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https://www.readbyqxmd.com/read/29327109/a-novel-biologic-platform-elicits-profound-t-cell-costimulatory-activity-and-antitumor-immunity-in-mice
#1
Joseph M Ryan, Payal Mittal, Antoine Menoret, Julia Svedova, Jeffrey S Wasser, Adam J Adler, Anthony T Vella
Combination immunotherapies utilizing complementary modalities that target distinct tumor attributes or immunosuppressive mechanisms, or engage different arms of the antitumor immune response, can elicit greater therapeutic efficacy than the component monotherapies. Increasing the number of agents included in a therapeutic cocktail can further increase efficacy, however, this approach poses numerous challenges for clinical translation. Here, a novel platform to simplify combination immunotherapy by covalently linking immunotherapeutic agonists to the costimulatory receptors CD134 and CD137 into a single heterodimeric drug, "OrthomAb", is shown...
January 11, 2018: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29322427/immunophenotyping-of-pediatric-brain-tumors-correlating-immune-infiltrate-with-histology-mutational-load-and-survival-and-assessing-clonal-t-cell-response
#2
Ashley S Plant, Shohei Koyama, Claire Sinai, Isaac H Solomon, Gabriel K Griffin, Keith L Ligon, Pratiti Bandopadhayay, Rebecca Betensky, Ryan Emerson, Glenn Dranoff, Mark W Kieran, Jerome Ritz
There is little known regarding the immune infiltrate present in pediatric brain tumors and how this compares to what is known about histologically similar adult tumors and its correlation with survival. Here, we provide a descriptive analysis of the immune infiltrate of 22 fresh pediatric brain tumor tissue samples of mixed diagnoses and 40 peripheral blood samples. Samples were analyzed using a flow cytometry panel containing markers for immune cell subtypes, costimulatory markers, inhibitory signals, and markers of activation...
January 10, 2018: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29321143/control-of-humoral-response-in-renal-transplantation-by-belatacept-depends-on-a-direct-effect-on-b-cells-and-impaired-t-follicular-helper-b-cell-crosstalk
#3
Claire Leibler, Allan Thiolat, Carole Hénique, Chloé Samson, Caroline Pilon, Marie Tamagne, France Pirenne, Benoit Vingert, José L Cohen, Philippe Grimbert
Generation of de novo donor-specific antibodies (dnDSAs) after renal transplant is recognized as the leading cause of late transplant failure. Hence, the optimal immunosuppressive strategies to limit dnDSA development need to be defined. Recent clinical trials using the novel costimulatory blockade agent CTLA4-Ig (Belatacept) have shown that kidney transplant recipients (KTRs) treated with Belatacept have better graft survival and function and a lower proportion of dnDSAs than control-treated KTRs. Mechanisms involved in the control of humoral responses by Belatacept remain to be investigated...
January 10, 2018: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/29316944/car-t-cells-targeting-cll-1-as-an-approach-to-treat-acute-myeloid-leukemia
#4
Jinghua Wang, Siyu Chen, Wei Xiao, Wende Li, Liang Wang, Shuo Yang, Weida Wang, Liping Xu, Shuangye Liao, Wenjian Liu, Yang Wang, Nawei Liu, Jianeng Zhang, Xiaojun Xia, Tiebang Kang, Gong Chen, Xiuyu Cai, Han Yang, Xing Zhang, Yue Lu, Penghui Zhou
BACKGROUND: Acute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts...
January 10, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29313959/cardiolipin-activates-antigen-presenting-cells-via-tlr2-pi3k-pkn1-akt-p38-nf-kb-signaling-to-prime-antigen-specific-na%C3%A3-ve-t-cells-in-mice
#5
Jung-Ah Cho, Tae-Joo Kim, Hye-Jung Moon, Young-Joo Kim, Hye-Kyung Yoon, Seung-Yong Seong
Mitochondrial defects and anti-mitochondrial cardiolipin (CL) antibodies are frequently detected in autoimmune disease patients. CL from dysregulated mitochondria activates various pattern recognition receptors, such as NLRP3. However, the mechanism by which mitochondrial CL activates antigen-presenting cells (APCs) as a damage-associated molecular pattern to prime antigen-specific naïve T cells, which is crucial for T-cell-dependent anti-cardiolipin IgG antibody production in autoimmune diseases is unelucidated...
