The Importance of Dendritic Cells in Maintaining Immune Tolerance

Audiger, Cindy; Rahman, M. Jubayer; Yun, Tae Jin; Tarbell, Kristin V.; Lesage, Sylvie

doi:10.4049/jimmunol.1601629

Cited by 223 publications

(179 citation statements)

References 167 publications

(169 reference statements)

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“…15,16 However, administration of a vaccine containing only a protein or peptide Ag does not stimulate antitumour immunity. 18,19 The activation of innate immunity is required for the induction of Ag-specific acquired immunity. 18,19 The activation of innate immunity is required for the induction of Ag-specific acquired immunity.…”

Section: Introductionmentioning

confidence: 99%

An agonistic anti‐Toll‐like receptor 4 monoclonal antibody as an effective adjuvant for cancer immunotherapy

et al. 2019

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Summary Immune‐checkpoint blockade antibodies have been approved for the treatment of cancer. However, poorly immunogenic tumours are less responsive to such therapies. Agonistic anti‐Toll‐like receptor 4 (TLR4) monoclonal antibodies (mAbs) activate only cell‐surface TLR4; in contrast, lipopolysaccharide (LPS) activates both TLR4 and intracellular inflammatory caspases. In this study, we investigated the adjuvant activity of an anti‐TLR4 mAb in T‐cell‐mediated antitumour immunity. The anti‐TLR4 mAb induced the activation of antigen‐specific T‐cells in adoptive transfer studies. The growth of ovalbumin (OVA)‐expressing tumours was significantly suppressed by administration of OVA and the anti‐TLR4 mAb in combination, but not individually. The antitumour effect of anti‐PD‐1 mAb was enhanced in mice administered with OVA plus the anti‐TLR4 mAb. The OVA‐specific IFN‐γ‐producing CD8 T‐cells were induced by administration of OVA and the anti‐TLR4 mAb. The suppression of tumour growth was diminished by depletion of CD8, but not CD4, T‐cells. The inflammatory response to the anti‐TLR4 mAb was of significantly lesser magnitude than that to LPS, as assessed by NF‐κB activation and production of TNF‐α, IL‐6 and IL‐1β. Administration of LPS (at a dose that elicited levels of proinflammatory cytokines comparable to those by the anti‐TLR4 mAb) plus OVA induced no or less‐marked activation of OVA‐specific T‐cells and failed to suppress tumour growth in mice. In conclusion, the agonistic anti‐TLR4 mAb induces potent CD8 T‐cell‐dependent antitumour immunity and an inflammatory response of lesser magnitude than does LPS. The agonistic anti‐TLR4 mAb has potential as an adjuvant for use in vaccines against cancer.

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Section: Introductionmentioning

confidence: 99%

An agonistic anti‐Toll‐like receptor 4 monoclonal antibody as an effective adjuvant for cancer immunotherapy

et al. 2019

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“…[8] For example, skin has a high density of resident immune cells, particularly DCs, to combat the constant exposure to antigens from external environments and the bacteria that reside on the skin of a host. [10] Biomaterials are able to target and exploit specific DC subsets that can control the highly specific, and potentially protective or therapeutic, aspects of adaptive immunity. [9] Interestingly, similar DC phenotypes serve opposing functions in different tissues, which may be important for identifying the appropriate sites for introducing a vaccine or therapeutic agent.…”

Section: Antigen-presenting Cells Are Diverse and Specializedmentioning

confidence: 99%

Engineering Biomaterials to Direct Innate Immunity

Oakes

Froimchuk

Jewell

2019

Advanced Therapeutics

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Small alterations during early stages of innate immune response can drive large changes in how adaptive immune cells develop and function during protective immunity or disease. Controlling these events creates exciting potential in the development of immune engineered vaccines and therapeutics. This progress report discusses recent biomaterial technologies exploiting innate immunity to dissect immune function and to design new vaccines and immunotherapies for infectious diseases, cancer, and autoimmunity. Across these examples, an important idea is the possibility to co-opt innate immune mechanisms to enhance immunity during infection and cancer. During inflammatory or autoimmune disease, some of these same innate immune mechanisms can be manipulated in different ways to control excess inflammation by promotion of immunological tolerance.

