Generation of Tolerogenic Dendritic Cells by Treatment With Mitomycin C: Inhibition of Allogeneic T-Cell Response Is Mediated by Downregulation of Icam-1, Cd80, and Cd86

Jiga, Lucian P.; Bauer, Thomas M.; Chuang, Jing-Jing; Opelz, Gerhard; Terness, Peter

doi:10.1097/01.tp.0000131165.37177.6e

Cited by 32 publications

(34 citation statements)

References 8 publications

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“…70 Interestingly, higher concentrations of mitomycin C (up to 6.0 lM) induce the generation of tolerogenic DCs, which express low levels of CD80 and CD86 and display weak activity in the MLR assay. 18 Increased expression of CD40 molecules on DCs treated with methotrexate and mitomycin C is in agreement with their increased ability to stimulate T cell proliferation in the MLR assay. However, this correlation was not seen for other tested drugs, suggesting the importance of other mechanisms involved in up-regulation of antigen-presenting function of DCs by chemomodulation.…”

Section: Immunomodulatory Effects Of Ultra-low Concentrations Of Chemsupporting

confidence: 62%

“…In fact, such drugs can interfere on antigen presentation processes, 16 reduce cell mobilization 17 and downregulate the expression of cell surface markers such as CD80 and CD86. 18 Such effects on the immunocompetent cells may enable tumor escape, thus allowing the proliferation of chemo-resistant variants. 19,20 To avoid extreme side effects and immunosuppression, administration of cytotoxic drugs are followed by 3-4-week intervals to allow hematopoiesis and restoration of peripheral leukocyte count.…”

Section: Conventional Chemotherapymentioning

confidence: 99%

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Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy

Nars

Kaneno

2012

Intl Journal of Cancer

107

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Given that cancer is one of the main causes of death worldwide, many efforts have been directed toward discovering new treatments and approaches to cure or control this group of diseases. Chemotherapy is the main treatment for cancer; however, a conventional schedule based on maximum tolerated dose (MTD) shows several side effects and frequently allows the development of drug resistance. On the other side, low dose chemotherapy involves antiangiogenic and immunomodulatory processes that help host to fight against tumor cells, with lower grade of side effects. In this review, we present evidence that metronomic chemotherapy, based on the frequent administration of low or intermediate doses of chemotherapeutics, can be better than or as efficient as MTD. Finally, we present some data indicating that noncytotoxic concentrations of antineoplastic agents are able to both up-regulate the immune system and increase the susceptibility of tumor cells to cytotoxic T lymphocytes. Taken together, data from the literature provides us with sufficient evidence that low concentrations of selected chemotherapeutic agents, rather than conventional high doses, should be evaluated in combination with immunotherapy.

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Section: Immunomodulatory Effects Of Ultra-low Concentrations Of Chemsupporting

confidence: 62%

Section: Conventional Chemotherapymentioning

confidence: 99%

Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy

Nars

Kaneno

2012

Intl Journal of Cancer

107

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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%

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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“…This is particularly interesting because we previously reported decreased progesterone levels in mice in response to stress (38), which subsequently led to a predominance of Th1 cytokine production (28), suggesting that progesterone is a prerequisite for a DC-induced Th2 predominance. Furthermore, the conversion of DC into tolerogenic cells has recently been reported to be mediated by decrease of ICAM-1, CD80, and CD86 (39).…”

Section: Increased Decidual Th1 Cytokines Induce Maturation Of Apc Bymentioning

confidence: 99%

Intercellular Adhesion Molecule-1/LFA-1 Cross Talk Is a Proximate Mediator Capable of Disrupting Immune Integration and Tolerance Mechanism at the Feto-Maternal Interface in Murine Pregnancies

Blois

Tometten

Kandil

et al. 2005

The Journal of Immunology

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Our understanding why a woman’s immune system does not reject her histoincompatible fetus is still very limited. Distinct insights into the mechanisms involved in pregnancy maintenance may help us to prevent pregnancy complications, e.g., miscarriages or pre-eclampsia. Immune integration and tolerance at the feto-maternal interface appear to be indispensable for successful pregnancy maintenance. Little is known about the cross talk between ICAM-1, expressed on epithelium, endothelium, and APC, and its ligand, LFA-1, at the feto-maternal interface. However, based on the role of ICAM-1/LFA-1 in allograft acceptance or rejection upon transplantation, adhesion molecules are likely to interfere with successful pregnancy outcome. In this study, we tested the hypothesis that ICAM-1/LFA-1 pathways may be involved in pregnancy rejection in murine models. By blocking ICAM-1/LFA-1-mediated intercellular adhesion events, we show that fetal immune acceptance is restored in challenged pregnancies (e.g., upon exposure to sound stress), and adoptive transfer of LFA-1 cells into pregnant mice induces rejection only in abortion-prone mouse models. ICAM-1/LFA-1 cross talk leads to increased recruitment of proinflammatory cells to the implantation site, promotes dendritic cell maturation in the decidua, and subsequently induces additional local Th1 polarization via mature dendritic cells. Furthermore, our observations clearly point out that mechanisms of fetal tolerance, e.g., indoleamine 2,3-dioxygenase expression, presence of CD4+CD25bright regulatory T cells, and synthesis of asymmetric Abs, are ICAM-1/LFA-1 dependent. Hence, our data shed light on a hierarchical network of immune integration at the feto-maternal interface, in which ICAM-1/LFA-1 cross talk is clearly a proximate mediator capable of disrupting successful pregnancy maintenance.

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Generation of Tolerogenic Dendritic Cells by Treatment With Mitomycin C: Inhibition of Allogeneic T-Cell Response Is Mediated by Downregulation of Icam-1, Cd80, and Cd86

Abstract: MMC treatment converts rat DC into tolerogenic cells. This mechanism is mediated by decrease of ICAM-1, CD80, and CD86.

Cited by 32 publications

References 8 publications

Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy

Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy

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

Intercellular Adhesion Molecule-1/LFA-1 Cross Talk Is a Proximate Mediator Capable of Disrupting Immune Integration and Tolerance Mechanism at the Feto-Maternal Interface in Murine Pregnancies

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