Immuno-vasculogenic hydrogels for islet engraftment and localized tolerance

用于胰岛移植和局部耐受的免疫血管生成水凝胶

• 批准号: 8869094
• 负责人: Andres J Garcia
• 金额: $ 19.67万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8869094
• 关键词: Abdomen; Adult; Affect; Allogenic; Antigens; Apoptosis; Autoantigens; Autoimmune Diseases; Beta Cell; Biocompatible Materials; Biotin; Cells; Cessation of life; Child; Chronic; Dendritic Cells; Development; Diabetes Mellitus; Diabetic mouse; Drug Formulations; Effector Cell; Encapsulated; Engineering; Engraftment; Enzymes; Extrahepatic; Generations; Goals; Graft Rejection; Graft Survival; Health Care Costs; Homeostasis; Human; Hydrogels; Hypoglycemia; IL2RA gene; Immune; Immune Tolerance; Immune response; Immune system; Immunology; Immunosuppression; Implant; In Vitro; Infection; Inflammatory Infiltrate; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Islets of Langerhans Transplantation; Label; Lead; Lectin; Life; Ligands; Liver; Longitudinal Studies; Maintenance; Malignant Neoplasms; Mesentery; Metabolic Control; Monitor; Mus; Nature; Pancreas; Patients; Performance; Phenotype; Population; Proteins; Quality of life; Regulatory T-Lymphocyte; Research; Signaling Molecule; Sirolimus; Site; Small Intestines; Source; Streptavidin; Testing; Therapeutic; Transplantation; Tryptophan 2,3 Dioxygenase; Vascular Endothelial Growth Factors; Vascularization; Work; base; clinical application; clinical practice; cytokine; density; efficacy testing; graft failure; improved; in vivo; innovation; islet; novel; novel strategies; peripheral tolerance; prevent; programs; public health relevance; receptor; response; standard care

 DESCRIPTION: Type 1 diabetes (T1D) is an autoimmune disease caused by immune destruction of insulin-producing pancreatic ß cells. T1D affects 3 million children and adults in the US with healthcare costs exceeding $14.9 billion. Allogeneic islet transplantation has proven effective in improving metabolic control/quality of life and in preventing severe hypoglycemia in patients with T1D. However, broad clinical application of allogeneic islets is limited by i) immune rejection despite the chronic use of immunosuppression and its sequelae, ii) transplantation into the liver, which compromises immediate post-graft islet engraftment as well as long-term survival, and iii) insufficient human islet supply from cadaveric pancreata. Thus, there is a significant need for innovative strategies that overcome these limitations of islet transplantation for a broader clinical practice. This R21 application is formulated to overcome graft rejection without chronic use of immunosuppression and establish the small bowel mesentery as an extrahepatic site for islet transplantation, thereby overcoming two critical barriers of islet transplantation. This will be achieved by engineering dual-action immunomodulatory and vasculogenic hydrogels for controlled delivery of a novel form of PD-L1 and VEGF for islet transplantation in the small bowel mesentery. PD-L1 (programmed death-ligand 1) is an important immunoregulatory molecule involved in tolerance to self-antigens and has extensively been exploited by chronic infections and cancer for immune evasion. PD-L1 interaction with PD-1 receptor on various adaptive and innate immune effector cells results in inhibition of effector function and/or physical elimination of these cells. Importantly, PD-1/PD-L1 interaction is involved in the generation of tolerogenic DCs and induced CD4+CD25+FoxP3+ Treg cells that are critical to peripheral tolerance to self-antigens and acquired tolerance to foreign antigens in various experimental settings. VEGF has recently been shown to confer a stable tolerogenic phenotype to DCs by inducing the expression of indoleamine 2,3-dioxygenase (IDO). IDO is an important immunoregulatory enzyme and signaling molecule that is involved in fetomaternal tolerance and generation of Treg cells. Our central hypothesis is that PD-L1 and VEGF delivered by biomaterials will work in synergy to induce localized tolerance and promote islet vascularization for long-term allogeneic islet survival and function without continuous use of immunosuppression. The overall objective will be accomplished by testing our central hypothesis through two Aims: 1) Engineer PD-L1/VEGF- presenting hydrogels to generate Treg cells in vitro and facilitate allogeneic islet engraftment, vascularization, and survival in short-erm in vivo studies; and 2) Test the efficacy of the PD-L1/VEGF hydrogels to support long-term engraftment, vascularization, tolerance induction, and treatment of diabetes. Studies will be conducted to elucidate the mechanistic basis of graft failure and/or long-term survival with particular focus on innate and adaptive effector immune and regulatory (tolerogenic dendritic cells and Treg cells) responses.

 描述：1型糖尿病（T1D）是一种自身免疫性疾病，是由产生胰岛素的胰腺肿瘤细胞免疫抑制引起的。 T1D在美国影响300万儿童和成人，其医疗费用超过149亿美元。事实证明，同种异体胰岛移植可有效改善代谢控制/生活质量，并防止T1D患者的严重低血糖。但是，同种异体胰岛的广泛临床应用受到i）免疫的限制 尽管长期使用免疫抑制及其后遗症，但排斥反应ii）移植到肝脏中，这会损害直接的移植后胰岛和长期生存，以及iiii）尸体胰腺的人类胰岛供应不足。这是克服这些胰岛移植的这些局限性的创新策略的重要需求 该R21应用于不长期使用免疫抑制而在不长期使用免疫抑制的情况下格式排斥反应，并将小肠肠系膜作为胰岛移植的外膜外部位，从而克服了两个胰岛移植的关键障碍。这将通过工程双动作免疫调节和血管生成水凝胶来控制一种新型的PD-L1和VEGF形式，用于小肠肠系膜中的胰岛移植。 PD-L1（编程死亡配体1）是一种重要的免疫调节分子，涉及对自我抗原的耐受性，并且已通过慢性感染和癌症进行了广泛的探索。 PD-L1与PD-1受体的相互作用在各种适应性和先天免疫阻塞细胞上的相互作用会导致抑制效应子功能和/或物理消除这些细胞。重要的是，PD-1/PD-L1相互作用与耐受性DC的产生和诱导的CD4+CD25+Foxp3+Treg细胞有关，这对于对自我抗原的外围耐受性至关重要，并获得了对异物抗原的耐受性 各种实验设置。最近，VEGF通过诱导吲哚胺2,3-二加氧酶（IDO）的表达来将VEGF与DC稳定的耐受性表型相连。 IDO是一种重要的免疫调节酶和信号分子，与胎儿耐受性和Treg细胞的产生有关。我们的核心假设是，生物材料传递的PD-L1和VEGF将在协同作用下诱导局部耐受性并促进胰岛血管化，用于长期同种异体同种异体胰岛存活和功能，而无需不断使用免疫抑制。总体目标将通过通过两个目的测试我们的中心假设来实现：1）工程师PD-L1/VEGF-呈现水凝胶，以在体外生成Treg细胞并促进同种异体胰岛植入，血管形成，血管形成和在体内研究中的短疗法中生存； 2）测试PD-L1/VEGF水凝胶的效率支持长期植入，血管形成，耐受性诱导和糖尿病治疗。将进行研究，以阐明移植失败和/或长期生存的机理基础，特别关注先天和适应性效应的免疫和调节性（耐受性树突状细胞和Treg细胞）反应。