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Qiong Liu, Wen Wen, Liang Tang, Chen-Jie Qin, Yan Lin, Hui-Lu Zhang, Han Wu, Charles Ashton, Hong-Ping Wu, Jin Ding, Wei Dong, Le-Xing Yu, Wen Yang, Dan-Dan Huang, Meng-Chao Wu, Hong-Yang Wang, He-Xin Yan
Despite their central function in tumor immunity, dendritic cells (DCs) can respond to inhibitory signals and become tolerogenic, curtailing T cell responses in vivo. Here, we provide the evidence for an inhibitory function of signal regulatory protein (SIRP) α in DC survival and activation. In tumors from human liver cancer patients, infiltrative DCs expressed elevated levels of SIRPα, which is correlated with the induction of immune tolerance within the tumors. Silencing of SIRPα resulted in a significant increase in the longevity of antigen-pulsed DCs in the draining lymph nodes...
2016: Oncoimmunology
Jie Qin, Yusuke Arakawa, Miwa Morita, John J Fung, Shiguang Qian, Lina Lu
BACKGROUND: Islet transplantation is a promising therapeutic approach for restore the physical response to blood glucose in type 1 diabetes. Current chronic use of immunosuppressive reagents for preventing islet allograft rejection is associated with severe complications. In addition, many of the immunosuppressive drugs are diabetogenic. The induction of transplant tolerance to eliminate the dependency on immunosuppression is ideal, but remains challenging. METHODS: Addition of hepatic stellate cells allowed generation of myeloid-derived suppressor cells (MDSC) from precursors in mouse bone marrow...
October 17, 2016: Transplantation
Masanori Inui, Akiko Sugahara-Tobinai, Hiroshi Fujii, Ari Itoh-Nakadai, Hidehiro Fukuyama, Tomohiro Kurosaki, Tomonori Ishii, Hideo Harigae, Toshiyuki Takai
Plasmablasts and plasma cells (PBs/PCs) producing pathogenic autoantibodies in patients with systemic autoimmune diseases could be a better target for specific therapies for the disease than general immunosuppression or pan- or activated B-cell targeting. Our previous study indicated that Leukocyte Ig-like receptor (LILR)B4 (B4, also known as ILT3/LIR-5/CD85k), a tolerogenic receptor in antigen-presenting cells, is ectopically expressed on the PB/PC surface in healthy individuals. Here we show that the enlarged population size of PBs/PCs with augmented B4 expression is characteristic in non-treated systemic lupus erythematosus (SLE)...
October 14, 2016: International Immunology
Ali Moravej, Mohammad-Hossein Karimi, Bita Geramizadeh, Negar Azarpira, Amir-Hasan Zarnani, Ramin Yaghobi, Maryam Khosravi, Mehdi Kalani, Behrouz Gharesi-Fard
OBJECTIVE: Mesenchymal stem cells (MSCs) show immunomodulatory functions. But the exact mechanism underlying these activities of MSCs is still not completely understood. There have been a few studies which have assessed the effects of these cells on dendritic cells (DCs) function. Given the importance of programmed cell death receptor-1 (PD-L1) and vitamin D receptor (VDR) expression in induction of tolerance in DCs, we were encouraged to investigate if one of the immunomodulatory functions of MSCs could be inducing upregulation of PD-L1 and VDR on DCs or not...
October 13, 2016: Immunological Investigations
Mei Song, Xiaojing Ma
Interleukin-35 (IL-35) is the latest addition to the IL-12 family of heterodimeric cytokines, consisting of IL-12 p35 subunit and IL-27β subunit Epstein-Barr virus induced 3 (EBI3). Since its discovery, IL-35 has been shown to exhibit immunosuppressive activities which are distinct from other members of IL-12 family. IL-35 is also unique in that it is expressed primarily by regulatory T-cells (Tregs) rather than by antigen-presenting cells (APCs). IL-35 can directly suppress effector T-cell proliferation and function and inhibit the differentiation of Th17 cells...
