Induction of antigen-specific tolerance by nanobody–antigen adducts that target class-II major histocompatibility complexes

Pishesha, Novalia; Harmand, Thibault J.; Smeding, Liyan Y.; Ma, Weiyi; Ludwig, Leif S.; Janssen, Robine; Islam, Ashraful; Xie, Yushu Joy; Fang, Tao; McCaul, Nicholas; Pinney, William; Sugito, Harun R.; Rossotti, Martín A.; González‐Sapienza, Gualberto; Ploegh, Hidde L.

doi:10.1038/s41551-021-00738-5

Cited by 31 publications

(16 citation statements)

References 47 publications

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“…In this study, we describe TACs as a novel ASIT approach that harnesses the physiological mechanism of RBC clearance to deliver antigens to cognate T cells in a tolerogenic context. Several antigen-coupled apoptotic cell-based approaches have been previously explored to induce antigen-specific tolerance ( 50 ). These include conjugation of antigen to leukocytes by chemical methods and covalent or non-covalent linkage of antigen to RBCs ( 18 – 20 , 23 ).…”

Section: Discussionmentioning

confidence: 99%

Engineered RBCs Encapsulating Antigen Induce Multi-Modal Antigen-Specific Tolerance and Protect Against Type 1 Diabetes

et al. 2022

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Antigen-specific therapies that suppress autoreactive T cells without inducing systemic immunosuppression are a much-needed treatment for autoimmune diseases, yet effective strategies remain elusive. We describe a microfluidic Cell Squeeze® technology to engineer red blood cells (RBCs) encapsulating antigens to generate tolerizing antigen carriers (TACs). TACs exploit the natural route of RBC clearance enabling tolerogenic presentation of antigens. TAC treatment led to antigen-specific T cell tolerance towards exogenous and autoantigens in immunization and adoptive transfer mouse models of type 1 diabetes (T1D), respectively. Notably, in several accelerated models of T1D, TACs prevented hyperglycemia by blunting effector functions of pathogenic T cells, particularly in the pancreas. Mechanistically, TACs led to impaired trafficking of diabetogenic T cells to the pancreas, induced deletion of autoreactive CD8 T cells and expanded antigen specific Tregs that exerted bystander suppression. Our results highlight TACs as a novel approach for reinstating immune tolerance in CD4 and CD8 mediated autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Engineered RBCs Encapsulating Antigen Induce Multi-Modal Antigen-Specific Tolerance and Protect Against Type 1 Diabetes

et al. 2022

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“…Opposite on the immune spectrum are efforts to dampen immunity for autoimmune disease therapy. For example, nanobodies that recognize major histocompatibility complex class II molecules are conjugated to the relevant self‐antigen under noninflammatory conditions 120 . Epigenetic reprogramming of dendritic cells, macrophages, or natural killer cells provides potential therapeutic approaches to treat inflammatory and autoimmune diseases, such as rheumatoid arthritis, and have been recently reviewed 121 .…”

Section: Targeting Dendritic Cells or Their Exosomes As An Immunother...mentioning

confidence: 99%

“…For example, nanobodies that recognize major histocompatibility complex class II molecules are conjugated to the relevant self-antigen under noninflammatory conditions. 120 Epigenetic reprogramming of dendritic cells, macrophages, or natural killer cells provides potential therapeutic approaches to treat inflammatory and autoimmune diseases, such as rheumatoid arthritis, and have been recently reviewed. 121 In the case of periodontitis, immunotherapeutic approaches to harness regulatory T cells to mitigate inflammatory tissue damage have been widely proposed.…”

Section: Targ E Ting Dendritic Cell S or Their E Xosome S A S An Immu...mentioning

confidence: 99%

Dendritic cells a critical link to alveolar bone loss and systemic disease risk in periodontitis: Immunotherapeutic implications

