Antigen‐specific suppression of established arthritis in mice by dendritic cells deficient in NF‐κB

Martin, Ela; Capini, Christelle; Duggan, Emily; Lutzky, Viviana P.; Stumbles, Philip A.; Pettit, Allison R.; O’Sullivan, B.; Thomas, Ranjeny

doi:10.1002/art.22655

Cited by 90 publications

(98 citation statements)

References 49 publications

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“…One of the additional biochemical requirements for immunogenicity is believed to be activation of the NF-κB subunit RelB (13). DCs derived from RelB −/− mice or RelB −/− chimeras, or treated with an NF-κB inhibitor (RelB low DCs), can induce antigen-specific tolerance (13) and suppress inflammatory arthritis (28). Our finding that LCs fail both to activate RelB (Fig.…”

Section: Discussionmentioning

confidence: 68%

Langerhans cells are precommitted to immune tolerance induction

Shklovskaya¹,

O’Sullivan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Antigen-dependent interactions between T lymphocytes and dendritic cells (DCs) can produce two distinct outcomes: tolerance and immunity. It is generally considered that all DC subsets are capable of supporting both tolerogenic and immunogenic responses, depending on their exposure to activating signals. Here, we tested whether epidermal Langerhans cells (LCs) can support immunogenic responses in vivo in the absence of antigen presentation by other DC subsets. CD4 T cells responding to antigen presentation by activated LCs initially proliferated but then failed to differentiate into effector/memory cells or to survive long term. The tolerogenic function of LCs was maintained after exposure to potent adjuvants and occurred despite up-regulation of the costimulatory molecules CD80, CD86, and IL-12, but was consistent with their failure to translocate the NF-κB family member RelB from the cytoplasm to the nucleus. Commitment of LCs to tolerogenic function may explain why commensal microorganisms expressing Toll-like receptor (TLR) ligands but confined to the skin epithelium are tolerated, whereas invading pathogens that breach the epithelial basement membrane and activate dermal DCs stimulate a strong immune response.D endritic cells (DCs) initiate adaptive immune responses by priming antigen-specific T cells in secondary lymphoid organs. After sampling antigens in peripheral tissues, DCs migrate to lymph nodes (LN), where they present antigenic peptides bound to major histocompatibility (MHC) molecules (1). Epidermal Langerhans cells (LCs) have long been regarded as prototypic DCs, highly active in antigen uptake and rapidly acquiring potent costimulatory capacity after in vitro culture (2). Recently, the immunogenicity of LCs has been questioned on the basis of findings in several in vivo experimental models. During herpes viral infection of the skin, migrated LCs isolated from draining LN (dLN) were unable to induce proliferation of virusspecific CD8 T cells in vitro (3). In LC ablation models, positive (4, 5), negative (6-8), and redundant (9) contributions of LCs to contact hypersensitivity responses were reported. The current lack of consensus regarding LC function may relate, at least in part, to the difficulties in determining the contribution of a relatively small number of LCs to responses driven primarily by non-LC DC subsets in cutaneous LN (cLN).Here we directly tested the in vivo function of LCs, using a previously described bone marrow (BM) chimeric mouse model in which only LCs can present specific antigen to CD4 T cells (10). In this model, all DC subsets express MHC class II IA molecules but only LCs express MHC class II IE, which is absolutely required to present moth cytochrome C peptide (pMCC) to 5C.C7 T-cell receptor (TCR) transgenic T cells (11,12). The response of adoptively transferred 5C.C7 CD4 T cells can thus be used as a readout for LC function. We compared 5C.C7 T-cell responses to LCs with those in chimeras expressing IE on nonepidermal DCs or all DC subsets, immunizing with peptide o...

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Section: Discussionmentioning

confidence: 68%

Langerhans cells are precommitted to immune tolerance induction

Shklovskaya¹,

O’Sullivan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

149

134

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“…The data shown in Table 1 demonstrate that, based on the various doses, routes, and number of injections tested, 3 intravenous injections with 1 ϫ 10 6 tolerogenic DCs was the optimal tolerogenic DC treatment regimen. However, data from other studies indicate that optimal treatment regimens are different for other types of tolerogenic DCs (15,16,23,30).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, DCs transduced with FasL or IL-4 have been used to prevent CIA and to inhibit arthritis symptoms in mice with established disease (15)(16)(17). Tolerogenic DCs modified by drugs (dexamethasone; Bay 11-7082) or cytokines (tumor necrosis factor [TNF]) have been used successfully to prevent the onset of CIA (18)(19)(20)(21)(22) or to suppress established arthritis in a different model, the antigeninduced arthritis model (23).…”

Section: Conclusion Treatment With Type II Collagenpulsed Tolerogenimentioning

confidence: 99%

Therapeutic effect of tolerogenic dendritic cells in established collagen‐induced arthritis is associated with a reduction in Th17 responses

Stoop¹,

Harry²,

Delwig³

et al. 2010

Arthritis & Rheumatism

121

111

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Results. Tolerogenic DCs displayed a semimature phenotype, produced low levels of inflammatory cytokines, and exhibited low T cell stimulatory capacity. Upon intravenous injection into arthritic mice, tolerogenic DCs migrated to the spleen, liver, lung, feet, and draining lymph nodes. Treatment of arthritic mice with type II collagen-pulsed tolerogenic DCs, but not unpulsed tolerogenic DCs or mature DCs, significantly inhibited disease severity and progression. This improvement coincided with a significant decrease in the number of Th17 cells and an increase in the number of interleukin-10-producing CD4؉ T cells, whereas tolerogenic DC treatment had no detectable effect on Th1 cells or interleukin-17-producing ␥/␦ T cells.Conclusion. Treatment with type II collagenpulsed tolerogenic DCs decreases the proportion of Th17 cells in arthritic mice and simultaneously reduces the severity and progression of arthritis.

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“…After 10 min. of incubation, reaction was stopped by addition of H 2 SO 4 (2 N; 50 ll/well) and the optical density was measured at 450 nm [16].…”

Section: Assessment Of Anti-mbsa Specific Igg Antibodiesmentioning

confidence: 99%

Immuno-Modulatory Effect and Therapeutic Potential of Brugia malayi Cystatin in Experimentally Induced Arthritis

et al. 2015

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Helminths are known to modulate host's immune system and understanding this modulation can help in identification of novel therapeutic agents for autoimmune diseases. In this study, we have assessed the immune-modulatory activity and the therapeutic effect of Brugia malayi recombinant cystatin (rBmCys) in methylated BSA (mBSA) induced arthritis using rodent model. Administration of rBmCys has suppressed the severity of mBSA-arthritis in mastomys by reducing paw swelling and other clinical disease parameters as evident from significantly decreased arthritic index. The anti-arthritic effect of rBmCys was also confirmed by decreased histopathological score for synovitis, bone erosion and fibrosis in the tissue sections of paws. Further, this therapeutic effect of cystatin was found to be associated with significantly decreased production of IFN-c and TNF-a and increased release of IL-4 and IL-10 cytokines. These results implied that rBmCys treatment has alleviated mBSA-induced arthritis and thus can be a promising alternative agent for the treatment of arthritis.

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Antigen‐specific suppression of established arthritis in mice by dendritic cells deficient in NF‐κB

Cited by 90 publications

References 49 publications

Langerhans cells are precommitted to immune tolerance induction

Langerhans cells are precommitted to immune tolerance induction

Therapeutic effect of tolerogenic dendritic cells in established collagen‐induced arthritis is associated with a reduction in Th17 responses

Immuno-Modulatory Effect and Therapeutic Potential of Brugia malayi Cystatin in Experimentally Induced Arthritis

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