ROLE OF SOCS3 AND STAT-1 SIGNALLING PATHWAYS IN INDOLEAMINE 2,3-DIOXYGENASE (IDO)-EXPRESSING DENDRITIC CELLS: A POTENTIAL THERAPEUTIC STRATEGY FOR REGULATION OF ALLO-IMMUNE RESPONSES.

Abstract Dendritic cells (DCs) are essential for the initiation of acquired immune responses through antigen acquisition, migration, maturation, and T-cell stimulation. One of the critical mechanisms in this response is the process actin nucleation and polymerization, which is mediated by several groups of proteins, including mammalian Diaphanous-related formins (mDia). However, the role of mDia in DCs remains unknown. Herein, we examined the role of mDia1 (one of the isoforms of mDia) in DCs. Although the proliferation and maturation of bone marrow-derived DCs were comparable between control C57BL/6 and mDia1-deficient (mDia1−/−) mice, adhesion and spreading to cellular matrix were impaired in mDia1−/− bone marrow–derived DCs. In addition, fluorescein isothiocyanate-induced cutaneous DC migration to draining lymph nodes in vivo and invasive migration and directional migration to CCL21 in vitro were suppressed in mDia1−/− DCs. Moreover, sustained T-cell interaction and T-cell stimulation in lymph nodes were impaired by mDia1 deficiency. Consistent with this, the DC-dependent delayed hypersensitivity response was attenuated by mDia1-deficient DCs. These results suggest that actin polymerization, which is mediated by mDia1, is essential for several aspects of DC-initiated acquired immune responses.

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P01.11 Role of exosomes as promotors or biomarkers to study activation of leukemia-derived dendritic cells (DCleu)-mediated antileukemic activation of adaptive and innate immune-reactive cells against AML-blasts

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-itoc7.24 ◽

2020 ◽

Vol 8 (Suppl 2) ◽

pp. A13.2-A14

Author(s):

L Li ◽

V Mussack ◽

E Pepeldjiyska ◽

A Hartz ◽

A Rank ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Healthy Volunteers ◽

Information Transfer ◽

Immune Monitoring ◽

Lymphocyte Culture ◽

Innate Immune ◽

Proliferating Cells ◽

Continuous Increase

BackgroundAntileukemic responses of immune reactive cells in AML-patients need to be improved. Combinations of blast-modulatory kitM (GM-CSF+PGE1) (vs control) convert myeloid blasts into dendritic cells of leukemic origin (DCleu), that effectively activate immune-cells against leukemic blasts. Exosomes are small (30–150 nm) membranous vesicles of endocytic origin produced by all cells under physiological and pathological conditions. Their involvement in nearly all aspects of malignant transformation has generated much interest in their biology, mechanisms responsible for information transfer and their role in immune-surveillance as well as -escape.Exosomes secreted by dendritic cells (DCs) have been shown to allow efficient activation of T lymphocytes, displaying potential as promoters of adaptive immune responses.Materials and Methods1)DC/DCleu-culture of blast containing AML patients’ whole blood (WB) (n=10) and of healthy volunteers(n=8) with kits, T-cell enriched mixed lymphocyte culture (MLC) with kit- vs un-treated WB, functional blast-cytotoxicity and, leukemia-specificity assays (Degranulation/intracellular cytokine-assays), Flowcytometric evaluation of blast-,DC- and lymphocyte composition before or after cultures. 2)Exosomes were isolated by immunoaffinity from serum, DC- and MLC-culture supernatants of 3 AML patients and 3 healthy volunteers. Exosomes were negatively stained and characterized by transmission electron microscopy (TEM). Fluorescence nanoparticle tracking analysis (fNTA) was performed to determine exosomal size and -concentration. Obtained results were compared in AML and healthy volunteers.ResultsAddition of kitM to blast-containing WB significantly increased frequencies of mature DC/DCleu and their subtypes compared to untreated WB without induction of blasts’ proliferation. Immune monitoring showed a continuous increase ofactivated/proliferating cells of the adaptive and innate immune system after Tcell-enriched MLC using kitM pretreated vs -untreated WB, suggesting a production/activation of (potentially leukemia-specific) cells after kit-stimulation. Moreover kit-pretreated WB regularly and significantly improved provision, activation as well as antileukemic and leukemia-specifically directed immune reactive cells after MLC. TEM showed exosome-like structures with a typically cup-shaped appearance without any differences between healthy and AML samples. fNTA revealed average vesicle sizes of 177±23 nm (healthy) and 178±17 nm (AML). Higher levels of EVs were detectable in AML samples compared to healthy controls in serum and after DC-culture, but lower levels after MLC independent of culture conditions.Interestingly, the number of EVs increased during cultivation of DC of AML and healthy samples, but not in AML-derived MLC samples.ConclusionsWe will provide data in AML patients and healthy volunteers about a potential role of DCs- and MLC-derived exosomes as biomarkers in immune responses, malignant progression or as potential therapeutic targets for AML patients.Disclosure InformationL. li: None. V. Mussack: None. E. Pepeldjiyska: None. A. Hartz: None. A. Rank: None. C. Schmid: None. E. Özkaya: None. S. Ugur: None. M. Pfaffl: None. H. Schmetzer: None.