January 4, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/29312539/regulatory-t-cells-with-a-defect-in-inhibition-on-co-stimulation-deteriorated-primary-biliary-cholangitis
#6
Jianing Chen, Xianliang Hou, Hongyu Jia, Guangying Cui, Zhongwen Wu, Lin Wang, Chong Lu, Wei Wu, Yingfeng Wei, Toshimitsu Uede, Lanjuan Li, Zhexiong Lian, Hongyan Diao
Regulatory T cells (Tregs) play an indispensable role in the progression of primary biliary cholangitis (PBC). Although Tregs could normalize costimulation in in vivo and in vitro models, it is obscure whether and how Tregs mediate these effects in PBC. Herein we focused on the quantitative and functional characteristics of Tregs in PBC. The number and proportion of Tregs, and the production of interleukin (IL)-10 were all significantly less in the PBC patients than in the healthy controls (HCs). In addition, compared to the HCs, the costimulatory CD86 of the circulation and liver were significantly higher in the patients with PBC...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29311317/tolerogenic-nanoparticles-restore-the-antitumor-activity-of-recombinant-immunotoxins-by-mitigating-immunogenicity
#7
Ronit Mazor, Emily M King, Masanori Onda, Nicolas Cuburu, Selamawit Addissie, Devorah Crown, Xiu-Fen Liu, Takashi Kei Kishimoto, Ira Pastan
Protein-based drugs are very active in treating cancer, but their efficacy can be limited by the formation of neutralizing antidrug antibodies (ADAs). Recombinant immunotoxins are proteins that are very effective in patients with leukemia, where immunity is suppressed, but induce ADAs, which compromise their activity, in patients with intact immunity. Here we induced a specific, durable, and transferable immune tolerance to recombinant immunotoxins by combining them with nanoparticles containing rapamycin (SVP-R)...
January 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29305435/an-immunotherapeutic-cd137-agonist-releases-eomesodermin-from-thpok-repression-in-cd4-t-cells
#8
Payal Mittal, Rebecca Abblett, Joseph M Ryan, Adam T Hagymasi, Archibald Agyekum-Yamoah, Julia Svedova, Steven L Reiner, Marie-Clare St Rose, Matthew P Hanley, Anthony T Vella, Adam J Adler
Agonists to the TNF/TNFR costimulatory receptors CD134 (OX40) and CD137 (4-1BB) elicit antitumor immunity. Dual costimulation with anti-CD134 plus anti-CD137 is particularly potent because it programs cytotoxic potential in CD8+ and CD4+ T cells. Cytotoxicity in dual-costimulated CD4 T cells depends on the T-box transcription factor eomesodermin (Eomes), which we report is induced via a mechanism that does not rely on IL-2, in contrast to CD8+ CTL, but rather depends on the CD8 T cell lineage commitment transcription factor Runx3, which supports Eomes expression in mature CD8+ CTLs...
January 5, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29298866/a-mirna181a-nfat5-axis-links-impaired-t-cell-tolerance-induction-with-autoimmune-type-1-diabetes
#9
Isabelle Serr, Martin G Scherm, Adam M Zahm, Jonathan Schug, Victoria K Flynn, Markus Hippich, Stefanie Kälin, Maike Becker, Peter Achenbach, Alexei Nikolaev, Katharina Gerlach, Nicole Liebsch, Brigitta Loretz, Claus-Michael Lehr, Benedikt Kirchner, Melanie Spornraft, Bettina Haase, James Segars, Christoph Küper, Ralf Palmisano, Ari Waisman, Richard A Willis, Wan-Uk Kim, Benno Weigmann, Klaus H Kaestner, Anette-Gabriele Ziegler, Carolin Daniel
Molecular checkpoints that trigger the onset of islet autoimmunity or progression to human type 1 diabetes (T1D) are incompletely understood. Using T cells from children at an early stage of islet autoimmunity without clinical T1D, we find that a microRNA181a (miRNA181a)-mediated increase in signal strength of stimulation and costimulation links nuclear factor of activated T cells 5 (NFAT5) with impaired tolerance induction and autoimmune activation. We show that enhancing miRNA181a activity increases NFAT5 expression while inhibiting FOXP3+ regulatory T cell (Treg) induction in vitro...
January 3, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29298689/anti-gd2-4-1bb-chimeric-antigen-receptor-t-cell-therapy-for-the-treatment-of-chinese-melanoma-patients
#10
Jiayi Yu, Xiaowen Wu, Junya Yan, Huan Yu, Longwen Xu, Zhihong Chi, Xinan Sheng, Lu Si, Chuanliang Cui, Jie Dai, Meng Ma, Tianxiao Xu, Yan Kong, Jun Guo
BACKGROUND: Chimeric antigen receptor (CAR)-engineered T cells have demonstrated promising clinical efficacy in patients with B cell lymphoma. However, the application of CAR-T cell therapy in the treatment of other solid tumors has been limited. We incorporated 4-1BB into the anti-GD2 CAR-T cells to test their cytotoxicity in melanoma in vitro and in vivo. Moreover, we reported the expression of ganglioside GD2 in non-Caucasian melanoma populations for the first time, thus providing a basis for future clinical research...
