Immunoprotection of cellular transplants for autoimmune type 1 diabetes through local drug delivery

Lansberry, T.R.; Stabler, C.L.

doi:10.1016/j.addr.2024.115179

Cited by 4 publications

(4 citation statements)

References 212 publications

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“…Islet transplantation has emerged as a promising therapeutic strategy for patients suffering from type 1 diabetes ( 20 , 21 ). Allogeneic islet transplantation offers potential cures, yet they are hindered by immune rejection and the scarcity of compatible donors ( 8 ). This study aimed to address these challenges by dissecting the molecular mechanisms underlying T-cell responses in both transplantation scenarios, highlighting the necessity for a deeper understanding of immune dynamics to improve transplant outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, Encapsulation techniques, which protect transplanted islets from the immune system using biomaterials, offer a potential solution to enhance graft survival and function ( 7 ). Targeted local drug delivery systems have also been developed to modulate immune responses directly at the transplantation site, thereby improving transplant outcomes by addressing non-specific, alloantigen-specific, and autoimmune rejection pathways ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

“…Allogeneic islet transplantation has demonstrated efficacy in restoring insulin independence in T1DM patients; however, donor scarcity and the necessity for chronic immunosuppression limit its widespread application ( 8 – 10 ). Moreover, allogeneic islet transplantation is also accompanied by significant immunological challenges, primarily due to robust T-cell-mediated rejection ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

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Elucidating T cell dynamics and molecular mechanisms in syngeneic and allogeneic islet transplantation through single-cell RNA sequencing

Zhou,

Pu,

et al. 2024

Front. Immunol.

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Islet transplantation is a promising therapy for diabetes treatment. However, the molecular underpinnings governing the immune response, particularly T-cell dynamics in syngeneic and allogeneic transplant settings, remain poorly understood. Understanding these T cell dynamics is crucial for enhancing graft acceptance and managing diabetes treatment more effectively. This study aimed to elucidate the molecular mechanisms, gene expression differences, biological pathway alterations, and intercellular communication patterns among T-cell subpopulations after syngeneic and allogeneic islet transplantation. Using single-cell RNA sequencing, we analyzed cellular heterogeneity and gene expression profiles using the Seurat package for quality control and dimensionality reduction through t-SNE. Differentially expressed genes (DEGs) were analyzed among different T cell subtypes. GSEA was conducted utilizing the HALLMARK gene sets from MSigDB, while CellChat was used to infer and visualize cell-cell communication networks. Our findings revealed genetic variations within T-cell subpopulations between syngeneic and allogeneic islet transplants. We identified significant DEGs across these conditions, highlighting molecular discrepancies that may underpin rejection or other immune responses. GSEA indicated activation of the interferon-alpha response in memory T cells and suppression in CD4+ helper and γδ T cells, whereas TNFα signaling via NFκB was particularly active in regulatory T cells, γδ T cells, proliferating T cells, and activated CD8+ T cells. CellChat analysis revealed complex communication patterns within T-cell subsets, notably between proliferating T cells and activated CD8+ T cells. In conclusion, our study provides a comprehensive molecular landscape of T-cell diversity in islet transplantation. The insights into specific gene upregulation in xenotransplants suggest potential targets for improving graft tolerance. The differential pathway activation across T-cell subsets underscores their distinct roles in immune responses posttransplantation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Elucidating T cell dynamics and molecular mechanisms in syngeneic and allogeneic islet transplantation through single-cell RNA sequencing

Zhou,

Pu,

et al. 2024

Front. Immunol.

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“…Both nMIC and nFIB have been shown to provide one of the highest water solubilities reported for cyclosporine A (CsA; 4.5 mg/mL) together with two-week sustained release in vitro, efficient uptake into immune cells, morphology-controllable biodistribution following subcutaneous administration, and effective immune suppression at lower dosage than that used with unformulated CsA [14]. Therefore, we believe that our nanomaterial platform could significantly improve many current treatments, particularly those chronic treatments needed for transplantation of cells and tissues like β-cell replacement therapies in patients with type 1 diabetes (T1D) [18,19] to prolong graft survival and function while minimizing unwanted deleterious side effects [20,21].…”

Section: Introductionmentioning

confidence: 99%

Drug Integrating Amphiphilic Nano-Assemblies: 2. Spatiotemporal Distribution within Inflammation Sites

