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 几乎所有的同种异体胰岛移植的临床尝试 到目前为止，移植失败了，大多数都表现出原发性非- 功能（PNF），甚至没有短暂的正常周期。 我们有 开发了一种PNF小鼠，其中PNF的不成比例频率 发生在B10.BR和C57BL/6之间的同种异体胰岛移植中 菌株 在该小鼠模型中，PNF可以通过施用以下物质来消除： 抗巨噬细胞剂，二氧化硅，并通过施用 环孢菌素、15-脱氧精胍菌素或较大的胰岛质量。 注意，使用 15-观察到脱氧精胍菌素降低鼠同种移植物中的PNF， 这意味着PNF可能是非特异性的。 其他人发现， 细胞因子（IL）-1、IL-6、干扰素（IFN）-γ和肿瘤坏死 因子（TNF）在体外抑制β细胞功能。 因此，我们假设， 巨噬细胞或其他免疫活性细胞对 β细胞功能通过替代细胞因子产生的非特异性 炎症反应，在同种异体移植物的情况下， 通过同种免疫反应 我们将检验行政管理的效果 抗巨噬细胞剂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 浓度和评估细胞浸润的胰岛移植物在各种 移植后的时间间隔，比较同种异体移植物和 为了将水平或细胞类型与同种移植物相关联， PNF的发生。 最后，我们将确定细胞因子是否 被鉴定为在体内对胰岛有害，直接影响β细胞 功能或通过放大炎性细胞因子的其他成分来发挥作用。 反应 将测试细胞因子对β细胞功能的影响 在体外研究其抑制刺激的胰岛素分泌的能力。 是 预计来自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的减少可能会使更多的 有效的植入和改善移植胰岛的功能， 可能会减少目前临床上使用一种以上的浪费方法 用于人胰岛分离和移植的供体胰腺。

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.