January 3, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29297233/deficiency-of-autoimmune-regulator-impairs-the-immune-tolerance-effect-of-bone-marrow-derived-dendritic-cells-in-mice
#11
Feifei Huo, Dongbei Li, Bo Zhao, Yadong Luo, Bingjie Zhao, Xueyang Zou, Yi Li, Wei Yang
As a transcription factor, autoimmune regulator (Aire) participates in thymic negative selection and maintains immune tolerance mainly by regulating the ectopic expression of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs). Aire is also expressed in dendritic cells (DCs). DCs are professional antigen-presenting cells (APCs) that affect the differentiation of T cells toward distinct subpopulations and participate in the immune response and tolerance, thereby playing an important role in maintaining homeostasis...
January 3, 2018: Autoimmunity
https://www.readbyqxmd.com/read/29259723/effects-of-ctla4-ig-on-human-monocytes
#12
Toshihiro Tono, Satoko Aihara, Takayuki Hoshiyama, Yoshiyuki Arinuma, Tatsuo Nagai, Shunsei Hirohata
Background: Abatacept, a CTLA4-Ig fusion protein attenuates T cell activation by inhibiting the CD80/86-CD28 costimulatory pathway that is required for the proper T cell activation and thus displays beneficial effects in the treatment of rheumatoid arthritis (RA). Although some studies have disclosed the in vitro effects of this biological agent on the immune-competent cells, the precise mechanisms of action in RA still remain unclear. The current studies were therefore undertaken to explore the effects of abatacept on monocytes in detail...
2017: Inflammation and Regeneration
https://www.readbyqxmd.com/read/29251582/association-between-cytotoxic-t-lymphocyte-antigen-4-gene-polymorphisms-and-torque-teno-virus-infection-after-hematopoietic-stem-cell-transplantation
#13
Mani Ramzi, Mahdiyar Iravani Saadi, Tahereh Zarei, Ramin Yaghobi, Nargess Arandi
OBJECTIVES: An association between costimulatory molecule gene polymorphisms and viral infection after hematopoietic stem cell transplantation may be related to clinical outcomes, especially acute graft-versus-host disease. Cytotoxic T-lymphocyte antigen 4 has been suggested as a crucial negative regulator of the immune system. In this study, our objective was to investigate the association between cytotoxic T-lymphocyte antigen-4 gene polymorphisms (including -1722 T/C, -1661 A/G, -318 C/T, and +49 A/G) and torque teno virus infection after hematopoietic stem cell transplantation in patients with and without acute graft-versus-host disease...
December 18, 2017: Experimental and Clinical Transplantation
https://www.readbyqxmd.com/read/29250066/dendritic-cells-transduced-with-single-immunoglobulin-il-1-related-receptor-exhibit-immature-properties-and-prolong-islet-allograft-survival
#14
Zhicheng Xue, Xuzhi Zhang, Maogen Chen, Xinjun Lu, Ronghai Deng, Yi Ma
Members of toll-like receptor-interleukin 1 receptor signaling [TLR/IL-1R (TIR)] superfamily mediate maturation of dendritic cells (DCs) and launch immune response in transplanted organs. In this study, we hypothesized that TIR8, also known as single immunoglobulin IL-1-related receptor (SIGIRR) molecule, refrain DCs from maturation and induce immune tolerance of transplanted organ. DCs were transduced with the recombinant adenovirus Ad5F35 to highly express SIGIRR (DC-SIGIRR), then injected to murine recipient before islet transplantation...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29245962/associations-between-hvem-light-btla-cd160-polymorphisms-and-the-occurrence-of-antibody-mediate-rejection-in-renal-transplant-recipients
#15
Zijie Wang, Ke Wang, Haiwei Yang, Zhijian Han, Jun Tao, Hao Chen, Yuqiu Ge, Miao Guo, Chuanjian Suo, Ji-Fu Wei, Ruoyun Tan, Min Gu
Antibody-mediated rejection (ABMR) is a serious complications that can occur following renal transplantation. The production of donor-specific antibodies by the humoral immune response can trigger costimulatory signals, which are crucial in activating immune cells, and therefore, playing a potential role in ABMR. To investigate the role of HVEM/LIGHT/BTLA/CD160 polymorphisms in ABMR, we retrospectively analyzed 200 renal transplant recipients. We adopted next-generation sequencing (NGS) to identify HVEM/LIGHT/BTLA/CD160 single-nucleotide polymorphisms (SNPs) in the genotypes of these patients...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29243267/naegleria-fowleri-immunization-modifies-lymphocytes-and-apc-of-nasal-mucosa
#16
M M Carrasco-Yepez, R Campos-Rodríguez, A A Reséndiz-Albor, C Peña-Juárez, A Contis-Montes de Oca, I M Arciniega-Martínez, P Bonilla-Lemus, S Rojas-Hernandez
We investigated if intranasal immunization with amoebic lysates plus cholera toxin modified the populations of T and B lymphocytes, macrophages and dendritic cells by flow cytometry from nose-associated lymphoid tissue (NALT), cervical lymph nodes (CN), nasal passages (NP) and spleen (SP). In all immunized groups, the percentage of CD4 was higher than CD8 cells. CD45 was increased in B cells from mice immunized. We observed IgA-antibody forming cell (IgA-AFC) response, mainly in NALT and NP. Macrophages from NP and CN expressed the highest levels of CD80 and CD86 either in N...
