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https://www.readbyqxmd.com/read/27931590/cytotoxic-t-lymphocyte-associated-protein-4-acts-on-local-draining-lymph-nodes-in-the-allogeneic-abdominal-skin-flap-of-a-rat-model-to-extend-its-survival
#1
G Ma, J Pei, Y Li, Y Han, D Liu
BACKGROUND: Early acute allograft rejection is the result of immune cells mainly composed of thymocyte (T) cells, which are activated, mature, and differentiate in lymphoid tissue. METHODS: Cytotoxic T lymphocyte-associated protein 4 immunoglobulin (CTLA4-Ig) competitively suppresses the cluster of differentiation 28/CTLA4-B7 costimulatory signaling pathway and alters the ratio of T helper 1 to T helper 2, leading to the inhibition of T cell activation. RESULTS: We used lentivirus-packed CTLA4-Ig to infect the local draining lymph nodes of the allograft skin flap in a rat model, which effectively extended the survival of the allograft...
December 2016: Transplantation Proceedings
https://www.readbyqxmd.com/read/27931084/association-of-higher-cd4-cd25-high-cd127-low-foxp3-and-il-2-t-cell-frequencies-early-after-lung-transplantation-with-less-chronic-lung-allograft-dysfunction-at-two-years
#2
J Salman, F Ius, A-K Knoefel, W Sommer, Th Siemeni, C Kuehn, I Tudorache, M Avsar, T Nakagiri, G Preissler, R Hatz, M Greer, T Welte, A Haverich, G Warnecke
Regulatory T cells (Treg) can regulate alloantigens and may counteract chronic lung allograft dysfunction (CLAD) in lung transplantation. We analyzed Treg in peripheral blood prospectively and correlated percentages of subpopulations with the incidence of CLAD at two years. Among lung-transplanted patients between 01/2009 and 07/2011, only patients with sufficient Treg measurements were included into the study. Tregs were measured immediately before lung transplantation, at 3 weeks and 3, 6, 12 and 24 months after transplantation and were defined as CD4(+) CD25(high) T cells and further analyzed for CTLA4, CD127, FoxP3 and IL-2 expressions...
December 8, 2016: American Journal of Transplantation
https://www.readbyqxmd.com/read/27920706/ipilimumab-induced-enteritis-without-colitis-a-new-challenge
#3
Marcus Messmer, Sunita Upreti, Yaman Tarabishy, Nikhilesh Mazumder, Reezwana Chowdhury, Mark Yarchoan, Matthias Holdhoff
INTRODUCTION: Ipilimumab is an immune checkpoint inhibitor targeting cytotoxic T-lymphocyte associated antigen 4 (CTLA4), approved to treat metastatic melanoma. It was the first therapy shown to prolong survival in a large, randomized clinical trial. However, immune-related adverse events are common and can be severe. Enterocolitis is a common adverse event with ipilimumab, but enteritis without colitis has not been previously described. CASE REPORT: An 83-year-old man presented to our hospital with grade 3 diarrhea for 5 days...
September 2016: Case Reports in Oncology
https://www.readbyqxmd.com/read/27920704/autoimmune-hemolytic-anemia-as-a-complication-of-nivolumab-therapy
#4
Amruth R Palla, Devin Kennedy, Hossain Mosharraf, Donald Doll
Recently, immunotherapeutic drugs, including PD-1 inhibitors (nivolumab, pembrolizumab), PD-L1 inhibitors (atezolizumab, avelumab), and CTLA4 inhibitors (ipiliumumab), have emerged as important additions to the armamentarium against certain malignancies and have been incorporated into therapeutic protocols for first-, second-, or third-line agents for these metastatic cancers. Immune checkpoint inhibitor nivolumab is currently FDA approved for the treatment of patients with metastatic malignant melanoma [Redman et al...
September 2016: Case Reports in Oncology
https://www.readbyqxmd.com/read/27918555/gene-expression-profiling-of-anti-ctla4-treated-metastatic-melanoma-in-patients-with-treatment-induced-autoimmunity
#5
Scott C Bresler, Le Min, Scott J Rodig, Andrew C Walls, Shuyun Xu, Songmei Geng, F Stephen Hodi, George F Murphy, Christine G Lian
Ipilimumab (IPI) is a monoclonal antibody that targets the inhibitory CTLA4 receptor of T cells, enhancing T-cell-driven antitumor responses. IPI therapy in metastatic melanoma results in significant improvement in disease-free and overall survival, although after initial responses disease progression generally ensues. Identification of specific responses in tissue where melanoma tumor cells are subjected to IPI-driven immune attack may reveal mechanisms of treatment efficacy or resistance, permitting refinement of targeted therapeutic approaches...
