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CD8 tolerance

Lorenz Jahn, Dirk M van der Steen, Renate S Hagedoorn, Pleun Hombrink, Michel G D Kester, Marjolein P Schoonakker, Daniëlle de Ridder, Peter A van Veelen, J H Frederik Falkenburg, Mirjam H M Heemskerk
Immunotherapy of B-cell leukemia and lymphoma with CD20-targeting monoclonal antibodies (mAbs) has demonstrated clinical efficacy. However, the emergence of unresponsive disease due to low or absent cell surface CD20 urges the need to develop additional strategies. In contrast to mAbs, T-cells via their T-cell receptor (TCR) can recognize not only extracellular but also intracellular antigens in the context of HLA molecules. We hypothesized that T-cells equipped with high affinity CD20-targeting TCRs would be able to recognize B-cell malignancies even in the absence of extracellular CD20...
October 20, 2016: Oncotarget
Hu Luo, Liang Gong, Bingjing Zhu, Ying Huang, Chunlan Tang, Shicang Yu, Zhi Yang, Xiangdong Zhou
OBJECTIVE: Few clinical studies have confirmed the role of cytokine-induced killer cells (CIKs) in the maintenance therapy of advanced lung cancer patients. We investigate effectiveness and tolerability of CIKs as a maintenance therapy in the treatment of advanced lung cancer patients. METHODS: 70 patients with advanced lung cancer (stage IIIB to IV) admitted to the First Affiliated Hospital of Third Military Medical University in Chongqing from Nov. 2011 to Jan...
October 17, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Jing Zhang, Ya-Qin Tan, Ming-Hui Wei, Xiao-Jing Ye, Guan-Ying Chen, Rui Lu, Ge-Fei Du, Gang Zhou
Oral lichen planus (OLP) is a T-cell-mediated autoimmune mucocutaneous disease affected by the interactions among the keratinocytes, CD4(+) T cells and CD8(+) T cells. B7-H1 induced by Toll-like receptors (TLRs), can suppress T cell immune reaction, thereby resulting in immune tolerance. However, the role of TLRs-mediated B7-H1 on keratinocytes in the immune response of OLP is still unknown. The present study showed that TLR4 could induce time-coursed B7-H1 expression on oral keratinocytes, and blocking NF-κB or PI3K/mTOR pathway down-regulated B7-H1 transcriptional expression...
October 20, 2016: Experimental Dermatology
Emilie Duvallet, Mathilde Boulpicante, Takahiro Yamazaki, Chrysoula Daskalogianni, Rodrigo Prado Martins, Sonia Baconnais, Bénédicte Manoury, Robin Fahraeus, Sébastien Apcher
Cellular immune reactions against non-self-epitopes require activation of cytotoxic CD8(+) T-cells via cross-presentation of MHC class I-restricted peptides by professional antigen presenting cells (pAPCs), with the consequent detection and elimination of cells expressing the same antigens via the endogenous (direct) pathway. The source of peptides for the endogenous pathway is constituted of alternative mRNA translation products; however, it is still unclear which source of peptides is used for cross-presentation...
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
Xu Shi, Ying Tang, Xiguang Sun, Yufei Liu, Ying Sun, Munan Sun, Yanfang Jiang, Yulin Li
The current study aimed to investigate the distribution of memory and naïve T cell (TN) subsets in hepatitis B virus (HBV)‑infected patients at different immune stages and investigate the effect of interleukin 33 (IL‑33) on the regulation of the T‑cell subsets. The distributions of memory and naïve T cells were detected by flow cytometry. ELISA was conducted to assess the levels of IL‑4, IL‑5, IL‑10, IL‑12, interferon γ and tumor necrosis factor α. The expression levels of IL‑33 and HBV x protein (HBx) were measured by reverse transcription‑quantitative polymerase chain reaction and western blot analysis, respectively...
October 13, 2016: Molecular Medicine Reports
Jong Man Kim, Choon Hyuck David Kwon, Jae-Won Joh, Gyu-Seong Choi, Jae Berm Park, Eun-Suk Kang, Sung Joo Kim, Suk-Koo Lee
PURPOSE: T lymphocytes are an essential component of allograft rejection and tolerance. The aims of the present study are to analyze the characteristics of T-cell subsets between ABO-incompatible living donor liver transplantation (ABO-I LDLT) and ABO-compatible LDLT (ABO-C LDLT). MATERIALS AND METHODS: Between April 2013 and June 2014, 61 patients underwent adult LDLT. ABO-I LDLT patients received rituximab and all patients received basiliximab as induction therapy and tacrolimus as maintenance therapy...