December 15, 2017: Parasite Immunology
https://www.readbyqxmd.com/read/29227213/productive-common-light-chain-libraries-yield-diverse-panels-of-high-affinity-bispecific-antibodies
#17
Thomas Van Blarcom, Kevin Lindquist, Zea Melton, Wai Ling Cheung, Chris Wagstrom, Dan McDonough, Cendy Valle Oseguera, Sheng Ding, Andrea Rossi, Shobha Potluri, Purnima Sundar, Steven Pitts, Marina Sirota, Meri Galindo Casas, Yu Yan, Jeffrey Jones, Zygy Roe-Zurz, Surabhi Srivatsa Srinivasan, Wenwu Zhai, Jaume Pons, Arvind Rajpal, Javier Chaparro-Riggers
The commercial success of bispecific antibodies generally has been hindered by the complexities associated with generating appropriate molecules for both research scale and large scale manufacturing purposes. Bispecific IgG (BsIgG) based on two antibodies that use an identical common light chain can be combined with a minimal set of Fc mutations to drive heavy chain heterodimerization in order to address these challenges. However, the facile generation of common light chain antibodies with properties similar to traditional monoclonal antibodies has not been demonstrated and they have only been used sparingly...
December 11, 2017: MAbs
https://www.readbyqxmd.com/read/29222312/harnessing-the-power-of-the-immune-system-in-non-hodgkin-lymphoma-immunomodulators-checkpoint-inhibitors-and-beyond
#18
REVIEW
Stephen M Ansell
Non-Hodgkin lymphoma is a malignancy of B lymphocytes that typically infiltrate sites of disease, including the lymph nodes, spleen, and bone marrow. Beyond the presence of malignant cells, many immune cells are also present within the tumor microenvironment. Although these immune cells have the potential to regulate the growth of malignant B cells, intratumoral immune cells are unable to eradicate lymphoma cells and most patients with lymphoma have clinical evidence of disease progression. Recent data have identified some of the mechanisms that account for the suppressed antitumor immune response and have created opportunities for treatment to overcome the deficiencies...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29217299/high-pd-l1-cd86-mfi-ratio-and-il-10-secretion-characterize-human-regulatory-dendritic-cells-generated-for-clinical-testing-in-organ-transplantation
#19
Alan F Zahorchak, Camila Macedo, David E Hamm, Lisa H Butterfield, Diana M Metes, Angus W Thomson
Human regulatory dendritic cells (DCreg) were generated from CD14 immunobead-purified or elutriated monocytes in the presence of vitamin D3 and IL-10. They exhibited similar, low levels of costimulatory CD80 and CD86, but comparatively high levels of co-inhibitory programed death ligand-1 (PD-L1) and IL-10 production compared to control immature DC (iDC). Following Toll-like receptor 4 ligation, unlike control iDC, DCreg resisted phenotypic and functional maturation and further upregulated PD-L1:CD86 expression...
September 14, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/29212947/requirement-of-treg-intrinsic-ctla4-pkc%C3%AE-signaling-pathway-for-suppressing-tumor-immunity
#20
Christophe Pedros, Ann J Canonigo-Balancio, Kok-Fai Kong, Amnon Altman
The ability of Tregs to control the development of immune responses is essential for maintaining immune system homeostasis. However, Tregs also inhibit the development of efficient antitumor responses. Here, we explored the characteristics and mechanistic basis of the Treg-intrinsic CTLA4/PKCη signaling pathway that we recently found to be required for contact-dependent Treg-mediated suppression. We show that PKCη is required for the Treg-mediated suppression of tumor immunity in vivo. The presence of PKCη-deficient (Prkch-/-) Tregs in the tumor microenvironment was associated with a significantly increased expression of the costimulatory molecule CD86 on intratumoral CD103+ DCs, enhanced priming of antigen-specific CD8+ T cells, and greater levels of effector cytokines produced by these cells...
December 7, 2017: JCI Insight
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