PRIMARY NONFUNCTION AFTER ISLET TRANSPLANTATION

我们的最终目标是通过同种异体胰岛治疗糖尿病 移植。几乎所有治疗同种异体胰岛的临床尝试 到目前为止，移植手术已经失败，大多数人表现出了原发的非 功能(PNF)，甚至没有一过性的正常血糖。我们有 建立了一种PNF小鼠，其中PNF的频率不成比例 发生在B10.BR和C57BL/6之间的同种异体胰岛移植中 菌株。在这个小鼠模型中，PNF可以通过给药来消除 抗巨噬细胞制剂，二氧化硅，并通过给药或 环孢素、15-脱氧精胺或较大的胰岛肿块。值得注意的是，使用 观察到15-脱氧精灵可减少小鼠同系移植物中的PNF， 这意味着PnF在本质上可能是非特异性的。其他人发现 细胞因子IL-1、IL-6、干扰素-γ与肿瘤坏死 肿瘤坏死因子在体外对胰岛细胞功能有抑制作用。因此，我们假设 巨噬细胞或其他免疫活性细胞对 由β细胞功能替代细胞因子产生的非特异性 炎症反应，在同种异体移植的情况下，可能会增强 通过同种异体免疫反应。我们将测试管理的效果 抗巨噬细胞药物和细胞因子特异性抑制剂对PNF的影响 小鼠胰岛移植模型。我们还将测量细胞因子 胰岛移植物在不同时间的浓度和细胞渗入的评估 同种异体移植物和同种异体肾移植后间隔时间的比较 同种异体移植，以便将水平或细胞类型与 PnF的发生。最后，我们将确定细胞因子是否 体内发现对胰岛有害的物质直接影响胰岛β细胞 功能或通过放大炎症的其他成分来实现 回应。将测试细胞因子对β细胞功能的影响。 在体外研究它们抑制刺激的胰岛素分泌的能力。它是 预计来自拟议的小鼠实验的数据将有助于形成 合理治疗或预防人类PNF的基础 胰岛移植。我们推测PNF的减少可能会允许更多的 有效植入和改善移植胰岛的功能， 可以避免目前临床上浪费的使用一种以上的方法 人胰岛分离与移植的供体胰腺。

Our ultimate goal is to cure diabetes mellitus by allogeneic islet transplantation. Almost all clinical attempts at allogeneic islet transplants have so far failed, and most have exhibited primary non- function (PNF) without even a transient period of normoglycemia. We have developed a murine of PNF in which disproportionate frequencies of PNF occur in reciprocal islet allograft transplants between B10.BR and C57BL/6 strains. In this mouse model, PNF can be abolished by administration of the anti-macrophage agent, silica, and reduced by administration of either cyclosporine, 15-deoxyspergualin, or larger islet mass. Of note, use of 15-deoxyspergualin was observed to decrease PNF in murine isografts, implying that PNF may be non-specific in nature. Others have found that the cytokines (IL)-1, IL-6, interferon (IFN)-gamma, and tumor necrosis factor (TNF) inhibit beta cell function in vitro. Thus we hypothesize that macrophages or other immunologically competent cells are detrimental to beta cell function by lieu of cytokines generated in a non-specific inflammatory response, which may, in the case of allografts, be augmented by an alloimmune response. We will test the effect of the administration of anti-macrophage agents and specific inhibitors of cytokines on PNF in the mouse islet transplant model. We will also measure cytokine concentrations and evaluate cellular infiltrates in islet grafts at various intervals after transplantation with comparison between allografts and isografts in order to correlate the levels or cell types with the occurrence of PNF. Finally, we will determine whether the cytokines identified as deleterious to islets in vivo directly affect beta cell function or do so by amplification of other components of the inflammatory response. The effect of the cytokines on beta cell function will be tested in vitro for their ability to suppress stimulated insulin secretion. It is expected that data from the proposed experiments in mice will help to form the basis of a rational approach to treatment or prevention of PNF in human islet transplantation. We speculate that reduction of PNF may allow a more efficient engraftment and improved function of transplanted islets, which may obviate the current clinically wasteful approach of using more than one donor pancreas for human islet isolation and transplantation.