October 13, 2016: Journal of Investigative Surgery: the Official Journal of the Academy of Surgical Research
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
Thilo Oelert, Amos Gilhar, Ralf Paus
The hair follicle (HF) epithelium can present self-antigens to cognate CD8+ T cells. These cells express periodically during the hair cycle arising or age-related immunogenic proteins including HF-specific neo-antigens. We propose, that IFN-gamma derived from the respective antigen-specific T cells spotting the particular self-peptides may thereby significantly induce and alter self-antigen presentation ("induced-self"). This induction, at first, may silence T cells, including neo-epitope-specific T cells. As the thymus cannot significantly recapitulate neo-epitopes evolving in the periphery, we propose that peripheral tissue-specific induction of MHC molecules presenting exactly these neo-epitopes by self- MHC/peptide-reactive CD8+ T cells is a key element of self-tolerance...
October 7, 2016: Experimental Dermatology
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
Antonella Riccomi, Valentina Gesa, Alessandra Sacchi, Maria Teresa De Magistris, Silvia Vendetti
We have shown that cholera toxin (CT) and other cyclic AMP (cAMP)-elevating agents induce upregulation of the inhibitory molecule CTLA-4 in human resting CD4(+) T lymphocytes, which following the treatment acquired suppressive functions. In this study, we evaluated the effect of cAMP-elevating agents on human CD4(+)CD25(+) T cells, which include the T regulatory cells (Tregs) that play a pivotal role in the maintenance of immunological tolerance. We found that cAMP-elevating agents induce upregulation of CTLA-4 in CD4(+)CD25(-) and further enhance its expression in CD4(+)CD25(+) T cells...
2016: Frontiers in Immunology
Gokul Swaminathan, Elizabeth A Thoryk, Kara S Cox, Jeffrey S Smith, Jayanthi J Wolf, Marian E Gindy, Danilo R Casimiro, Andrew J Bett
Dengue virus has emerged as an important arboviral infection worldwide. As a complex pathogen, with four distinct serotypes, the development of a successful Dengue virus vaccine has proven to be challenging. Here, we describe a novel Dengue vaccine candidate that contains truncated, recombinant, Dengue virus envelope protein from all four Dengue virus serotypes (DEN-80E) formulated with ionizable cationic lipid nanoparticles (LNPs). Immunization studies in mice, Guinea pigs, and in Rhesus macaques, revealed that LNPs induced high titers of Dengue virus neutralizing antibodies, with or without co-administration or encapsulation of a Toll-Like Receptor 9 agonist...
October 5, 2016: Scientific Reports
Kirsteen M Tullett, Ingrid M Leal Rojas, Yoshihito Minoda, Peck S Tan, Jian-Guo Zhang, Corey Smith, Rajiv Khanna, Ken Shortman, Irina Caminschi, Mireille H Lahoud, Kristen J Radford
DC-based vaccines that initiate T cell responses are well tolerated and have demonstrated efficacy for tumor immunotherapy, with the potential to be combined with other therapies. Targeting vaccine antigens (Ag) directly to the DCs in vivo is more effective than cell-based therapies in mouse models and is therefore a promising strategy to translate to humans. The human CD141(+) DCs are considered the most clinically relevant for initiating CD8(+) T cell responses critical for killing tumors or infected cells, and they specifically express the C-type lectin-like receptor CLEC9A that facilitates presentation of Ag by these DCs...
May 19, 2016: JCI Insight
Gaurang Jhala, Jonathan Chee, Prerak M Trivedi, Claudia Selck, Esteban N Gurzov, Kate L Graham, Helen E Thomas, Thomas W H Kay, Balasubramanian Krishnamurthy
High-affinity self-reactive thymocytes are purged in the thymus, and residual self-reactive T cells, which are detectable in healthy subjects, are controlled by peripheral tolerance mechanisms. Breakdown in these mechanisms results in autoimmune disease, but antigen-specific therapy to augment natural mechanisms can prevent this. We aimed to determine when antigen-specific therapy is most effective. Islet autoantigens, proinsulin (PI), and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) were expressed in the antigen-presenting cells (APCs) of autoimmune diabetes-prone nonobese diabetic (NOD) mice in a temporally controlled manner...
July 7, 2016: JCI Insight
Jérémie Martinet, Gwladys Bourdenet, Amine Meliani, Laetitia Jean, Sahil Adriouch, Jose L Cohen, Federico Mingozzi, Olivier Boyer
BACKGROUND: Gene therapy is a promising treatment option for hemophilia and other protein deficiencies. However, immune responses against the transgene product represent an obstacle to safe and effective gene therapy, urging for the implementation of tolerization strategies. Induction of a hematopoietic chimerism via bone marrow transplantation (BMT) is a potent means for inducing immunological tolerance in solid organ transplantation. OBJECTIVES: We reasoned, here, that the same viral vector could be used, first, to transduce BM cells for inducing chimerism-associated transgene-specific immune tolerance and, second, for correcting protein deficiencies by vector-mediated systemic production of the deficient coagulation factor...
