The mucosal factors retinoic acid and TGF-B induce phenotypically and functionally distinct dendritic cell types
Hartog, C.G. den; Altena, S.E.C. van; Savelkoul, H.F.J. ; Neerven, R.J.J. van - \ 2013
International Archives of Allergy and Immunology 162 (2013)3. - ISSN 1018-2438 - p. 225 - 236.
bronchial lymph-node - t-cells - tgf-beta - intestinal inflammation - vitamin-a - tolerance - generation - expression - responses - outcomes
Non-inflammatory dendritic cell (DC) subsets play an essential role in preventing massive inflammation in mucosal tissues. We investigated whether mucosa-related factors, namely retinoic acid (RA) and transforming growth factor-ß (TGF-ß1), can induce such DC types. DCs were differentiated from monocytes in the absence or presence TGF-ß1 and RA. The phenotype as well as responsiveness to bacterial ligands was studied in detail. Compared to monocyte-derived DCs (moDCs), the expression of co-stimulatory molecule CD86 and DC maturation marker CD83 were strongly reduced by RA and TGF-ß1. In addition, both RA- and TGF-ß1-induced DCs showed strongly decreased responsiveness to stimulation with the bacterial ligands lipopolysaccharide and peptidoglycan, and produced significantly lower levels of the pro-inflammatory cytokines IL-12 and TNF-a compared to moDCs, whilst IL-10 production was not significantly reduced. DCs differentiated under the influence of RA uniquely expressed markers related to intestinal homing (CD103 and integrin ß7). In addition, CCR7, which mediates homing to lymph nodes, was expressed by DCs differentiated in the presence of RA, and also to a lesser extent by the other DC types. Furthermore, whereas moDCs and TGF-ß1-derived moDCs expressed high levels of CD32, RA-derived DCs lacked CD32 expression but expressed high levels of CD64, suggesting that RA-DCs may primarily respond to soluble proteins and moDCs, and TGF-ß DCs to immune complexes. The data presented here support the hypothesis that the mucosal factors TGF-ß1 and RA, which can also be provided through dietary intake of dairy products, result in functionally and phenotypically distinct DC types with non-inflammatory properties.
Angiopoietin-like 4: a decade of research
Zhu, P. ; Goh, Y.Y. ; Chin, H.F.A. ; Kersten, A.H. ; Tan, N.S. - \ 2012
Bioscience Reports 32 (2012)3. - ISSN 0144-8463 - p. 211 - 219.
induced adipose factor - fatty-acids - tgf-beta - anoikis resistance - lipoprotein-lipase - human adipocytes - target gene - protein - angptl4 - expression
The past decade has seen a rapid development and increasing recognition of ANGPTL4 (angiopoietin-like 4) as a remarkably multifaceted protein that is involved in many metabolic and non-metabolic conditions. ANGPTL4 has been recognised as a central player in various aspects of energy homoeostasis, at least in part, via the inhibitory interaction between the coiled-coil domain of ANGPTL4 and LPL (lipoprotein lipase). The fibrinogen-like domain of ANGPTL4 interacts and activates specific integrins to facilitate wound healing, modulates vascular permeability, and regulates ROS (reactive oxygen species) level to promote tumorigenesis. The present review summarizes these landmark findings about ANGPTL4 and highlights several important implications for future clinical practice. Importantly, these implications have also raised many questions that are in urgent need of further investigations, particularly the transcription regulation of ANGPTL4 expression, and the post-translation cleavage and modifications of ANGPTL4. The research findings over the past decade have laid the foundation for a better mechanistic understanding of the new scientific discoveries on the diverse roles of ANGPTL4.
Modulation of human immune responses by bovine interleukin-10
Hartog, C.G. den; Savelkoul, H.F.J. ; Schoemaker, R. ; Tijhaar, E. ; Westphal, A.H. ; Ruiter, T. de; Weg-Schrijver, Elise van de; Neerven, R.J.J. van - \ 2011
PLoS ONE 6 (2011)3. - ISSN 1932-6203 - 10 p.
t-cell proliferation - dendritic cells - necrotizing enterocolitis - human-milk - ifn-gamma - cytokine production - tgf-beta - sublingual immunotherapy - sequence identity - interferon-gamma
Cytokines can be functionally active across species barriers. Bovine IL-10 has an amino acid sequence identity with human IL-10 of 76.8%. Therefore, the aim of this study was to evaluate whether bovine IL-10 has immunomodulatory activities on human monocytes and dendritic cells. Peripheral blood monocytes were isolated from healthy donors, and used directly or allowed to differentiate to dendritic cells under the influence of IL-4 and GM-CSF. Recombinant bovine IL-10 inhibited TLR induced activation of monocytes, and dose-dependently inhibited LPS-induced activation of monocyte-derived DCs comparable to human IL-10. By using blocking antibodies to either bovine IL-10 or the human IL-10 receptor it was demonstrated that inhibition of monocyte activation by bovine IL-10 was dependent on binding of bovine IL-10 to the human IL-10R. These data demonstrate that bovine IL-10 potently inhibits the activation of human myeloid cells in response to TLR activation. Bovine IL-10 present in dairy products may thus potentially contribute to the prevention of necrotizing enterocolitis and allergy, enhance mucosal tolerance induction and decrease intestinal inflammation and may therefore be applicable in infant foods and in immunomodulatory diets.
