Jeffrey M H Liu1,2, Xiaomin Zhang3, Shelby Joe2, Xunrong Luo3,4,5, Lonnie D Shea2. 1. Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, IL, 60208, USA. 2. Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA. 3. Department of Surgery, Division of Transplantation, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. 4. Center for Kidney Research and Therapeutics, Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, 60611, USA. 5. Department of Medicine, Division of Nephrology and Hypertension, Northwestern University, Chicago, IL, 60611, USA.
Abstract
INTRODUCTION: 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. RESULTS: 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. CONCLUSIONS: 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.
INTRODUCTION: 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. RESULTS: 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. CONCLUSIONS: 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.
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