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“…Under normal conditions, DCs acquire self-antigens and present them to T cells and rendering the latter anergic [28]. DCs gain tolerogenic properties by reducing co-stimulatory molecules, maintaining low to intermediate maturation, decreasing production of IL-12 and by increasing production of IDO, TGF-β and IL-10 [28][29][30].…”

Section: Pathogenesis Of Ramentioning

confidence: 99%

Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine

Narendra¹

2017

Linköping University Medical Dissertations

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In this thesis, we have studied the immunological processes of joint inflammation that may be targets for future treatment of patients with arthritis. We focus on the immune-modulating properties of interferon-α (IFN-α) and uridine in experimental arthritis. The nucleoside uridine, which is regarded a safe treatment has anti-inflammatory properties notably by inhibiting tumor necrosis factor (TNF) release. Because the inflamed synovium in rheumatoid arthritis (RA) is characterised by pathogenic TNF-production, uridine could potentially be away to ameliorate arthritis. Systemic administration of uridine had no effect on antigeninduced arthritis (AIA), which is a T-cell dependent model where animals are immunized twice (sensitization) with bovine serum albumin (mBSA), before local triggering of arthritis by intra-articular antigen (mBSA) re-challenge. In contrast, intra-articular administration of uridine clearly down modulated development of AIA in a dose dependent manner and inhibited the expression of synovial adhesion molecules, influx of inflammatory leukocytes and synovial expression of TNF and interleukin 6, but did not affect systemic levels of proinflammatory cytokines or antigen-specific T-cell responses. Local administration of uridine may thus be a viable therapeutic option for treatment of arthritis in the future. Viral double-stranded deoxyribonucleic acid (dsRNA), a common nucleic acid found in most viruses, can be found in the joints of RA patients and local deposition of such viral dsRNA induces arthritis by activating IFN-α. Here we show that arthritis induced by dsRNA can be mediated by IFN-producing dendritic cells in the joint and this may thus explain why viral infections are sometimes associated with arthritis. Earlier, to study the effect of dsRNA and IFN-α in an arthritis model, that like RA, is dependent on adaptive immunity, dsRNA and IFN-α were administered individually during the development of AIA. Both molecules clearly protected against AIA in a type I IFN receptor-dependent manner but were only effective if administered in the sensitization phase of AIA. Here we show that the anti-inflammatory effect of IFN-α is critically dependent on signalling via transforming growth factor β (TGF-β) and the enzymatic activity of indoleamine 2,3 dioxygenase 1 (IDO). The IDO enzyme is produced by plasmacytoid DC and this cell type was critically required both during antigen sensitization and in the arthritis phase of AIA for the protective effect of IFN-α against AIA. In contrast, TGF-β and the enzymatic activity of IDO were only required during sensitization, which indicate that they are involved in initial steps of tolerogenic antigen sensitization. In this scenario, IFN- α first activates the enzymatic activity of IDO in pDC, which converts Tryptophan to Kynurenine, which thereafter activates TGF-β. Common for IDO-expressing pDC, Kyn and TGF-β is their ability to induce development of regulatory T cells (Tregs). We found that Tregs were crucial for IFN-α-mediated protection against AIA, but onl...

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The Importance of Dendritic Cells in Maintaining Immune Tolerance

Cited by 223 publications

References 167 publications

An agonistic anti‐Toll‐like receptor 4 monoclonal antibody as an effective adjuvant for cancer immunotherapy

An agonistic anti‐Toll‐like receptor 4 monoclonal antibody as an effective adjuvant for cancer immunotherapy

Engineering Biomaterials to Direct Innate Immunity

Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine

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