Immunotherapy of malignant gliomas using autologous and alllogeneic tissue cells
Hofman, F.M. ; Stathopoulos, A. ; Kruse, C.A. ; Chen, T.C. ; Schijns, V.E.J.C. - \ 2010
Anti-Cancer Agents in Medicinal Chemistry 10 (2010)6. - ISSN 1871-5206 - p. 462 - 470.
tumor-infiltrating lymphocytes - regulatory t-cells - glioblastoma-multiforme patients - dendritic cells - antitumor immunity - growth-factor - tgf-beta - therapeutic vaccination - adoptive immunotherapy - human cytomegalovirus
Immunotherapy of brain tumors is rapidly emerging as a potential clinical option [1-3]. The quality and magnitude of immune responses evoked by the new generation anti-tumor vaccines is in general highly dependent on the source or choice of peptide antigens, and as well, a suitable immunopotentiator. Poorly immunogenic antigens, such as those present in tumor cell lysates, may not reliably provide stimulation like recombinant or DNA-encoded protein antigens might be expected to. In addition, the efficacy of the vaccine may depend on inherent counteracting measures of the tumor which dampen immune surveillance and immune effector activity triggered by immunization . Our body has many means of limiting an immune response to our own (self) proteins. In particular, patients with gliomas exhibit a broad suppression of cell-mediated immunity [5-8]. Unfortunately, for most tumor vaccines the induction of local or systemic immune effector cells does not necessarily translate into objective clinical responses or increased survival . Here we review immunotherapeutic approaches against gliomas and recent pre-clinical and clinical initiatives based on cellular or active immunization of the patient's immune system using autologous and allogeneic tissues or cultured cells. Available evidence shows that single modality cancer therapies likely remain suboptimal. Combination regimens targeting the immune system at multiple coordinated levels must be developed, and possibly combined with strategies to inhibit immune suppressive factors if significant clinical benefit is to be achieved
Splenic CD8(+) T cells secrete TGF-beta 1 to exert suppression in mice with anterior chamber-associated immune deviation
Jiang, L.Q. ; He, H. ; Yang, P.Z. ; Lin, X.M. ; Zhou, H.Y. ; Huang, X.K. ; Kijlstra, A. - \ 2009
Graefes Archive for Clinical and Experimental Ophthalmology 247 (2009)1. - ISSN 0721-832X - p. 87 - 92.
antigen-presenting cells - tgf-beta - regulatory cells - ifn-gamma - in-vitro - interferon-gamma - cutting edge - induction - foxp3 - responses
Background CD8(+) regulatory T cells (Treg) have been considered to be involved in a model of ocular-induced tolerance, known as anterior chamber-associated immune deviation (ACAID). The mechanisms of suppression by CD8(+) T cells in ACAID remain only poorly understood. TGF-beta 1 is considered as an inhibitory cytokine for immunosuppression in some models. The production of TGF-beta 1 by CD8(+) T cells in ACAID, and whether CD8+ T cells exert suppression through TGF-beta 1, is unknown. Methods The suppressive effect of CD8(+) T cells in ACAID mice was determined by a local adoptive transfer (LAT) assay. The production of TGF-beta 1 by CD8(+) T cells was measured by enzyme-linked immunosorbent assay (ELISA). Anti-TGF-beta 1 antibodies were used in the LAT assay to test if they could block the inhibitory effect of CD8(+) T cells. Results CD8(+) T cells from ACAID mice were shown to block the delayed-type hypersensitivity (DTH) response in an antigen-specific manner in a LAT assay. These CD8+ T cells secreted TGF-beta 1, and their suppression could partially be blocked by anti-TGF-beta 1 antibodies. Conclusions Our study confirms that CD8+ T cells from ACAID mice possess inhibitory properties. This population exerts part of its suppressive function via the production of TGF-beta 1.
Upregulation of CD94 on CD8+T Cells in Anterior Chamber Immune Deviation
He, H. ; Yang, P. ; Jiang, L. ; Zhang, J. ; Zhao, Changlin ; Chen, L. ; Lin, X. ; Zhou, H. ; Kijlstra, A. - \ 2008
BMC Immunology 9 (2008). - ISSN 1471-2172 - 11 p.
human natural-killer - human t-lymphocytes - i molecule qa-1(b) - tgf-beta - inhibitory receptors - cytolytic activity - interferon-gamma - foxp3 expression - soluble-antigen - ifn-gamma
Background CD8+ regulatory T cells (Treg) have been considered to be involved in a model of ocular-induced tolerance, known as anterior chamber-associated immune deviation (ACAID). The phenotype and characteristics of CD8+Treg in ACAID remain only poorly understood. Recent studies have reported that the CD94-Qa-1 system is implicated in the induction of ACAID CD8+Treg, but the functions and characteristics of CD8+CD94+T cells remain unclear. Results Both mRNA and protein of CD94 and NKG2A were markedly up-regulated on splenic CD8+T cells of ACAID mice compared with controls. Flow cytometric analysis showed that very few CD8+CD94+T cells express granzyme B, perforin and Foxp3. CD8+CD94+T cells, but not CD8+CD94-T cells, magnetically isolated from the spleens of ACAID mice, produced large amounts of TGF-beta1 and exhibited suppressive activity in vitro. Neutralization of TGF-beta1 caused reversal of suppression mediated by CD8+CD94+T cells. Conclusion CD8+CD94+T cells from ACAID mice exhibited suppressive activity in association with enhanced expression of TGF-beta1, suggesting that CD8+Treg are mainly distributed in CD94+T cell subpopulations.