Weber C J, Zabinski S, Koschitzky T, Wicker L, Rajotte R, D'Agati V, Peterson L, Norton J, Reemtsma K
Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
Transplantation. 1990 Feb;49(2):396-404. doi: 10.1097/00007890-199002000-00034.
Islet transplants for large numbers of patients with diabetes will require xenografts. Microencapsulation is an appealing method for islet xenografting. However, graft function has been limited by a cellular reaction, particularly intense in spontaneously diabetic, NOD mice. The purpose of this study was to elucidate the mechanism of this reaction. Poly-1-lysine-alginate microcapsules containing 4000-12,000 dog or 1800-2000 rat islets were xenografted intraperitoneally into streptozotocin (SZN)-diabetic C57BL/6J and NOD mice, with or without recipient treatment with GK 1.5 (anti-CD4 monoclonal antibody) (20-30 microliters i.p. every 5 days, begun on day -7. Grafts were considered technically successful if random blood glucose (BG) was normalized (less than 150 mg/dl) within 36 hr. Graft failure was defined as BG greater than 250 mg/dl. Dog and rat islets in microcapsules normalized BG in both SZN and NOD mice within 24 hr routinely. Empty microcapsules and GK 1.5 treatments alone did not affect BG. NODs destroyed both microencapsulated dog and rat islets more rapidly than did SZN-diabetic mice (P less than .01). Graft biopsies showed an intense cellular reaction, composed of lymphocytes, macrophages and giant cells, and no viable islets. GK 1.5 treatment significantly prolonged both dog-to-NOD and rat-to-NOD grafts (P less than 0.01). Biopsies of long-term functioning grafts (on days 65-85) demonstrated viable islets and no cellular reaction around microcapsules; 1/4 rat and 1/8 dog islet xenografts continued to function indefinitely in NOD recipients, even after cessation of GK 1.5 therapy. Prediabetic NODs receiving encapsulated dog or rat islets mounted a moderate cellular reaction to grafts. Empty microcapsules excited no cellular reaction in diabetic or prediabetic NODs. We conclude that the NOD reaction to microencapsulated xenogeneic islets is helper T cell-dependent, and that the target of this reaction is not the microcapsule itself, but the donor cells within.
为大量糖尿病患者进行胰岛移植将需要异种移植。微囊化是胰岛异种移植的一种有吸引力的方法。然而，移植功能一直受到细胞反应的限制，在自发性糖尿病的非肥胖糖尿病（NOD）小鼠中这种反应尤为强烈。本研究的目的是阐明这种反应的机制。将含有4000 - 12000个犬胰岛或1800 - 2000个大鼠胰岛的聚-1-赖氨酸-海藻酸盐微囊经腹腔异种移植到链脲佐菌素（SZN）诱导糖尿病的C57BL/6J和NOD小鼠体内，部分受体接受GK 1.5（抗CD4单克隆抗体）治疗（每5天腹腔注射20 - 30微升，从第 - 7天开始）。如果随机血糖（BG）在36小时内恢复正常（低于150mg/dl），则认为移植在技术上成功。移植失败定义为BG大于250mg/dl。微囊中的犬和大鼠胰岛通常在24小时内使SZN和NOD小鼠的BG恢复正常。单独的空微囊和GK 1.5治疗不影响BG。与SZN诱导糖尿病的小鼠相比，NOD小鼠更快地破坏了微囊化的犬和大鼠胰岛（P小于0.01）。移植活检显示有强烈的细胞反应，由淋巴细胞、巨噬细胞和巨细胞组成，且无存活的胰岛。GK 1.5治疗显著延长了犬胰岛到NOD小鼠和大鼠胰岛到NOD小鼠的移植存活时间（P小于0.01）。长期功能良好的移植（第65 - 85天）活检显示有存活的胰岛，微囊周围无细胞反应；即使在停止GK 1.5治疗后，1/4的大鼠胰岛和1/8的犬胰岛异种移植在NOD受体中仍能无限期发挥功能。接受微囊化犬或大鼠胰岛的糖尿病前期NOD小鼠对移植产生中度细胞反应。空微囊在糖尿病或糖尿病前期NOD小鼠中未引发细胞反应。我们得出结论，NOD小鼠对微囊化异种胰岛的反应依赖于辅助性T细胞，并且这种反应的靶标不是微囊本身，而是其中的供体细胞。
