Protein-Releasing Microporous Scaffolds for Cell Replacement Therapy

用于细胞替代疗法的蛋白质释放微孔支架

• 批准号: 8886518
• 负责人: Xunrong Luo
• 金额: $ 55.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886518
• 关键词: Acute; Address; Affect; Allogenic; American; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Antigens; Apoptotic; Autologous; Biocompatible Materials; Biomedical Engineering; CD8B1 gene; Carbodiimides; Cell Therapy; Cell Transplantation; Cell Transplants; Cell physiology; Cell-Free System; Cells; Chronic; Development; Disease; Drug Delivery Systems; Engineering; Engraftment; Environment; Extracellular Matrix; Extrahepatic; Funding; Glycolic-Lactic Acid Polyester; Graft Rejection; Grant; Growth; Growth Factor; Homologous Transplantation; Hybrids; Immune; Immune Tolerance; Immune response; Immunosuppression; Immunosuppressive Agents; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Investigation; Investigational Therapies; Islets of Langerhans Transplantation; Laboratories; Life; Liver; Malignant Neoplasms; Marketing; Opportunistic Infections; Organ Transplantation; Patient risk; Pharmaceutical Preparations; Phenotype; Predisposition; Production; Proteins; Recruitment Activity; Regulation; Regulatory T-Lymphocyte; Replacement Therapy; Research; Signal Transduction; Site; Solid; Source; Specificity; Splenocyte; Staging; Stem cells; System; Testing; Tissues; Transplantation; Vaccination; Work; abdominal fat; adaptive immunity; base; chemokine; clinically relevant; cytokine; cytotoxicity; graft function; immunoregulation; implantation; improved; islet; killer T cell; migration; novel; particle; prevent; public health relevance; scaffold

 DESCRIPTION (provided by applicant): The cell therapy market had revenue exceeding one billion dollars, with significant growth expected. While autologous cells are ideal to avoid immune rejection, allogeneic sources are attractive for diseases in which autologous cells are not readily available due to disease (e.g., Type 1 Diabetes (T1D)). Allogeneic islet transplantation for the treatment of T1D, which affects an estimated 1.5 million Americans, is an experimental therapy with limited tissue availability, with allogeneic stem cell-derived ß-cells showing great promise. In the previous funding for this grant, we developed microporous scaffolds to support engraftment of the transplanted islets at a clinically translatable extrahepatc site, and demonstrated the ability to modulate the local environment in order to maximize engraftment of transplanted cells. In this proposal, we investigate the induction of immune tolerance via biomaterials for allogeneic cell donors, which would avoid the long-term use of immunosuppressive drugs. Immunosuppressive drugs are currently used for solid organ and cell transplantation to prevent rejection, which leads to the non-specific immune suppression and may be diabetogenic. We propose a two-pronged approach: i) microporous scaffolds that locally modulate the immune response, and ii) i.v. infused particles delivering tolerogenic allogeneic antigens that systemically modulate the immune response. Our previous funding period supported the development of scaffolds to create an environment that supports islet engraftment, and Aim 1 of this proposal extends those results by locally delivering factors to modulate the immune response. Locally providing anti-inflammatory cytokines, chemokines may redirect immune cells away from an inflammatory phenotype in order to interrupt inflammation at an early stage. Importantly, these cytokines may limit APC activation and migration, which may decrease activation of CD4+ helper and CD8+ killer T cells that are responsible for graft rejection. We anticipate that these scaffolds may reduce the number of islets necessary for transplantation and facilitate tolerance induction by particles carrying donor antigen (Aim 2). Specific Aim 2 will investigate particle-based modulation of systemic anti-donor adaptive immune response for effective donor-specific tolerance induction for islet transplantation. Preliminary studies have demonstrated the capacity of PLG particles carrying solubilized donor antigens (PLG-dAg). Antigen isolation and loading into the particles will be investigated for their tolerogenic effects on APC function, along with the specificity and stability of transplant tolerance. We hypothesize that functionalized PLG-dAg effectively target and tolerize host APCs, and consequently induce stable and donor-specific transplant tolerance. Taken together, we anticipate that the scaffold microenvironment and antigen-loaded particles can synergize to effectively induce tolerance, which will reduce the number of islets needed for transplantation, and will enable allogeneic transplantation without immunosuppression, which would be a significant advance enabling numerous cell therapies.

 描述（申请人提供）：细胞治疗市场收入超过10亿美元，预计将显着增长。虽然自体细胞是避免免疫排斥的理想选择，但同种异体来源对于因疾病而不易获得自体细胞的疾病（例如 1 型糖尿病 (T1D)）很有吸引力。用于治疗 T1D 的同种异体胰岛移植是一种实验性疗法，其组织可用性有限，而同种异体干细胞衍生的 β 细胞显示出巨大的前景，该疾病影响了大约 150 万美国人。在之前的资助中，我们开发了微孔支架来支持移植胰岛在临床可移植的肝外部位的植入，并证明了调节局部环境以最大限度地移植细胞植入的能力。在该提案中，我们研究通过生物材料诱导同种异体细胞供体的免疫耐受，这将避免长期使用免疫抑制药物。目前实体器官和细胞移植中使用免疫抑制药物来预防排斥反应，导致非特异性免疫抑制，并可能导致糖尿病。我们提出了一种双管齐下的方法：i）局部调节免疫反应的微孔支架，ii）静脉注射。注入的颗粒可传递可系统调节免疫反应的耐受性同种异体抗原。我们之前的资助期支持支架的开发，以创造支持胰岛移植的环境，而该提案的目标 1 通过局部传递因子来调节免疫反应来扩展这些结果。趋化因子在局部提供抗炎细胞因子，可以使免疫细胞远离炎症表型，从而在早期阶段中断炎症。重要的是，这些细胞因子可能会限制 APC 的激活和迁移，从而减少导致移植物排斥的 CD4+ 辅助细胞和 CD8+ 杀伤 T 细胞的激活。我们预计这些支架可以减少移植所需的胰岛数量，并促进携带供体抗原的颗粒诱导耐受性（目标 2）。具体目标 2 将研究基于颗粒的全身抗供体适应性免疫反应的调节，以有效诱导胰岛移植的供体特异性耐受。初步研究已证明 PLG 颗粒携带溶解的供体抗原 (PLG-dAg) 的能力。将研究抗原分离和加载到颗粒中的效果 对 APC 功能的耐受性影响，以及移植耐受的特异性和稳定性。我们假设功能化的 PLG-dAg 有效地靶向和耐受宿主 APC，从而诱导稳定的供体特异性移植耐受。综上所述，我们预计支架微环境和负载抗原的颗粒可以协同作用，有效诱导耐受，这将减少移植所需的胰岛数量，并使同种异体移植无需免疫抑制，这将是实现多种细胞疗法的重大进步。