种异体间充质干细胞在跨恒河猴MHC边界移植时免疫原性较弱，这对持久的植入水平产生了负面影响。因此，应在人类患者中仔细评估无关供体MSC的使用。
The emerging paradigm that MSCs are immune privileged has fostered the use of “off-the-shelf” allogeneic MSC-based therapies in human clinical trials. However, this approach ignores studies in experimental animals wherein transplantation of MSCs across MHC boundaries elicits measurable allo-immune responses. To determine if MSCs are hypo-immunogeneic, we characterized the immune response in rhesus macaques following intracranial administration of allogeneic vs. autologous MSCs. This analysis revealed unambiguous evidence of productive allo-recognition based on expansion of NK, B and T cell subsets in peripheral blood and detection of allo-specific antibodies in animals administered allogeneic but not autologous MSCs. Moreover, the degree of MHC class I and II mismatch between the MSC donor and recipient significantly influenced the magnitude and nature of the allo-immune response. Consistent with these findings, real-time PCR analysis of brain tissue from female recipients administered varying doses of male, allogeneic MSCs revealed a significant inverse correlation between MSC engraftment levels and cell dose. Changes in post-transplant neutrophil and lymphocyte counts also correlated with dose and were predictive of overall MSC engraftment levels. However, secondary antigen challenge failed to elicit a measurable immune response in allogeneic recipients. Finally, extensive behavior testing of animals revealed no main effect of cell dose on motor skills, social development, or temperament. Collectively, these data indicate that allogeneic MSCs are weakly immunogenic when transplanted across MHC boundaries in rhesus macaques and this negatively impacts durable engraftment levels. Therefore the use of unrelated donor MSCs should be carefully evaluated in human patients.
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影响因子：
2.2
作者：
Autissier, Patrick;Soulas, Caroline;Burdo, Tricia H.;Williams, Kenneth C.
通讯作者：
Williams, Kenneth C.
影响因子：
4.3
作者：
Boyiadzis, Michael;Memon, Sarfraz;Hakint, Frances T.
通讯作者：
Hakint, Frances T.
DOI：
10.1084/jem.185.12.2053
发表时间：
1997-06-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Carbone E;Ruggiero G;Terrazzano G;Palomba C;Manzo C;Fontana S;Spits H;Kärre K;Zappacosta S
通讯作者：
Zappacosta S
影响因子：
9.3
作者：
Camp DM;Loeffler DA;Farrah DM;Borneman JN;LeWitt PA
通讯作者：
LeWitt PA
影响因子：
20.3
作者：
Bryceson, YT;March, ME;Long, EO
通讯作者：
Long, EO