Protein-Releasing Microporous Scaffolds for Cell Replacement Therapy

 描述（由申请人提供）：细胞治疗市场的收入超过10亿美元，预计将大幅增长。虽然自体细胞对于避免免疫排斥是理想的，但是同种异体来源对于其中自体细胞由于疾病而不容易获得的疾病（例如，1型糖尿病（T1 D））。用于治疗T1 D的同种异体胰岛移植影响了估计150万美国人，是一种组织可用性有限的实验性疗法，同种异体干细胞衍生的胰岛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，以支持移植胰岛在临床上可转移的肝外部位的植入，并证明了调节局部环境以最大限度地移植细胞的植入的能力。在这个提议中，我们研究了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。免疫抑制剂目前用于实体器官和细胞移植以防止排斥反应，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）局部调节免疫应答的微孔支架，和ii）静脉内输注的颗粒，其递送全身调节免疫应答的致耐受性同种异体抗原。我们之前的资助期支持支架的开发，以创造一个支持胰岛移植的环境，本提案的目标1通过局部递送因子来调节免疫反应，从而扩展了这些结果。局部提供抗炎细胞因子，趋化因子可以将免疫细胞重定向远离炎性表型，以便在早期阶段中断炎症。重要的是，这些细胞因子可以限制APC活化和迁移，这可以减少负责移植物排斥的CD 4+辅助和CD 8+杀伤T细胞的活化。我们预期这些支架可以减少移植所需的胰岛数量，并通过携带供体抗原的颗粒促进耐受诱导（Aim 2）。具体目标2将研究基于颗粒的全身性抗供体适应性免疫应答的调节，以有效诱导胰岛移植的供体特异性耐受。初步研究已经证明了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特性。 对APC功能的致耐受作用，沿着移植耐受的特异性和稳定性。我们假设功能化PLG-dAg有效地靶向并耐受宿主APC，并因此诱导稳定的和供体特异性的移植耐受。综上所述，我们预期支架微环境和负载抗原的颗粒可以协同作用以有效地诱导耐受性，这将减少移植所需的胰岛数量，并且将使同种异体移植能够在没有免疫抑制的情况下进行，这将是实现多种细胞疗法的重大进步。

 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.