Soluble Antigen Arrays Displaying Mimotopes Direct the Response of Diabetogenic T Cells

Leon, Martin A.; Firdessa-Fite, Rebuma; Ruffalo, Justin K; Pickens, Chad J.; Sestak, Joshua O.; Creusot, Rémi J.; Berkland, Cory

doi:10.1021/acschembio.9b00090

Cited by 11 publications

(26 citation statements)

References 41 publications

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“…Indeed, the number of antigenic moieties per nanoparticle is also a parameter that needs to be considered in nanovaccine design. For soluble antigenic determinants, with the exception of multivalent antigens, the number of antigens in the endosomes of APCs equals the number of particles internalized [173]. In sharp contrast, higher concentrations of antigens can be achieved by decorating nanoparticles with multiple copies of the antigen [174].…”

Section: Modulating Immune Responses With Tailored Protein Nanostructmentioning

confidence: 99%

Protein Supramolecular Structures: From Self-Assembly to Nanovaccine Design

et al. 2020

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Life-inspired protein supramolecular assemblies have recently attracted considerable attention for the development of next-generation vaccines to fight against infectious diseases, as well as autoimmune diseases and cancer. Protein self-assembly enables atomic scale precision over the final architecture, with a remarkable diversity of structures and functionalities. Self-assembling protein nanovaccines are associated with numerous advantages, including biocompatibility, stability, molecular specificity and multivalency. Owing to their nanoscale size, proteinaceous nature, symmetrical organization and repetitive antigen display, protein assemblies closely mimic most invading pathogens, serving as danger signals for the immune system. Elucidating how the structural and physicochemical properties of the assemblies modulate the potency and the polarization of the immune responses is critical for bottom-up design of vaccines. In this context, this review briefly covers the fundamentals of supramolecular interactions involved in protein self-assembly and presents the strategies to design and functionalize these assemblies. Examples of advanced nanovaccines are presented, and properties of protein supramolecular structures enabling modulation of the immune responses are discussed. Combining the understanding of the self-assembly process at the molecular level with knowledge regarding the activation of the innate and adaptive immune responses will support the design of safe and effective nanovaccines.

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Section: Modulating Immune Responses With Tailored Protein Nanostructmentioning

confidence: 99%

Protein Supramolecular Structures: From Self-Assembly to Nanovaccine Design

et al. 2020

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“…For uptake studies, FITC was conjugated directly to HA using stable click linker chemistry (two FITC molecules on average per SAgA molecule for both hSAgA p79 and hSAgA 2.5HIP ). Azide-functionalized HA, hSAgAs, and cSAgAs were characterized by nuclear magnetic resonance, dynamic light scattering, and circular dichroism, as previously reported ( 9 ). Peptide conjugation was determined through gradient reversed-phase high-performance liquid chromatography.…”

Section: Methodsmentioning

confidence: 99%

“…Free peptides and SAgAs were always injected based on the same equimolar amount of peptides (1 nmol SAgA ∼10 nmol peptides). Donor CD4 + CD25 − T cells from pooled LNs and spleen of BDC2.5 or BDC2.5.Foxp3/GFP mice (with CD45.2 congenic marker) were purified using the MojoSort Mouse CD4 T Cell Isolation Kit supplemented with biotinylated anti-CD25 (BioLegend) and then labeled with Violet Cell Proliferation Dye (eBioscience) as previously described ( 9 ). These antigen-specific T cells (0.5 × 10 6 to 1 × 10 6 cells) were injected intravenously on the same day as the treatment in all adoptive transfer studies, except in studies assessing persistence of antigen presentation, in which T cells were injected 1, 2, or 3 days after treatment with peptide or SAgA.…”

Section: Methodsmentioning

confidence: 99%

“…The multivalent display of antigens by SAgAs enables high-avidity interactions (e.g., proteins linked on SAgAs with B cells), resulting in more effective anergy induction ( 8 ). Two forms of SAgAs were evaluated in this study, one in which the linkers for grafted peptides are hydrolysable (hSAgAs) and one in which the peptides are more stably linked by click chemistry (cSAgAs) ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

“…We previously showed that SAgAs can ameliorate disease in the experimental autoimmune encephalomyelitis model of multiple sclerosis ( 10 ) and that SAgAs can efficiently engage diabetogenic T cells ( 9 ). In both patients with T1D and NOD mice, the list of targeted epitopes has been greatly extended from native epitopes to neoepitopes, including posttranslationally modified versions of native epitopes and hybrid peptides ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

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Soluble Antigen Arrays Efficiently Deliver Peptides and Arrest Spontaneous Autoimmune Diabetes

et al. 2021

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Antigen-specific immunotherapy (ASIT) offers a targeted treatment of autoimmune diseases that selectively inhibits autoreactive lymphocytes, but there remains an unmet need for approaches that address the limited clinical efficacy of ASIT. Soluble antigen arrays (SAgAs) deliver antigenic peptides or proteins in multivalent form, attached to a hyaluronic acid backbone using either hydrolysable linkers (hSAgAs) or stable click chemistry linkers (cSAgAs). They were evaluated for the ability to block spontaneous development of disease in a nonobese diabetic mouse model of type 1 diabetes (T1D). Two peptides, a hybrid insulin peptide and a mimotope, efficiently prevented the onset of T1D when delivered in combination as SAgAs, but not individually. Relative to free peptides administered at equimolar dose, SAgAs (particularly cSAgAs) enabled a more effective engagement of antigen-specific T cells with greater persistence and induction of tolerance markers, such as CD73, interleukin-10, programmed death-1, and KLRG-1. Anaphylaxis caused by free peptides was attenuated using hSAgA and obviated using cSAgA platforms. Despite similarities, the two peptides elicited largely nonoverlapping and possibly complementary responses among endogenous T cells in treated mice. Thus, SAgAs offer a novel and promising ASIT platform superior to free peptides in inducing tolerance while mitigating risks of anaphylaxis for the treatment of T1D.

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Biomaterial Strategies for Selective Immune Tolerance: Advances and Gaps

2023

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Autoimmunity and allergies affect a large number of people across the globe. Current approaches to these diseases target cell types and pathways that drive disease, but these approaches are not cures and cannot differentiate between healthy cells and disease‐causing cells. New immunotherapies that induce potent and selective antigen‐specific tolerance is a transformative goal of emerging treatments for autoimmunity and serious allergies. These approaches offer the potential of halting—or even reversing—disease, without immunosuppressive side effects. However, translating successful induction of tolerance to patients is unsuccessful. Biomaterials offer strategies to direct and maximize immunological mechanisms of tolerance through unique capabilities such as codelivery of small molecules or signaling molecules, controlling signal density in key immune tissues, and targeting. While a growing body of work in this area demonstrates success in preclinical animal models, these therapies are only recently being evaluated in human trials. This review will highlight the most recent advances in the use of materials to achieve antigen‐specific tolerance and provide commentary on the current state of the clinical development of these technologies.

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Soluble Antigen Arrays Displaying Mimotopes Direct the Response of Diabetogenic T Cells

Cited by 11 publications

References 41 publications

Protein Supramolecular Structures: From Self-Assembly to Nanovaccine Design

Protein Supramolecular Structures: From Self-Assembly to Nanovaccine Design

Soluble Antigen Arrays Efficiently Deliver Peptides and Arrest Spontaneous Autoimmune Diabetes

Biomaterial Strategies for Selective Immune Tolerance: Advances and Gaps

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