Liu Jeffrey M H, Zhang Xiaomin, Joe Shelby, Luo Xunrong, Shea Lonnie D
Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, IL, 60208, USA.
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
J Immunol Regen Med. 2018 Mar;1:1-12. doi: 10.1016/j.regen.2018.01.003. Epub 2018 Feb 22.
The development of novel immunomodulatory strategies that might decrease the need for systemic immune suppression would greatly enable the utility of cell-based therapies. Cell transplantation on biomaterial scaffolds offers a unique opportunity to engineer a site to locally polarize immunogenic antigen generation. Herein, we investigated the localized delivery of IL-33, which is a novel cytokine that has been shown to have beneficial immunomodulatory effects in certain transplant models as mediating anti-inflammatory properties in the adipose tissue, to determine its feasibility for use as an immunomodulatory agent.
Localized IL-33 delivery from poly(lactide-co-glycolide) (PLG) scaffolds implanted into the epididymal fat specifically increased the Foxp3+ population of CD4+ T cells in both blank scaffold implants and scaffolds seeded with allogeneic islets. In allogeneic islet transplantation, we found IL-33 delivery results in a local upregulation of graft-protective T cells where 80% of the local CD4+ population is Foxp3+ and overall numbers of graft destructive CD8+ T cells are decreased, resulting in a prolonged graft survival. Interestingly, local IL-33 also delayed islet engraftment by primarily inducing a local upregulation of Th2 cytokines, including IL-4 and IL-5, leading to increased populations of ST2+ Type 2 innate lymphoid cells (ILC2s) and Siglec F+ eosinophils.
These results suggest that local IL-33 delivery from biomaterial scaffolds can be used to increase Tregs enriched in adipose tissue and reduce graft-destructive T cell populations but may also promote innate cell populations that can delay cell engraftment.
开发可能减少全身免疫抑制需求的新型免疫调节策略将极大地促进基于细胞的疗法的应用。在生物材料支架上进行细胞移植提供了一个独特的机会，可构建一个局部极化免疫原性抗原生成的位点。在此，我们研究了白细胞介素-33（IL-33）的局部递送，IL-33是一种新型细胞因子，在某些移植模型中已显示出有益的免疫调节作用，可介导脂肪组织中的抗炎特性，以确定其作为免疫调节药物的可行性。
植入附睾脂肪的聚（丙交酯-乙交酯）（PLG）支架局部递送IL-33，特异性增加了空白支架植入物和接种同种异体胰岛的支架中CD4+T细胞的Foxp3+群体。在同种异体胰岛移植中，我们发现IL-33递送导致移植保护性T细胞在局部上调，其中80%的局部CD4+群体为Foxp3+，而移植破坏性CD8+T细胞的总数减少，从而延长了移植物存活时间。有趣的是，局部IL-33还主要通过诱导包括IL-4和IL-5在内的Th2细胞因子局部上调来延迟胰岛植入，导致ST2+2型固有淋巴细胞（ILC2s）和Siglec F+嗜酸性粒细胞群体增加。
这些结果表明，从生物材料支架局部递送IL-33可用于增加脂肪组织中富集的调节性T细胞（Tregs），减少移植破坏性T细胞群体，但也可能促进可延迟细胞植入的固有细胞群体。
