Dendritic Cells with Galectin-1 to Enhance Islet Grafts

描述（由申请人提供）：胰岛素依赖型糖尿病（IDDM）是一种选择性破坏胰腺产生胰岛素的β细胞的自身免疫性疾病。唯一可能的治疗方法是更换被破坏的β细胞群。与胰岛分离相关的技术问题不再限制从同种异体供体获得的胰岛的治疗用途。然而，用于防止同种异体胰岛排斥反应的免疫抑制药物引起广泛的免疫抑制和有害的副作用。胰岛细胞同种异体移植物的排斥反应主要是因为同种异体抗原（Ag）特异性T细胞对移植组织的反应。树突状细胞（DC）是Ag呈递细胞（APC），其激活受体幼稚T细胞，从而触发移植排斥。半乳糖凝集素-1是一种有效的T细胞反刺激因子，在抗原呈递过程中DC-T细胞相互作用的早期阶段干扰免疫突触的形成。因此，半乳糖凝集素-1诱导T细胞凋亡。 在这个提议中，我们假设，供体来源的DC表达转基因半乳糖凝集素-1可以被用作“致耐受性DC”，以诱导胰岛细胞移植的小鼠模型中的Ag特异性T细胞耐受。DC将用编码人半乳糖凝集素-1加上报告基因增强的绿色荧光蛋白（EGFP）的重组腺病毒（rAd）载体（rAd-GaI-1 -EGFP）转导。目的1和2）研究表达转基因半乳糖凝集素-1的DC在体外和体内与初始T细胞的相互作用;目的3）研究rAd-Gal-1-EGFP转导的DC能否逆转高血糖和促进胰岛移植物长期存活。细胞耐受性结合了移植领域中两种有前途的工具：致耐受性DC和T细胞反刺激因子（即半乳糖凝集素-1）。在胰岛细胞同种异体移植排斥反应中，DC激活受体I细胞的机制将被研究。这种方法可以显著延长同种异体移植物的存活时间，并最大限度地减少对免疫抑制药物的副作用和对胰岛的毒性。这些结果可能对β细胞自身免疫的调节和其他移植领域产生重要影响。

DESCRIPTION (provided by applicant): Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disorder that destroys selectively the insulin-producing beta cells of pancreas. The only possible cure for IDDM is the replacement of the destroyed beta cell mass. Technical problems related to pancreatic islet isolation no longer limit the therapeutic use of pancreatic islets obtained from allogeneic donors. However, the immunosuppressive drugs employed to prevent rejection of allogeneic islets induce generalized immunosuppression and harmful side-effects. Rejection of islet cell allografts occurs mainly because allo-antigen (Ag)-specific T cells react against the transplanted tissue. Dendritic cells (DC) are the Ag-presenting cells (APC) that activate the recipient na¿ve T cells that trigger the transplant rejection. Galectin-1 is a potent T cell counterstimulator that interferes with the formation of the immunological synapse at the early stages of DC-T cell interaction during Ag presentation. As a consequence, galectin-1 induces T cell apoptosis. In this proposal, we hypothesize that donor-derived DC expressing transgenic galectin-1 can be used as "tolerogenic DC" to induce Ag-specific T cell tolerance in a murine model of islet cell transplantation. DC will be transduced with a recombinant adenovirus (rAd) vector encoding human galectin-1 plus the reporter gene enhanced green fluorescent protein (EGFP) (rAd-GaI-1 -EGFP). The aims of this proposal are the following:Aims 1 and 2) to investigate the interaction of DC expressing transgenic galectin-1 with na¿ve T cells in vitro and in vivo; and Aim 3) to determine whether transfer of donor-derived rAd-Gal-1-EGFP-transduced DC can reverse hyperglycemia and promote long-term pancreatic islet allograft survival.These studies will explore novel ways to generate allo-Ag specific 1-cell tolerance combining two promising tools in the transplantation field: tolerogenic DC and T cell counterstimulators (i.e. galectin-1). The mechanisms by which DC activate recipient I cells during rejection of islet cell allografts will be investigated. This approach may achieve significant prolongation of allograft survival and minimize the need for immunosuppressive drugs with side-effects and toxicity against pancreatic islets. The results may have an important impact on regulation of beta-cell autoimmunity and in other areas of transplantation.