El‐Awady

Elashiry

Morandini

et al. 2022

Periodontology 2000

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Extensive research in humans and animal models has begun to unravel the complex mechanisms that drive the immunopathogenesis of periodontitis. Neutrophils mount an early and rapid response to the subgingival oral microbiome, producing destructive enzymes to kill microbes. Chemokines and cytokines are released that attract macrophages, dendritic cells, and T cells to the site. Dendritic cells, the focus of this review, are professional antigen‐presenting cells on the front line of immune surveillance. Dendritic cells consist of multiple subsets that reside in the epithelium, connective tissues, and major organs. Our work in humans and mice established that myeloid dendritic cells are mobilized in periodontitis. This occurs in lymphoid and nonlymphoid oral tissues, in the bloodstream, and in response to Porphyromonas gingivalis. Moreover, the dendritic cells mature in situ in gingival lamina propria, forming immune conjugates with cluster of differentiation (CD) 4+ T cells, called oral lymphoid foci. At such foci, the decisions are made as to whether to promote bone destructive T helper 17 or bone‐sparing regulatory T cell responses. Interestingly, dendritic cells lack potent enzymes and reactive oxygen species needed to kill and degrade endocytosed microbes. The keystone pathogen P. gingivalis exploits this vulnerability by invading dendritic cells in the tissues and peripheral blood using its distinct fimbrial adhesins. This promotes pathogen dissemination and inflammatory disease at distant sites, such as atherosclerotic plaques. Interestingly, our recent studies indicate that such P. gingivalis–infected dendritic cells release nanosized extracellular vesicles called exosomes, in higher numbers than uninfected dendritic cells do. Secreted exosomes and inflammasome‐related cytokines are a key feature of the senescence‐associated secretory phenotype. Exosomes communicate in paracrine with neighboring stromal cells and immune cells to promote and amplify cellular senescence. We have shown that dendritic cell–derived exosomes can be custom tailored to target and reprogram specific immune cells responsible for inflammatory bone loss in mice. The long‐term goal of these immunotherapeutic approaches, ongoing in our laboratory and others, is to promote human health and longevity.

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“…Overall, the anti-DEC-205-mediated delivery of antigens from pathogens and tumors is likely to further render these recombinant antibodies as central to the design of new vaccine-based immunotherapies. In addition to full immunoglobulins, single-chain fragment variable region (scFv) and single-domain antibody (sdAb) have also been used for antigen delivery under multiple immune conditions [ 9 , 33 , 59 , 148 , 149 , 150 , 151 , 152 , 153 ].…”

Section: Translational Perspectives Of Targeted Antigen Delivery To D...mentioning

confidence: 99%

Applications of Antibody-Based Antigen Delivery Targeted to Dendritic Cells In Vivo

Bourque

Hawiger

2022

Antibodies

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Recombinant immunoglobulins, derived from monoclonal antibodies recognizing the defined surface epitopes expressed on dendritic cells, have been employed for the past two decades to deliver antigens to dendritic cells in vivo, serving as critical tools for the investigation of the corresponding T cell responses. These approaches originated with the development of the recombinant chimeric antibody against a multilectin receptor, DEC-205, which is present on subsets of murine and human conventional dendritic cells. Following the widespread application of antigen targeting through DEC-205, similar approaches then utilized other epitopes as entry points for antigens delivered by specific antibodies to multiple types of dendritic cells. Overall, these antigen-delivery methodologies helped to reveal the mechanisms underlying tolerogenic and immunogenic T cell responses orchestrated by dendritic cells. Here, we discuss the relevant experimental strategies as well as their future perspectives, including their translational relevance.

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Induction of antigen-specific tolerance by nanobody–antigen adducts that target class-II major histocompatibility complexes

Cited by 31 publications

References 47 publications

Engineered RBCs Encapsulating Antigen Induce Multi-Modal Antigen-Specific Tolerance and Protect Against Type 1 Diabetes

Engineered RBCs Encapsulating Antigen Induce Multi-Modal Antigen-Specific Tolerance and Protect Against Type 1 Diabetes

Dendritic cells a critical link to alveolar bone loss and systemic disease risk in periodontitis: Immunotherapeutic implications

Applications of Antibody-Based Antigen Delivery Targeted to Dendritic Cells In Vivo

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