2016: Frontiers in Immunology
Y Maurice Morillon, Elizabeth Chase Lessey-Morillon, Matthew Clark, Rui Zhang, Bo Wang, Keith Burridge, Roland Tisch
The use of nondepleting Abs specific for CD4 and CD8 is an effective strategy to tolerize CD4(+) and CD8(+) T cells in a tissue-specific manner. We reported that coreceptor therapy reverses diabetes in new onset NOD mice. A striking feature of coreceptor-induced remission is the purging of T cells from the pancreatic lymph nodes (PLN) and islets of NOD mice. Evidence indicates that Abs binding to the coreceptors promotes T cell egress from these tissues. The present study examined how coreceptor therapy affects the migration of CD4(+) T cells residing in the PLN of NOD mice...
September 30, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
María Del Mar Valenzuela-Membrives, Francisco Perea-García, Abel Sanchez-Palencia, Francisco Ruiz-Cabello, Mercedes Gómez-Morales, María Teresa Miranda-León, Inmaculada Galindo-Angel, María Esther Fárez-Vidal
Immune cell infiltration is a common feature of many human solid tumors. Innate and adaptative immune systems contribute to tumor immunosurveillance. We investigated whether tumors evade immune surveillance by inducing states of tolerance and/or through the inability of some immune subpopulations to effectively penetrate tumor nests. Immunohistochemistry and flow cytometry analysis were used to study the composition and distribution of immune subpopulations in samples of peripheral blood, tumor tissue (TT), adjacent tumor tissue (ATT), distant non-tumor tissue (DNTT), cancer nests, cancer stroma, and invasive margin in 61 non-small-cell lung cancer (NSCLC) patients...
September 26, 2016: Oncotarget
Lorenz Jahn, Renate S Hagedoorn, Dirk M van der Steen, Pleun Hombrink, Michel G D Kester, Marjolein P Schoonakker, Daniëlle de Ridder, Peter A van Veelen, J H Frederik Falkenburg, Mirjam H M Heemskerk
CD22 is currently evaluated as a target-antigen for the treatment of B-cell malignancies using chimeric antigen receptor (CAR)-engineered T-cells or monoclonal antibodies (mAbs). CAR- and mAbs-based immunotherapies have been successfully applied targeting other antigens, however, occurrence of refractory disease to these interventions urges the identification of additional strategies. Here, we identified a TCR recognizing the CD22-derived peptide RPFPPHIQL (CD22RPF) presented in human leukocyte antigen (HLA)-B*07:02...
September 26, 2016: Oncotarget
Xiao X Wei, Stephen Chan, Serena Kwek, Jera Lewis, Vinh Dao, Li Zhang, Matthew R Cooperberg, Charles J Ryan, Amy M Lin, Terence W Friedlander, Brian Rini, Christopher Kane, Jeffry P Simko, Peter R Carroll, Eric J Small, Lawrence Fong
Granulocytic-macrophage colony-stimulating factor (GM-CSF) is used as an adjuvant in cancer vaccine trials and has the potential to enhance antitumor efficacy with immunotherapy; however, its immunologic effects are not fully understood. Here, we report results from a phase I study of neoadjuvant GM-CSF in patients with localized prostate cancer undergoing radical prostatectomy. Patients received subcutaneous injections of GM-CSF (250 μg/m(2)/day) daily for 2 weeks (cohort 1; n = 6), 3 weeks (cohort 2; n = 6), or 4 weeks (cohort 3; n = 6)...
September 29, 2016: Cancer Immunology Research
Susan M Hiniker, Sunil A Reddy, Holden T Maecker, Priyanka B Subrahmanyam, Yael Rosenberg-Hasson, Susan M Swetter, Saurabh Saha, Lei Shura, Susan J Knox
PURPOSE: Local radiation therapy (RT) combined with systemic anti-cytotoxic T-lymphocyte-associated protein-4 immunotherapy may enhance induction of systemic antimelanoma immune responses. The primary objective of the present trial was to assess the safety and efficacy of combining ipilimumab with RT in patients with stage IV melanoma. The secondary objectives included laboratory assessment of induction of antimelanoma immune responses. METHODS AND MATERIALS: In our prospective clinical trial, 22 patients with stage IV melanoma were treated with palliative RT and ipilimumab for 4 cycles...
November 1, 2016: International Journal of Radiation Oncology, Biology, Physics
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