Induction of Interleukin-10 Producing Dendritic Cells As a Tool to Suppress Allergen-Specific T Helper 2 Responses

Abstract

Dendritic cells (DCs) are gatekeepers of the immune system that control induction and polarization of primary, antigen-specific immune responses. Depending on their maturation/activation status, the molecules expressed on their surface, and the cytokines produced DCs have been shown to either elicit immune responses through activation of effector T cells or induce tolerance through induction of either T cell anergy, regulatory T cells, or production of regulatory cytokines. Among the cytokines produced by tolerogenic DCs, interleukin 10 (IL-10) is a key regulatory cytokine limiting und ultimately terminating excessive T-cell responses to microbial pathogens to prevent chronic inflammation and tissue damage. Because of their important role in preventing autoimmune diseases, transplant rejection, allergic reactions, or in controlling chronic inflammation DCs have become an interesting tool to modulate antigen-specific immune responses. For the treatment of allergic inflammation, the aim is to downregulate allergen-specific T helper 2 (Th2) responses and the associated clinical symptoms [allergen-driven Th2 activation, Th2-driven immunoglobulin E (IgE) production, IgE-mediated mast cell and basophil activation, allergic inflammation]. Here, combining the presentation of allergens by DCs with a pro-tolerogenic, IL-10-producing phenotype is of special interest to modulate allergen-specific immune responses in the treatment of allergic diseases. This review discusses the reported strategies to induce DC-derived IL-10 secretion for the suppression of allergen-specific Th2-responses with a focus on IL-10 treatment, IL-10 transduction, and the usage of both whole bacteria and bacteria-derived components. Interestingly, while IL-10-producing DCs induced either by IL-10 treatment or IL-10 transduction are arrested in an immature/semi-mature state, treatment of DCs with live or killed bacteria as well as isolated bacterial components results in the induction of both anti-inflammatory IL-10 and pro-inflammatory, Th1-promoting IL-12 secretion often paralleled by an enhanced expression of co-stimulatory molecules on the stimulated DCs. By the secretion of DC-derived exosomes or CC-chemokine ligand 18, as well as the expression of inhibitory molecules like cytotoxic T lymphocyte-associated antigen 4, TNF receptor superfamily member 4, Ig-like transcript-22/cluster of differentiation 85, or programmed death-1, IL-10-producing DCs have been repeatedly shown to suppress antigen-specific Th2-responses. Therefore, DC-based vaccination approaches hold great potential to improve the treatment of allergic diseases.

The skin as an immune organ: Tolerance versus effector responses and applications to food allergy and hypersensitivity reactions

“…49,128 These effects can ameliorate allergic disorders, such as asthma and allergic rhinitis. 131,132 Together, these cytokines act in concert to tightly regulate the expression and induction of tolerogenic cells and signals.…”

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

“…The interleukins IL‐13, IL‐4, and IL‐10 are regarded as essential modulators of neuroinflammation by promoting M2‐like microglial polarization . IL‐10 possesses anti‐inflammatory properties through activation of JAK1/STAT3 signaling that inhibits NF‐kB to suppress proinflammatory cytokine expression . This pathway has been implicated in epilepsy; using hippocampal cultures from a picrotoxin‐mediated seizure model in mice, IL‐10 overexpression was able to suppress IL‐1β expression .…”

“…17 IL-10 possesses anti-inflammatory properties through activation of JAK1/STAT3 signaling that inhibits NF-kB to suppress proinflammatory cytokine expression. 74 This pathway has been implicated in epilepsy; using hippocampal cultures from a picrotoxin-mediated seizure model in mice, IL-10 overexpression was able to suppress IL-1β expression. 75 Using the closed cortical impact model of TBI, M2 polarization was induced by IL-10 secretion from transplanted, genetically modified MSCs.…”

Imunorregulação induzida pelo exercício físico na inflamação pulmonar alérgica crônica

“…O aumento da citocina IL-10 -apresentada nas amostras dos animais sensibilizados e treinados -pode estar ligado com a diminuição da expressão das moléculas coestimuladoras CD80 e CD86. Estudos mostram que a citocina IL-10 apresenta capacidade de diminuir a expressão destas moléculas co-estimuladoras e até mesmo da expressão de MHC II, o que reduziria o perfil inflamatório das células dendríticas (Schülke, 2018).…”

“…A diminuição da expressão de moléculas co-estimulatórias CD80, CD86, bem como a diminuição da citocina pró-inflamatória IL-6 nos grupos sensibilizados e submetidos ao protocolo experimental estão diretamente ligadas ao aumento da citocina IL-10 nestes grupos. (Schülke, 2018) ICOSL é uma molécula co-estimuladora, pertencente da família B7 e apresenta similaridade com CD80 e CD86. Foi mostrado que o bloqueio de ICOSL há a exacerbação alérgica como o caso de encefalomielite em modelos experimental, sugerindo que a sinalização negativa regula agentes patogênicos e apresentam fortes propriedades microbicidas, mas estas também contribuem para a destruição de tecidos (Chavez-Galan, et al, 2015).…”