2016: Advances in Experimental Medicine and Biology
Derrick P McCarthy, Jonathan Woon-Teck Yap, Christopher T Harp, W Kelsey Song, Jeane Chen, Ryan M Pearson, Stephen D Miller, Lonnie D Shea
Tolerogenic nanoparticles (NPs) are rapidly being developed as specific immunotherapies to treat autoimmune disease. However, many NP-based therapies conjugate antigen (Ag) directly to the NP posing safety concerns due to antibody binding or require the co-delivery of immunosuppressants to induce tolerance. Here, we developed Ag encapsulated NPs comprised of poly(lactide-co-glycolide) [PLG(Ag)] and investigated the mechanism of action for Ag-specific tolerance induction in an autoimmune model of T helper type 1/17 dysfunction - relapse-remitting experimental autoimmune encephalomyelitis (R-EAE)...
October 6, 2016: Nanomedicine: Nanotechnology, Biology, and Medicine
Ronald Schilderink, Matthew Bell, Eleonora Reginato, Chris Patten, Inmaculada Rioja, Francisca W Hilbers, Pawel A Kabala, Kris A Reedquist, David F Tough, Paul Peter Tak, Rab K Prinjha, Wouter J de Jonge
Transcription of inflammatory genes is tightly regulated by acetylation and deacetylation of histone tails. An inhibitor of the acetylated-lysine reader bromodomain and extra-terminal domain (BET) proteins, I-BET151, is known to counteract the induction of expression of inflammatory genes in macrophages. We have investigated the effects of I-BET151 on dendritic cell function, including expression of co-stimulatory molecules and cytokines, and capacity for T cell activation. Treatment of mouse bone marrow derived dendritic cells (BMDC) and human monocyte derived DCs (mdDC) with I-BET151 reduced LPS-induced expression of co-stimulatory molecules, as well as the production of multiple cyokines and chemokines...
October 3, 2016: Molecular Immunology
Carlos H Villa, Douglas B Cines, Don L Siegel, Vladimir Muzykantov
Red blood cells (RBCs) are innate carriers that can also be engineered to improve the pharmacokinetics and pharmacodynamics of many drugs, particularly biotherapeutics. Successful loading of drugs, both internally and on the external surface of RBCs, has been demonstrated for many drugs including anti-inflammatory, antimicrobial, and antithrombotic agents. Methods for internal loading of drugs within RBCs are now entering clinical use. Although internal loading can result in membrane disruption that may compromise biocompatibility, surface loading using either affinity or chemical ligands offers a diverse set of approaches for the production of RBC drug carriers...
August 17, 2016: Transfusion Medicine Reviews
A V C Coelho, R R Moura, S Crovella, F Celsi
Human leukocyte antigen (HLA)-G is a key tolerogenic molecule mainly expressed in the placenta and is crucial for implantation of the embryo and immunological tolerance of the fetus during pregnancy. However, under pathological conditions, such as cancer or viral infections, HLA-G can be expressed in other tissues. The gene coding for HLA-G (HLA-G, chromosome 6p21.3) presents numerous polymorphisms, some of them influencing its expression. One of the most studied, is the 14 bp ins/del (rs371194629) situated at the 3'-UTR of the gene...
August 26, 2016: Genetics and Molecular Research: GMR
Natalia Savelyeva, Alex Allen, Warayut Chotprakaikiat, Elena Harden, Jantipa Jobsri, Rosemary Godeseth, Yidao Wang, Freda Stevenson, Christian Ottensmeier
In the last decade, immunotherapy with monoclonal antibodies targeting immunological check points has become a breakthrough therapeutic modality for solid cancers. However, only up to 50 % of patients benefit from this powerful approach. For others vaccination might provide a plausible addition or alternative. For induction of effective anticancer immunity CD4+ T cell help is required, which is often difficult to induce to self cancer targets because of tolerogenic mechanisms. Our approach for cancer vaccines has been to incorporate into the vaccine design sequences able to activate foreign T cell help, through genetically linking cancer targets to microbial sequences (King et al...
