Functional Tolerance to Islet Allografts

描述(申请人提供)：自身免疫性疾病，如1型糖尿病(T1D)，当胰岛素产生细胞已经完全丧失时，在临床上表现出来。在这一点上，糖尿病的唯一治疗方法是替换这些产生胰岛素的细胞。然而，接受这种移植物的患者遭受终身免疫抑制治疗，导致感染倾向增加。如果能够赋予这些移植物对同种异体排斥反应的功能性抵抗，就可以避免对免疫抑制的需求，从而大大提高接受同种异体移植物的患者的生活质量。在R21的这一探索性应用中，我们提出了诱导同种异体胰岛移植排斥反应抵抗的新假说。由于这些移植物被渗透细胞产生的细胞因子破坏，我们建议设计对这些致病细胞因子无反应的胰岛。在本申请中提出了两种不同的实验设计。在第一组研究中，我们将确定靶向表达SOCS-1(一种抑制干扰素信号的蛋白质)是否可以改善移植物反应。我们提供了令人信服的初步数据，表明这一目标是可行的，并显示了有希望的结果。在第二组研究中，我们计划下调SOCS-3基因的表达，以确定调节IL-6的反应，增加对IL-10的反应，是否可以在移植物存活中发挥促进生存的作用。对于每个范例，都提出了广泛的机制研究，以了解全身和局部的同种异体移植反应。这些研究将导致诱导对同种异体胰岛移植排斥反应的抵抗的新方法。

DESCRIPTION (provided by applicant): Autoimmune diseases such as Type 1 diabetes (T1D) manifest themselves clinically when insulin producing cells are already completely lost. At this point, the only cure for diabetes is the replacement of these insulin-producing cells. However, patients receiving such grafts suffer from lifetime immunosuppressive treatments, leading to increased propensity to infection. If functional resistance.- to allograft rejection could be conferred on these grafts the requirement for immunosuppression would be avoided aid the quality of life for those receiving allografts would be greatly enhanced. In this exploratory R21 application we propose a new hypothesis for the induction of resistance to islet allograft rejection. Since these grafts are destroyed by cytokines produced by infiltrating cells, we proposed to engineer islets that are unresponsive to these pathogenic cytokines. Two different experimental designs are proposed in this application. In the first set of studies we will determine whether targeted expression of SOCS-1, a protein that inhibits interferon signaling, can ameliorate graft responses. We present compelling preliminary data stating that this aim is feasible and shows promising results. In the second set of studies we plan to down-modulate SOCS-3 gene expression to determine if modulation of IL-6 responses, with increased responses to IL-10, could play a pro-survival role in graft survival. Extensive mechanistic studies, to understand both systemic and localized allograft responses, are proposed for each paradigm. These studies should lead to new methods for inducing resistance to islet allograft rejection.