Troppmann C, Gruessner A C, Papalois B E, Nakhleh R E, Gruessner R W
Department of Surgery, University of Minnesota, Minneapolis, USA.
Surgery. 1997 Feb;121(2):194-205. doi: 10.1016/s0039-6060(97)90290-7.
It is not known whether discordant, free, nonvascularized xenoislets-akin to discordant, vascularized, solid xenoorgans-are hyperacutely rejected. Quantitative xenoislet requirements and the optimal transplant site also remain to be defined.
We studied these questions with a discordant dog-to-diabetic Lewis rat xenoislet model, using (1) functional (cure of streptozotocin-induced diabetes) and (2) histologic (biopsies of intraportal grafts) parameters. WF-to-Lewis alloislet recipients served as histologic controls.
(1) We found that 5000 xenoislet equivalents (IEs) transplanted into the portal veins of nonimmunosuppressed rats never functioned. Peritransplant combination therapy (rapamycin, cyclosporin A, anti-rat lymphocyte serum) significantly prolonged graft survival of 5000 intraportal IEs (median, 3 days) but not of 2500 intraportal or of 5000 intraperitoneal or renal subcapsular IEs. (2) By means of immunofluorescence (at 1 hour after transplantation), we noted immunoglobulin M (IgM) and IgG binding to islets in xenografts but not allografts; we noted complement and fibrinogen binding in both xenografts and allografts. Insulin-positive islet cells within intact xenoislets were demonstrated in nonimmunosuppressed rats up to 48 hours after transplantation. Cellular xenograft infiltration and inflammation, beginning at 6 hours, were observed even in immunosuppressed rats. (3) Thus, in spite of IgM and IgG binding, intraportal discordant xenoislets were not hyperacutely rejected and destroyed. Nevertheless, universal xenoislet nonfunction in nonimmunosuppressed rats was immune mediated. A large xenoislet mass (more than 10,000 IEs/kg), the intraportal site, and combination therapy were absolute prerequisites for immediate function. But even if the prerequisites were all fulfilled, accelerated xenoislet graft failure occurred.
This outcome suggests that the specific binding of IgM and IgG to xenoislets, in conjunction with the binding of complement and fibrinogen, contributed to accelerated graft failure. Thus distinction between discordant and concordant species combinations is important for free, nonvascularized xenoislet transplants. These findings and the steroid-free combination protocol (rapamycin, cyclosporin A, anti-T-cell therapy) warrant further testing in preclinical discordant xenoislet studies.
与不匹配的、血管化的实体异种器官类似，不匹配的、游离的、无血管化的异种胰岛是否会发生超急性排斥反应尚不清楚。异种胰岛的定量需求以及最佳移植部位也有待确定。
我们使用不匹配的犬至糖尿病Lewis大鼠异种胰岛模型研究了这些问题，采用了（1）功能参数（链脲佐菌素诱导的糖尿病的治愈情况）和（2）组织学参数（门静脉内移植物活检）。WF至Lewis同种胰岛受体作为组织学对照。
（1）我们发现，将5000个异种胰岛当量（IEs）移植到未免疫抑制大鼠的门静脉中从未发挥功能。移植周围联合治疗（雷帕霉素、环孢素A、抗大鼠淋巴细胞血清）显著延长了5000个门静脉内IEs的移植物存活时间（中位数为3天），但对2500个门静脉内、5000个腹腔内或肾被膜下的IEs则没有效果。（2）通过免疫荧光（移植后1小时），我们注意到异种移植物中的胰岛有免疫球蛋白M（IgM）和IgG结合，但同种移植物中没有；我们在异种移植物和同种移植物中都注意到了补体和纤维蛋白原结合。在未免疫抑制的大鼠中，移植后48小时内完整异种胰岛内的胰岛素阳性胰岛细胞得到证实。即使在免疫抑制的大鼠中，也观察到从6小时开始的细胞异种移植物浸润和炎症。（3）因此，尽管有IgM和IgG结合，门静脉内不匹配的异种胰岛并未发生超急性排斥和破坏。然而，未免疫抑制大鼠中异种胰岛普遍无功能是由免疫介导的。大量的异种胰岛团块（超过10,000个IEs/kg）、门静脉部位和联合治疗是立即发挥功能的绝对先决条件。但即使所有先决条件都满足，异种胰岛移植物仍会加速失败。
这一结果表明，IgM和IgG与异种胰岛的特异性结合，以及补体和纤维蛋白原的结合，导致了移植物加速失败。因此，对于游离的、无血管化的异种胰岛移植，区分不匹配和匹配的物种组合很重要。这些发现以及无类固醇联合方案（雷帕霉素、环孢素A、抗T细胞治疗）值得在临床前不匹配异种胰岛研究中进一步测试。