October 5, 2016: Current Topics in Microbiology and Immunology
Wai-Ping Lee, Barbara Willekens, Patrick Cras, Herman Goossens, Eva Martínez-Cáceres, Zwi N Berneman, Nathalie Cools
While emerging evidence indicates that dendritic cells (DC) play a central role in the pathogenesis of multiple sclerosis (MS), their modulation with immunoregulatory agents provides prospect as disease-modifying therapy. Our observations reveal that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment of monocyte-derived DC results in a semimature phenotype and anti-inflammatory cytokine profile as compared to conventional DC, in both healthy controls and MS patients. Importantly, 1,25(OH)2D3-treated DC induce T cell hyporesponsiveness, as demonstrated in an allogeneic mixed leukocyte reaction...
2016: Journal of Immunology Research
Jaxaira Maggi, Katina Schinnerling, Bárbara Pesce, Catharien M Hilkens, Diego Catalán, Juan C Aguillón
Tolerogenic dendritic cells (DCs) are a promising tool to control T cell-mediated autoimmunity. Here, we evaluate the ability of dexamethasone-modulated and monophosphoryl lipid A (MPLA)-activated DCs [MPLA-tolerogenic DCs (tDCs)] to exert immunomodulatory effects on naive and memory CD4(+) T cells in an antigen-specific manner. For this purpose, MPLA-tDCs were loaded with purified protein derivative (PPD) as antigen and co-cultured with autologous naive or memory CD4(+) T cells. Lymphocytes were re-challenged with autologous PPD-pulsed mature DCs (mDCs), evaluating proliferation and cytokine production by flow cytometry...
2016: Frontiers in Immunology
L Malaguarnera, A Marsullo, K Zorena, G Musumeci, M Di Rosa
The family of lysosome-associated membrane proteins (LAMPs) encompassing LAMP1, LAMP2 and DC-LAMP (LAMP3) are the major constituents of the glycoconjugates coat present on the inside of the lysosomal membrane. LAMP3 is highly expressed only in certain cell types and during the differentiation stages. Its expression is linked the maturation of dendritic cells, inflammation, poor prognosis of certain tumors, and the locus where it is encoded was identified as a risk factor for Parkinson's disease (PD). Here, we investigated the capacity of Vitamin D3 to modulate the expression of LAMP3 during the dendritic cells differentiation and maturation...
September 28, 2016: Cellular Immunology
Elisa Albini, Verdiana Rosini, Marco Gargaro, Giada Mondanelli, Maria L Belladonna, Maria Teresa Pallotta, Claudia Volpi, Francesca Fallarino, Antonio Macchiarulo, Cinzia Antognelli, Roberta Bianchi, Carmine Vacca, Paolo Puccetti, Ursula Grohmann, Ciriana Orabona
The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) catalyses the initial, rate-limiting step in tryptophan (Trp) degradation, resulting in tryptophan starvation and the production of immunoregulatory kynurenines. IDO1's catalytic function has long been considered as the one mechanism responsible for IDO1-dependent immune suppression by dendritic cells (DCs), which are master regulators of the balance between immunity and tolerance. However, IDO1 also harbours immunoreceptor tyrosine-based inhibitory motifs, (ITIM1 and ITIM2), that, once phosphorylated, bind protein tyrosine phosphatases, (SHP-1 and SHP-2), and thus trigger an immunoregulatory signalling in DCs...
September 30, 2016: Journal of Cellular and Molecular Medicine
Silvia Casacuberta-Serra, Carme Costa, Herena Eixarch, María José Mansilla, Sergio López-Estévez, Lluís Martorell, Marta Parés, Xavier Montalban, Carmen Espejo, Jordi Barquinero
Previous work by our group showed that transferring bone marrow cells transduced with a self-antigen induced immune tolerance and ameliorated experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). We also found that following retroviral transduction of murine bone marrow (BM) cells, the majority of cells generated and transduced were myeloid-derived suppressor cells (MDSCs). Here, we aimed to determine whether purified antigen-expressing MDSCs have similar therapeutic effects than those of unfractionated BM, and to investigate their potential mechanisms...
