Reversal of diabetes in non-immunosuppressed rhesus macaques by intraportal porcine islet xenografts precedes acute cellular rejection
Reversal of diabetes in non-immunosuppressed rhesus macaques by intraportal porcine islet xenografts precedes acute cellular rejection
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DOI：
10.1111/j.1399-3089.2004.00157.x
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发表时间：
2004-09-01
影响因子：
3.9
通讯作者：
Hering, BJ
中科院分区：
文献类型：
--
作者：
Kirchhof, N;Shibata, S;Hering, BJ
背景资料：主要的非血管化胰岛细胞异种移植的功能反应和免疫生物学仍然很难定义在非人primates.Methods：我们移植20 000成年猪胰岛当量/公斤（纯化和培养48小时）intraportally到6个链脲佐菌素糖尿病和两个非糖尿病猕猴。两个受体被杀死在不同的时间间隔移植后进行组织学检查的肝脏轴承xenografts.Results：糖尿病受体的血糖水平平均94 mg/dl，在12小时，92 mg/dl，在24小时，147 mg/dl，在48小时，和157 mg/dl在72小时移植后。血清猪C-肽存在于8个受体在12小时，在5个6在24小时，在4个4在48小时，在两个在移植后72小时。C3 a和SC 5 b-9血浆水平在移植后12小时增加，并在24小时恢复到移植前水平。IgG、IgM抗猪和抗半乳糖IgG血清抗体水平在移植后没有增加。排斥反应由IgM和补体沉积在胰岛上启动。中性粒细胞在12 h时占主导地位的细胞浸润; CD 4（+）和CD 8（+）T细胞是24、48和72 h时的主要浸润细胞;巨噬细胞从移植后24 h开始逐渐浸润异种移植物。许多异种胰岛存在于所有时间点，他们的比例从65%在24小时内胰岛内浸润下降到17%在72小时post-transplant.Conclusions：猪灵长类动物门静脉内胰岛异种移植逆转糖尿病和大多数的门静脉内移植异种胰岛不受超急性排斥反应。它们经历由CD 4（+）-和CD 8（+）T细胞和巨噬细胞介导的急性细胞排斥。
Background: The functional response and immunobiology of primarily non-vascularized islet cell xenografts remain poorly defined in non-human primates.Methods: We transplanted 20 000 adult porcine islet equivalents/kg (purified and cultured for 48-h) intraportally into six streptozotocin-diabetic and two non-diabetic rhesus macaques. Two recipients were killed at various intervals post-transplant for histologic examination of livers bearing xenografts.Results: Plasma glucose levels in diabetic recipients averaged 94 mg/dl at 12 h, 92 mg/dl at 24 h, 147 mg/dl at 48 h, and 157 mg/dl at 72 h post-transplant. Serum porcine C-peptide was present in eight of eight recipients at 12 h, in five of six at 24 h, in four of four at 48 h, and in one of two at 72 h post-transplant. C3a and SC5b-9 plasma levels increased at 12 h post-transplant and returned to pre-transplant levels by 24 h. IgG, IgM anti-pig and anti-Gal IgG serum antibody levels did not increase post-transplant. Rejection was initiated by IgM and complement deposition on islets. Neutrophils dominated the cellular infiltrate at 12 h; CD4(+) and CD8(+) T cells were the main infiltrating cells at 24, 48, and 72 h; and macrophages increasingly infiltrated xenografts starting at 24 h post-transplant. Numerous xenoislets were present at all time points; their proportion without intraislet infiltrates decreased from 65% at 24 h to 17% at 72 h post-transplant.Conclusions: Pig-to-primate intraportal islet xenografts reverse diabetes and the majority of intraportally transplanted xenogeneic islets are not subject to hyperacute rejection. They undergo acute cellular rejection mediated by CD4(+)- and CD8(+) T cells and macrophages.