December 5, 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/27912061/tumor-interferon-signaling-regulates-a-multigenic-resistance-program-to-immune-checkpoint-blockade
#6
Joseph L Benci, Bihui Xu, Yu Qiu, Tony J Wu, Hannah Dada, Christina Twyman-Saint Victor, Lisa Cucolo, David S M Lee, Kristen E Pauken, Alexander C Huang, Tara C Gangadhar, Ravi K Amaravadi, Lynn M Schuchter, Michael D Feldman, Hemant Ishwaran, Robert H Vonderheide, Amit Maity, E John Wherry, Andy J Minn
Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27893611/absence-of-mir-182-augments-cardiac-allograft-survival
#7
Liang Wei, Vandana Kaul, Xiumei Qu, Xiaoxing Xiong, Audrey H Lau, Naoharu Iwai, Olivia M Martinez, Sheri M Krams
BACKGROUND: MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate the posttranscriptional expression of target genes and are important regulators in immune responses. Previous studies demonstrated that the miRNA, miR-182 was significantly increased during allograft rejection. Further, the transcription factor Forkhead box (FOX) protein 1, (FOXO1) was shown to be a target of miR-182. The aim of this study is to further examine the role of miR-182 in alloimmune responses. METHODS: Transplantation of BALB/c cardiac allografts was performed in C57BL/6, miR-182, B6...
November 23, 2016: Transplantation
https://www.readbyqxmd.com/read/27888068/associations-of-single-nucleotide-polymorphisms-of-ptpn22-and-ctla4-genes-with-the-risk-of-allergic-rhinitis-in-a-chinese-han-population
#8
Xia Ke, Shanghua Song, Xiaoqiang Wang, Yang Shen, Houyong Kang, Suling Hong
BACKGROUND: Allergic rhinitis (AR) is an inflammatory disorder of the upper airway. Protein tyrosine phosphatase non-receptor 22 encoded by PTPN22 gene and cytotoxic T-lymphocyte associated 4 encoded by Ctla4 gene are associated with autoimmune diseases. PURPOSE: This study was performed to evaluate the potential association of PTPN22 and Ctla4 single nucleotide polymorphisms (SNPs) with AR in a Chinese Han population. METHODS: A case-control study was performed in 783 Chinese AR patients and 811 healthy controls...
November 22, 2016: Human Immunology
https://www.readbyqxmd.com/read/27887569/immune-modulation-of-cd4-cd25-regulatory-t-cells-by-zoledronic-acid
#9
Hsien Liu, Shih-Han Wang, Shin-Cheh Chen, Ching-Ying Chen, Jo-Lin Lo, Tsun-Mei Lin
BACKGROUND: CD4(+)CD25(+) regulatory T (Treg) cells suppress tumor immunity by inhibiting immune cells. Manipulation of Treg cells represents a new strategy for cancer treatment. Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, inhibits the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) on osteoblasts to inhibit osteoclastogenesis. In a mouse model of bisphosphonate-related osteonecrosis of the jaw, administration of ZA suppressed Treg-cell activity and activated inflammatory Th17 cells...
November 25, 2016: BMC Immunology
https://www.readbyqxmd.com/read/27885401/-cutaneous-side-effects-of-targeted-cancer-drugs
#10
REVIEW
J Below, B Homey, P A Gerber
In the past decades many new drugs were approved for the treatment of cancer and have been established as essential parts of various therapeutic regimens. In particular targeted therapies and immune checkpoint inhibitors that aim at specific carcinogenic signaling pathways or modulate the tumor-immune response have revolutionized cancer therapy. Despite their targeted actions, these drugs may lead to diverse adverse reactions. In particular, cutaneous toxicities represent a serious threat to patients' quality of life and may lead to dose reduction or therapy cessation...
November 24, 2016: Der Hautarzt; Zeitschrift Für Dermatologie, Venerologie, und Verwandte Gebiete
https://www.readbyqxmd.com/read/27881707/a-cd80-biased-ctla4-ig-fusion-protein-with-superior-in-vivo-efficacy-by-simultaneous-engineering-of-affinity-selectivity-stability-and-fcrn-binding
#11
Julie Douthwaite, Jacques Moisan, Cyril Privezentzev, Blagoje Soskic, Shereen Sabbah, Suzanne Cohen, Andie Collinson, Elizabeth England, Catherine Huntington, Ben Kemp, Li Zhuang, Suzanne Hudak, D Gareth Rees, Debbie Goldberg, Chris Barton, Linda Chang, Inna Vainshtein, Meina Liang, Laurie Iciek, Philip Ambery, Mark Peakman, Tristan J Vaughan, Tim I M Tree, David M Sansom, Michael A Bowen, Ralph R Minter, Lutz Jermutus
Affinity- and stability-engineered variants of CTLA4-Ig fusion molecules with enhanced pharmacokinetic profiles could yield improved therapies with the potential of higher efficacy and greater convenience to patients. In this study, to our knowledge, we have, for the first time, used in vitro evolution to simultaneously optimize CTLA4 affinity and stability. We selected for improved binding to both ligands, CD80 and CD86, and screened as dimeric Fc fusions directly in functional assays to identify variants with stronger suppression of in vitro T cell activation...