De Toni,

Dal Buono,

et al. 2024

Pharmaceutics

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The need for chronic systemic immunosuppression, which is associated with unavoidable side-effects, greatly limits the applicability of allogeneic cell transplantation for regenerative medicine applications including pancreatic islet cell transplantation to restore insulin production in type 1 diabetes (T1D). Cell transplantation in confined sites enables the localized delivery of anti-inflammatory and immunomodulatory drugs to prevent graft loss by innate and adaptive immunity, providing an opportunity to achieve local effects while minimizing unwanted systemic side effects. Nanoparticles can provide the means to achieve the needed localized and sustained drug delivery either by graft targeting or co-implantation. Here, we evaluated the potential of our versatile platform of drug-integrating amphiphilic nanomaterial assemblies (DIANAs) for targeted drug delivery to an inflamed site model relevant for islet transplantation. We tested either passive targeting of intravenous administered spherical nanomicelles (nMIC; 20–25 nm diameter) or co-implantation of elongated nanofibrils (nFIB; 5 nm diameter and >1 μm length). To assess the ability of nMIC and nFIB to target an inflamed graft site, we used a lipophilic fluorescent cargo (DiD and DiR) and evaluated the in vivo biodistribution and cellular uptake in the graft site and other organs, including draining and non-draining lymph nodes, after systemic administration (nMIC) and/or graft co-transplantation (nFIB) in mice. Localized inflammation was generated either by using an LPS injection or by using biomaterial-coated islet-like bead implantation in the subcutaneous site. A cell transplant inflammation model was used as well to test nMIC- and nFIB-targeted biodistribution. We found that nMIC can reach the inflamed site after systemic administration, while nFIB remains localized for several days after co-implantation. We confirmed that DIANAs are taken up by different immune cell populations responsible for graft inflammation. Therefore, DIANA is a useful approach for targeted and/or localized delivery of immunomodulatory drugs to decrease innate and adaptive immune responses that cause graft loss after transplantation of therapeutic cells.

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Preparation of magnetic scaffolds via supercritical carbon dioxide foaming process using iron oxide nanoparticles coated with CO₂‐philic materials as nucleating agents

Jiao,

Zhang,

Wang

et al. 2024

J of Applied Polymer Sci

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The iron oxide nanoparticles (IONs), coated with different materials, are synthesized and utilized as nucleating agents to prepare magnetic multi‐modal porous scaffolds of poly (lactic‐co‐glycolic acid)/IONs using the supercritical carbon dioxide (ScCO2) foaming process. The effects of the modification materials, including citric acid, polycaprolactone, and polyvinyl acetate, on the foaming process and properties of the magnetic scaffolds are systematically investigated. The results indicate that the solubility and diffusion ability of CO2 in the foaming materials played a vital role in the foaming process. The use of CO2‐philic materials and high pressure proves beneficial in generating micropores. The scaffolds with multi‐modal porous structures can be obtained at relatively low pressure for the ScCO2 foaming systems evaluated in this study. Furthermore, the prepared scaffolds exhibit high porosity and a good compressive modulus (higher than 0.4 MPa), satisfying the requirements of tissue engineering for soft tissue scaffolds.

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Immunoprotection of cellular transplants for autoimmune type 1 diabetes through local drug delivery

Cited by 4 publications

References 212 publications

Elucidating T cell dynamics and molecular mechanisms in syngeneic and allogeneic islet transplantation through single-cell RNA sequencing

Elucidating T cell dynamics and molecular mechanisms in syngeneic and allogeneic islet transplantation through single-cell RNA sequencing

Drug Integrating Amphiphilic Nano-Assemblies: 2. Spatiotemporal Distribution within Inflammation Sites

Preparation of magnetic scaffolds via supercritical carbon dioxide foaming process using iron oxide nanoparticles coated with CO₂‐philic materials as nucleating agents

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Immunoprotection of cellular transplants for autoimmune type 1 diabetes through local drug delivery

Cited by 4 publications

References 212 publications

Elucidating T cell dynamics and molecular mechanisms in syngeneic and allogeneic islet transplantation through single-cell RNA sequencing

Elucidating T cell dynamics and molecular mechanisms in syngeneic and allogeneic islet transplantation through single-cell RNA sequencing

Drug Integrating Amphiphilic Nano-Assemblies: 2. Spatiotemporal Distribution within Inflammation Sites

Preparation of magnetic scaffolds via supercritical carbon dioxide foaming process using iron oxide nanoparticles coated with CO2‐philic materials as nucleating agents

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Preparation of magnetic scaffolds via supercritical carbon dioxide foaming process using iron oxide nanoparticles coated with CO₂‐philic materials as nucleating agents