Phenotypic and functional markers for 1α,25-dihydroxyvitamin D3-modified regulatory dendritic cells

Pedersen, Ayako Wakatsuki; Holmstrøm, Kim; Jensen, Søren Buus; Fuchs, Dietmar; Rasmussen, Søren K.; Kvistborg, Pia; Claësson, Mogens H.; Zocca, Mai-Britt

doi:10.1111/j.1365-2249.2009.03961.x

Cited by 94 publications

(64 citation statements)

References 55 publications

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“…As a potential tolerogenic agent, we have focused on the use of vitD3 to generate tolDCs from RR-MS patients. The role of vitD3 in the generation of tolDCs has been previously reported in HCs [29,30].Our in vitro data demonstrate that vitD3 has a comparable effect on the differentiation and function of DCs derived from either HCs or MS patients, indicating that it is able to overcome any immune-activating factors associated with the autoimmune response in RR-MS patients. Comparative analyses of MDDCs between healthy donors and MS patients did not show any significant difference, except for the reduced expression of CD83 observed in matDCs and tolDCs from MS patients.…”

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confidence: 57%

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Stable antigen‐specific T‐cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients

et al. 2012

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Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease of the central nervous system. Current therapies decrease the frequency of relapses and limit, to some extent, but do not prevent disease progression. Hence, new therapeutic approaches that modify the natural course of MSneed to be identified. Tolerance induction to self‐antigens using monocyte‐derived dendritic cells (MDDCs) is a promising therapeutic strategy in autoimmunity. In this work, we sought to generate and characterize tolerogenic MDDCs (tolDCs) from relapsing‐remitting (RR) MSpatients, loaded with myelin peptides as specific antigen, with the aim of developing immunotherapeutics for MS. MDDCs were generated from both healthy‐blood donors and RR‐MSpatients, and MDDCmaturation was induced with a proinflammatory cytokine cocktail in the absence or presence of 1α,25‐dihydroxyvitamin‐D3, a tolerogenicity‐inducing agent. tolDCs were generated from monocytes of RR‐MSpatients as efficiently as from monocytes of healthy subjects. The RR‐MStolDCs expressed a stable semimature phenotype and an antiinflammatory profile as compared with untreated MDDCs. Importantly, myelin peptide‐loaded tolDCs induced stable antigen‐specific hyporesponsiveness in myelin‐reactive T cells from RR‐MS patients. These results suggest that myelin peptide‐loaded tolDCs may be a powerful tool for inducing myelin‐specific tolerance in RR‐MS patients.

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confidence: 57%

Section: Discussionmentioning

confidence: 99%

Stable antigen‐specific T‐cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients

et al. 2012

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“…As of today, various conditioning strategies are being considered to generate tolerogenic DCs. This includes DC treatment with anti-inflammatory cytokines (IL-10, TGF-b) (4,44,45), neuropeptides (46,47), immunosuppressive drugs (e.g., dexamethasone, mitomycin C, rapamycin) (16,19,48,49), or vitamins (1,25-dihydroxy-vitamin D3, vitamin A) (16,17,35,50,51). Genetic engineering of DCs has also been used to enhance the expression of IL-10 (52), TGF-b (53), soluble TNFR (54), intracellular CTLA-4 (55), or FOXP3 molecules (56) or to prevent activation of the NF-kB pathway (57).…”

Section: Discussionmentioning

confidence: 99%

“…Most particularly, DCs conditioned with dexamethasone (DEX-DCs) present a semimature phenotype and prevent the upregulation of costimulatory molecules as well as the secretion of proinflammatory cytokines like IL-12 (15)(16)(17). Such DEX-DCs inhibit the proliferation of allospecific T cells (18,19), prolong allograft survival in mice (20), and decrease the number of IFN-gproducing CD4…”

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confidence: 99%

Identification of a New Phenotype of Tolerogenic Human Dendritic Cells Induced by Fungal Proteases from Aspergillus oryzae

