Protein-Releasing Microporous Scaffolds for Cell Replacement Therapy

 描述(由申请者提供)：细胞治疗市场的收入超过10亿美元，预计将有显著增长。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由于疾病(如1型糖尿病(T1D))而不容易获得自体细胞的疾病很有吸引力。同种异体胰岛移植治疗T1D，估计影响到150万美国人，是一种组织可获得性有限的实验性疗法，同种异基因干细胞来源的？细胞显示出巨大的前景。在之前的资助中，我们开发了微孔支架来支持移植的胰岛在临床上可移植的肝外部位的植入，并展示了调节当地环境的能力，以最大限度地促进移植细胞的植入。在这项建议中，我们研究了通过生物材料诱导异基因细胞供者的免疫耐受，以避免长期使用免疫抑制药物。免疫抑制药物目前用于固体器官和细胞移植，以防止排斥反应，导致非特异性免疫抑制，并可能是糖尿病的原因。我们提出了一个双管齐下的方法：i)局部调节免疫反应的微孔支架，以及ii)静脉注射。输注的颗粒提供系统调节免疫反应的耐受性同种异体抗原。我们之前的资助时期支持支架的发展，以创造一个支持胰岛植入的环境，本提案的目标1通过在局部交付因子来调节免疫反应来扩大这些结果。局部提供抗炎细胞因子，趋化因子可将免疫细胞从炎症表型重新定向，以便在早期阶段阻断炎症。重要的是，这些细胞因子可能限制APC的激活和迁移，这可能会减少导致移植物排斥反应的CD4+辅助T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(目标2)。特定目的2将研究基于颗粒的系统抗供体适应性免疫反应的调节，以有效地诱导胰岛移植供体特异性耐受。初步研究证实PLG颗粒携带增溶供体抗原(PLG-DAG)的能力。将对抗原分离和装载到颗粒中进行研究 免疫耐受对APC功能的影响，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的APC，从而诱导稳定的和供体特异性的移植耐受。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有效地诱导耐受，这将减少移植所需的胰岛数量，并使异基因移植能够在没有免疫抑制的情况下进行，这将是使多种细胞治疗成为可能的重大进步。

 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.