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Immunosuppression-free islet transplantation via localized immunomodulatory exosome tethering

通过局部免疫调节外泌体束缚进行无免疫抑制的胰岛移植

基本信息

批准号：
10610867
负责人：
Jessica Diane Weaver
金额：
$ 22.33万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-19 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610867
关键词：
Address Allogenic American Antigen Presentation Antigen Presentation Pathway Antigen-Presenting Cells Antigens Binding Biological Blood Glucose Cell Therapy Cell Transplantation Cells Chronic Clinical Development Devices Diffusion Disease Dose Encapsulated Engineering Environment Flow Cytometry General Population Graft Survival Histology Human Hydrogels Immune Immune Tolerance Immune mediated destruction Immune response Immune system Immunosuppression In Vitro Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Label Life Malignant Neoplasms Maternal-Fetal Exchange Mediating Methods Mission Morbidity - disease rate Organ Transplantation Outcome Physiologic tolerance Placenta Procedures Protein Array Protocols documentation Public Health Reaction Regimen Replacement Therapy Research Risk Scheme Signal Transduction Site Solid Surface Tissue Transplantation Tissues Titrations Transplant Recipients Transplantation United States National Institutes of Health Work blood glucose regulation diabetes risk diabetic patient exosome experimental study fetal fluorescence imaging immune clearance immune modulating agents immunoregulation improved outcome in vivo in vivo imaging infection risk insulin signaling interest islet method development prevent response side effect success synergism tool trophoblast type I diabetic

项目摘要

PROJECT SUMMARY/ABSTRACT Clinical islet transplantation is a promising treatment for insulin-dependent diabetic patients, with the potential to eliminate long-term secondary complications by restoring native insulin signaling. While clinical successes have demonstrated the feasibility of achieving insulin independence through islet replacement therapy, the necessity of a long-term immunosuppressive regimen limits the widespread applicability of this procedure, as the substantial risk associated with chronic immunosuppression outweighs the risk of diabetes associated morbidities. As a result, there is great interest in the development of macroencapsulation devices to isolate transplanted cells from the recipient immune system, with the intent to eliminate immune recognition via the direct antigen presentation pathway. While this strategy can reduce immune response to the graft, encapsulation cannot prevent the diffusion of shed antigens, which activate immune cells via the indirect antigen presentation pathway to ultimately target and destroy the transplanted cells. As such, a synergistic approach to macroencapsulation is required to fully ameliorate the immune response to islet grafts. The placental microenvironment is a unique biological example of localized, normal physiological tolerance, maintained by trophoblasts at the fetal-maternal interface via two mechanisms: (1) creating a barrier to prevent contact between allogeneic tissue and host, and (2) localized presentation and secretion of immunomodulatory factors to induce tolerogenic innate and adaptive immune cells. One potent method by which trophoblasts deliver immunomodulatory payloads is via secreted exosomes. We aim to mimic these two mechanisms of trophoblast-mediated tolerance through encapsulating islets in an immunoisolating hydrogel device and tethering immunomodulatory trophoblast-derived exosomes to the device surface. We hypothesize that localized presentation of immunomodulatory trophoblast-derived exosomes at the surface of a synthetic hydrogel macroencapsulation device will synergize with immunoisolation to produce localized immune tolerance to the graft. We anticipate that localized exosome presentation will result in local tolerance to the graft by inducing tolerogenic innate and adaptive immune cells at the site of transplantation. Encapsulation within the hydrogel device will prevent direct antigen presentation, and surface-bound exosomes will induce tolerogenic antigen presenting cells, preventing immune destruction via indirect antigen recognition. These hypotheses will be addressed in the experiments of the following Specific Aims: (1) Engineer an immunomodulating exosome-presenting synthetic hydrogel-based macroencapsulation device; and (2) Evaluate immunomodulatory macroencapsulation device impact on the localized graft immune environment. We anticipate that this study will demonstrate the immunosuppressive capacity of tolerogenic trophoblast exosomes, and their potential for synergy with islet encapsulation.

项目总结/文摘