Cui Hong, Tucker-Burden Carol, Cauffiel Sean M D, Barry Adrienne K, Iwakoshi Neal N, Weber Collin J, Safley Susan A
Department of Surgery, Emory University, Atlanta, GA 30322, USA.
Transplantation. 2009 Jul 27;88(2):160-9. doi: 10.1097/TP.0b013e3181abbfc1.
The long-term metabolic function of microencapsulated xenogeneic adult porcine islets (API) was assessed in a murine model of type 1 diabetes mellitus.
API were encapsulated in barium-gelled alginate and transplanted intraperitoneally in diabetic nonobese diabetic (NOD) mice given no immunosuppression or given costimulatory blockade (CoB; CTLA4-Ig+anti-CD154 mAb). Control mice received nonencapsulated API under the kidney capsule. Graft function was monitored by measurement of random blood glucose levels, serum glycosylated hemoglobin (HbA1c), serum porcine C peptide, in vivo glucose tolerance tests, and histologic analyses of host pancreas and graft biopsies. Host immune responses to the islet xenografts were characterized by phenotyping peritoneal cellular infiltrates and by measuring serum antiporcine antibody levels.
Without immunosuppression, nonencapsulated API functioned for less than 1 week, and microencapsulated API functioned for 35+/-14 days before rejection, associated with both a cellular and a humoral immune response. With continuous CoB, nonencapsulated API functioned for 27+/-4 days, whereas microencapsulated API functioned for >450 days with measurable levels of serum porcine C peptide, near normal in vivo glucose tolerance tests and HbA1c levels, and intact microcapsules containing viable, insulin-positive porcine islets.
Microencapsulated API restored normoglycemia for more than 1 year in spontaneously diabetic NODs given dual CoB. To our knowledge, this is the first study to document long-term normalized HbA1c, porcine C peptide, and near normal glucose tolerance in immunosuppressed diabetic NOD mice transplanted intraperitoneally with microencapsulated API. Our study suggests that transplantation of microencapsulated porcine islet xenografts may be a future treatment for patients with type 1 diabetes mellitus.
在1型糖尿病小鼠模型中评估了微囊化异种成年猪胰岛（API）的长期代谢功能。
将API包裹于钡凝胶海藻酸盐中，并腹腔内移植到未接受免疫抑制或接受共刺激阻断（CoB；CTLA4-Ig+抗CD154单克隆抗体）的糖尿病非肥胖糖尿病（NOD）小鼠体内。对照小鼠在肾被膜下接受未包裹的API。通过测量随机血糖水平、血清糖化血红蛋白（HbA1c）、血清猪C肽、体内葡萄糖耐量试验以及宿主胰腺和移植物活检的组织学分析来监测移植物功能。通过对腹腔细胞浸润进行表型分析和测量血清抗猪抗体水平来表征宿主对胰岛异种移植物的免疫反应。
在未进行免疫抑制的情况下，未包裹的API发挥功能不到1周，而微囊化的API在排斥前发挥功能35±14天，这与细胞免疫和体液免疫反应均有关。持续进行CoB时，未包裹的API发挥功能27±4天，而微囊化的API发挥功能超过450天，血清猪C肽水平可测，体内葡萄糖耐量试验和HbA1c水平接近正常，且含有存活的、胰岛素阳性猪胰岛的完整微囊。
在给予双重CoB的自发糖尿病NOD小鼠中，微囊化的API使血糖正常化超过1年。据我们所知，这是第一项记录在腹腔内移植微囊化API的免疫抑制糖尿病NOD小鼠中HbA1c长期正常化、猪C肽以及接近正常的葡萄糖耐量的研究。我们的研究表明，微囊化猪胰岛异种移植物移植可能是1型糖尿病患者未来的一种治疗方法。