Zimmer

Luce

Gaignier

et al. 2011

The Journal of Immunology

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We characterized a new pathway to induce tolerogenic dendritic cells (DCs) following treatment of human monocyte-derived DCs with proteases from the fungus Aspergillus oryzae (ASP). ASP-treated DCs (ASP-DCs) exhibit a CD80−CD83−CD86−Ig-like transcript (ILT)2−ILT3−ILT4+ phenotype, do not secrete cytokines or chemokines, and express tolerogenic markers such as glucocorticoid-induced leucine zipper, NO synthetase-2, retinaldehyde dehydrogenase-1 or retinaldehyde dehydrogenase-2. When cocultured with naive CD4+ T cells, ASP-DCs induce an anergic state that can be reversed by IL-2. Generated T cells mediate a suppressive activity in third-party experiments that is not mediated by soluble factors. A comparison between dexamethasone-treated DCs used as a reference for regulatory T cell-inducing DCs and ASP-DCs reveals two distinct phenotypes. In contrast to dexamethasone, ASP treatment induces glucocorticoid-induced leucine zipper independently of glucocorticoid receptor engagement and leads to NF-κB p65 degradation. Abrogation of protease activities in ASP using specific inhibitors reveals that aspartic acid-containing proteases are key inducers of regulatory genes, whereas serine, cysteine, and metalloproteases contribute to NF-κB p65 degradation. Collectively, those features correspond to a previously unreported anergizing phenotype for human DCs. Such regulatory mechanisms may allow fungi to downregulate host immune responses and provide clues for new approaches to treat proinflammatory disorders.

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“…NLGP promoted the upregulation of CD1a (Fig. 2A), a protein that mediates the presentation of primarily lipid and glycolipid antigens of self or microbial origin to T cells (28).…”

Section: Resultsmentioning

confidence: 99%

Neem Leaf Glycoprotein Partially Rectifies Suppressed Dendritic Cell Functions and Associated T Cell Efficacy in Patients with Stage IIIB Cervical Cancer

Roy¹,

Goswami²,

Bose³

et al. 2011

Clin. Vaccine Immunol.

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Myeloid-derived dendritic cells (DCs) generated from monocytes obtained from stage IIIB cervical cancer (CaCx IIIB) patients show dysfunctional maturation; thus, antitumor T cell functions are dysregulated. In an objective to optimize these dysregulated immune functions, the present study is focused on the ability of neem leaf glycoprotein (NLGP), a nontoxic preparation of the neem leaf, to induce optimum maturation of dendritic cells from CaCx IIIB patients. In vitro NLGP treatment of immature DCs (iDCs) obtained from CaCx IIIB patients results in upregulated expression of various cell surface markers (CD40, CD83, CD80, CD86, and HLA-ABC), which indicates DC maturation. Consequently, NLGP-matured DCs displayed balanced cytokine secretions, with type 1 bias and noteworthy functional properties. These DCs displayed substantial T cell allostimulatory capacity and promoted the generation of cytotoxic T lymphocytes (CTLs). Although NLGPmatured DCs derived from CaCx monocytes are generally subdued compared to those with a healthy monocyte origin, considerable revival of the suppressed DC-based immune functions is noted in vitro at a fairly advanced stage of CaCx, and thus, further exploration of ex vivo and in vivo DC-based vaccines is proposed. Moreover, the DC maturating efficacy of NLGP might be much more effective in the earlier stages of CaCx, where the extent of immune dysregulation is less and, thus, the scope of further investigation may be explored.Cervical cancer (CaCx) is the second most common type of tumor worldwide, and its incidence is disproportionately high (Ͼ80%) in the developing world (35). It remains an important health problem for women, especially in underserved and socioeconomically backward classes (29). Immunotherapy with mature monocyte-derived dendritic cells (DCs) pulsed with human papillomavirus type 16 or 18 (HPV16/18) E7 oncoprotein antigens is a promising approach in treating this disease (32). These alternate therapeutic approaches are aimed toward controlling late-stage detection and preventing recurrence (31), an arena where application of traditional therapeutic approaches like radical surgery or radiotherapy is difficult. DCs are extremely potent antigen-presenting cells (APC) that function in vitro and in vivo to initiate T lymphocyte responses to antigens (14). The ability of DCs to stimulate T cells is attributed to their dichotomous nature as immature DCs (iDCs) and mature DCs (mDCs) (30). Immature DCs effectively capture antigens but lack full T cell stimulatory activity and are sensitive to the immunosuppressive effects of an immunoregulatory cytokine, interleukin-10 (IL-10). In contrast, mature DCs exhibit an enhanced level of antigen presentation, full T cell stimulatory activity, production of a type 1 cytokine, IL-12, and low production of a type 2 cytokine, IL-10 (36).In the last few years, a multitude of diagnostic studies have shown a strong immunosuppressive state of the cervical epithelium, which is one major reason for the fragile health of cervical cancer patient...

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Phenotypic and functional markers for 1α,25-dihydroxyvitamin D3-modified regulatory dendritic cells

Cited by 94 publications

References 55 publications

Stable antigen‐specific T‐cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients

Stable antigen‐specific T‐cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients

Identification of a New Phenotype of Tolerogenic Human Dendritic Cells Induced by Fungal Proteases from Aspergillus oryzae

Neem Leaf Glycoprotein Partially Rectifies Suppressed Dendritic Cell Functions and Associated T Cell Efficacy in Patients with Stage IIIB Cervical Cancer

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