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The Role of Dendritic Cells, B Cells, and M Cells in Gut-Oriented Immune Responses

The Journal of Immunology ◽

10.4049/jimmunol.166.8.4843 ◽

2001 ◽

Vol 166 (8) ◽

pp. 4843-4852 ◽

Cited By ~ 121

Author(s):

Oral Alpan ◽

Gregory Rudomen ◽

Polly Matzinger

Keyword(s):

Dendritic Cells ◽

B Cells ◽

Immune Responses ◽

M Cells

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Indoleamine 2,3-Dioxygenase 2 Deficiency Exacerbates Imiquimod-Induced Psoriasis-Like Skin Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms21155515 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5515

Author(s):

Kento Fujii ◽

Yasuko Yamamoto ◽

Yoko Mizutani ◽

Kuniaki Saito ◽

Mariko Seishima

Keyword(s):

Immune Responses ◽

Immune Cells ◽

Skin Inflammation ◽

Kynurenine Pathway ◽

Immune Functions ◽

Wild Type ◽

Indoleamine 2,3 Dioxygenase ◽

Tnf Α ◽

In The Wild

Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme known to suppress immune responses, and several reports have showed that it is associated with psoriasis. IDO2 is an isoform of IDO1, recently identified as a catalytic enzyme in the tryptophan-kynurenine pathway, which is expressed in dendritic cells and monocytes. The expression of IDO2 in immune cells suggests that IDO2 may contribute to immune functions. However, the role of IDO2 in the pathogenesis of psoriasis remains unclear. In this study, to elucidate the role of IDO2 in psoriasis, we assessed imiquimod (IMQ)-induced psoriasis-like dermatitis in IDO2 knockout (KO) mice. Skin inflammation, evaluated by scoring erythema, scaling, and ear thickness, was significantly worse in the IDO2 KO mice than in the wild-type (WT) mice. The mRNA expression levels of TNF-α, IL-23p19, and IL-17A, key cytokines involved in the development of psoriasis, were also increased in the IDO2 KO mice. Furthermore, immunohistochemistry revealed that the number of Ki67-positive cells in the epidermis and CD4-, CD8-, and IL-17-positive lymphocytes infiltrating the dermis were significantly increased in the IDO2 KO mice. These results suggest that IDO2 might decrease IL-17 expression, thereby resulting in the suppression of skin inflammation in IMQ-induced psoriasis-like dermatitis.

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Crosstalk between Dendritic Cells and Immune Modulatory Agents against Sepsis

Genes ◽

10.3390/genes11030323 ◽

2020 ◽

Vol 11 (3) ◽

pp. 323 ◽

Cited By ~ 1

Author(s):

Guoying Wang ◽

Xianghui Li ◽

Lei Zhang ◽

Abualgasim Elgaili Abdalla ◽

Tieshan Teng ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Immune Responses ◽

Critical Role ◽

Innate Immune ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Th2 Responses ◽

Novel Strategy

Dendritic cells (DCs) play a critical role in the immune system which sense pathogens and present their antigens to prime the adaptive immune responses. As the progression of sepsis occurs, DCs are capable of orchestrating the aberrant innate immune response by sustaining the Th1/Th2 responses that are essential for host survival. Hence, an in-depth understanding of the characteristics of DCs would have a beneficial effect in overcoming the obstacle occurring in sepsis. This paper focuses on the role of DCs in the progression of sepsis and we also discuss the reverse sepsis-induced immunosuppression through manipulating the DC function. In addition, we highlight some potent immunotherapies that could be used as a novel strategy in the early treatment of sepsis.

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Noncanonical NF-κB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation

Blood ◽

10.1182/blood-2006-11-056010 ◽

2007 ◽

Vol 110 (5) ◽

pp. 1540-1549 ◽

Cited By ~ 95

Author(s):

Sander W. Tas ◽

Margriet J. Vervoordeldonk ◽

Najat Hajji ◽

Joost H. N. Schuitemaker ◽

Koen F. van der Sluijs ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell Activation ◽

Cell Activation ◽

Indoleamine 2,3 Dioxygenase ◽

Early Production ◽

Domain Peptide ◽

Nemo Binding Domain ◽

Interfering Rna ◽

Regulatory Properties

Abstract Ligation of CD40 on dendritic cells (DCs) induces early production of inflammatory mediators via canonical NF-κB signaling, as well as late expression of the anti-inflammatory enzyme indoleamine 2,3-dioxygenase (IDO) via unknown signal transduction. By selective blocking of either the canonical NF-κB pathway using the NEMO-binding domain peptide or the noncanonical NF-κB pathway by small interfering RNA, we demonstrate that IDO expression requires noncanonical NF-κB signaling. Also, noncanonical NF-κB signaling down-regulates proinflammatory cytokine production in DCs. In addition, selective activation of the noncanonical NF-κB pathway results in noninflammatory DCs that suppress T-cell activation and promote the development of T cells with regulatory properties. These findings reveal an important role of the noncanonical NF-κB pathway in the regulation of immunity.

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