September 28, 2016: Experimental Neurology
Ricardo García-Muñoz, Carlos Panizo
The ultimate cause of follicular lymphoma (FL) remains unknown. Remarkably, almost nothing is known about immunological tolerance mechanisms that might contribute to FL development. Immunological tolerance mechanisms, like other stimuli, also induce persistent changes of B cell receptors that induce genetic instability and molecular aberrations promoting the development of a neoplasm. Using the same method as Burnet, we provide a new perspective taking advantage of the comparison of a normal linear B cell differentiation process and FL development within the framework of clonal selection theory...
September 29, 2016: Human Immunology
C Levy, F Fusil, F Amirache, C Costa, A Girard, D Negre, O Bernadin, G Garaulet, A Rodriguez, N Nair, T Vandendriessche, M Chuah, F-L Cosset, E Verhoeyen
BACKGROUND: B cells are attractive targets for gene therapy of diseases associated with B-cell dysfunction and particularly interesting for immunotherapy. Moreover, B cells are potent protein-secreting cells and can be tolerogenic antigen presenting cells. OBJECTIVE: Evaluation of human B cells for secretion of clotting factors such as factor IX (IX) as possible treatment for hemophilia. METHODS: We tested here for the first time our newly developed baboon envelope pseudotyped lentiviral vectors (BaEV-LVs) for human (h) B-cell transduction followed their adaptive transfer into NSG mouse...
September 29, 2016: Journal of Thrombosis and Haemostasis: JTH
Moanaro Biswas, Geoffrey L Rogers, Alexandra Sherman, Barry J Byrne, David M Markusic, Haiyan Jiang, Roland W Herzog
Development of antibodies (inhibitors) against coagulation factor VIII (FVIII) is a major complication of intravenous replacement therapy in haemophilia A (HA). Current immune tolerance induction (ITI) regimens are not universally effective. Rituximab, a B cell-depleting antibody against CD20, has shown mixed results for inhibitor reversal in patients. This study aims to develop a combinatorial therapy for inhibitor reversal in HA, using anti-murine CD20 (anti-mCD20) antibody and rapamycin, which targets both B and T cell responses...
September 29, 2016: Thrombosis and Haemostasis
Fanny Kryczanowsky, Verena Raker, Edith Graulich, Matthias P Domogalla, Kerstin Steinbrink
Dendritic cells (DCs) are key regulators of protective immune responses and tolerance to (self-)Ags. Therefore, the scientific rationale for the use of tolerogenic DC therapy in the fields of allergies, autoimmunity, and transplantation medicine is strong. In this study, we analyzed the tolerogenic capacity of IL-10-modulated DC (IL-10DC) subpopulations to identify a DC subset that combines potent immunosuppressive activities with valuable immune properties for clinical implementation. IL-10DCs consist of two phenotypically distinct subpopulations: CD83(high)CCR7(+) IL-10DCs and CD83(low)CCR7(-) IL-10DCs...
September 28, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Amy E Anderson, David J Swan, Oi Yean Wong, Matthew Buck, Oliver Eltherington, Rachel A Harry, Angela M Patterson, Arthur G Pratt, Gary Reynolds, John-Paul Doran, John A Kirby, John D Isaacs, Catharien M U Hilkens
Tolerogenic dendritic cells (tolDC) are a new immunotherapeutic tool for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders. We have established a method to generate stable tolDC by pharmacological modulation of human monocyte-derived DC. These tolDC exert potent pro-tolerogenic actions on CD4(+) T-cells. Lack of IL-12p70 production is a key immunoregulatory attribute of tolDC but does not fully explain their action. Here we show that tolDC express TGF-β1 at both mRNA and protein level, and that expression of this immunoregulatory cytokine is significantly higher in tolDC than in mature monocyte-derived DC...
September 26, 2016: Clinical and Experimental Immunology
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