November 23, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27878451/beyond-genetics-what-causes-type-1-diabetes
#12
REVIEW
Zhen Wang, Zhiguo Xie, Qianjin Lu, Christopher Chang, Zhiguang Zhou
Type 1 diabetes (T1D) is an autoimmune disease resulting from T cell-mediated β cell destruction in the pancreas of genetically susceptible individuals. Extensive familial and population genetic studies uncovered the strong linkage and association between HLA gene variants and T1D. Non-HLA genes have also been associated with T1D, such as INS, CTLA4, and PTPN22. T1D is considered as one of the most heritable common diseases. However, evidence that monozygotic twins have incomplete concordance of disease susceptibility provides convincing proof that environmental factors also play important roles in the pathogenesis of the disease...
November 22, 2016: Clinical Reviews in Allergy & Immunology
https://www.readbyqxmd.com/read/27873163/an-update-on-the-use-of-immunomodulators-in-primary-immunodeficiencies
#13
REVIEW
Pandiarajan Vignesh, Amit Rawat, Surjit Singh
The genomic revolution in the past decade fuelled by breathtaking advances in sequencing technologies has defined several new genetic diseases of the immune system. Many of these newly characterized diseases are a result of defects in genes involved in immune regulation. The discovery of these diseases has opened a vista of new therapeutic possibilities. Immunomodulatory agents, a hitherto unexplored therapeutic option in primary immunodeficiency diseases have been tried in a host of these newly described maladies...
November 21, 2016: Clinical Reviews in Allergy & Immunology
https://www.readbyqxmd.com/read/27866850/deubiquitination-and-stabilization-of-pd-l1-by-csn5
#14
Seung-Oe Lim, Chia-Wei Li, Weiya Xia, Jong-Ho Cha, Li-Chuan Chan, Yun Wu, Shih-Shin Chang, Wan-Chi Lin, Jung-Mao Hsu, Yi-Hsin Hsu, Taewan Kim, Wei-Chao Chang, Jennifer L Hsu, Hirohito Yamaguchi, Qingqing Ding, Yan Wang, Yi Yang, Chung-Hsuan Chen, Aysegul A Sahin, Dihua Yu, Gabriel N Hortobagyi, Mien-Chie Hung
Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of anti-tumor immunity and enhanced tumor cell survival. In the current study, we identified tumor necrosis factor alpha (TNF-α) as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNF-α-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1...
November 14, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27861289/the-effect-of-asp2409-a-novel-cd86-selective-variant-of-ctla4-ig-on-renal-allograft-rejection-in-nonhuman-primates
#15
Shinsuke Oshima, Erik E Karrer, Yuka Kawato, Masashi Maeda, Hidehiko Fukahori, Susumu Tsujimoto, Jun Hirose, Koji Nakamura, Takanori Marui, Fujiko Takamura, Takahisa Noto, Steven J Chapin, Yasutomo Fujii, Margaret Neighbors, Sridhar Viswanathan, Bruce H Devens, Yasuyuki Higashi
BACKGROUND: Blockade of CD28-mediated T cell costimulation by a modified cytotoxic T lymphocyte-associated antigen 4 (CTLA4-Ig), belatacept, is a clinically effective immunosuppressive therapy for the prevention of renal allograft rejection. Use of belatacept-based calcineurin inhibitor-free immunosuppression, however, has demonstrated an increased frequency of cellular rejection episodes and immunosuppression-related safety issues relative to conventional regimens. Furthermore, belatacept typically requires infusion for its administration chronically, which may present an inconvenience to patients...
December 2016: Transplantation
https://www.readbyqxmd.com/read/27859672/immune-activation-and-regulation-related-patterns-in-stable-hand-transplant-recipients
#16
Dorota Kamińska, Katarzyna Kościelska-Kasprzak, Magdalena Krajewska, Adam Chełmoński, Jerzy Jabłecki, Marcelina Żabińska, Marta Myszka, Mirosław Banasik, Maria Boratyńska, Agnieszka Gomółkiewicz, Piotr Dzięgiel, Marian Klinger
We assessed cell subsets and expression of a set of genes related to the T-cell populations in peripheral blood mononuclear cells to elucidate whether immune status of stable hand transplant recipients (HTx) differs from stable kidney transplant recipients (KTx). The study was conducted on five HTx 4.8 ± 1.7 years after transplantation and 30 stable KTx 7.9 ± 2.4 years after transplantation as well as 18 healthy volunteers. The research involved PBMC gene expression analysis of CD4, CD8, CTLA4, GZMB, FOXP3, IL10, IL4, ILR2A, NOTCH, PDCD1, PRF1, TGF-B, and TNF-A genes on a custom-designed low-density array (TaqMan) as well as flow cytometry assessment of lymphocyte subpopulations...
November 9, 2016: Transplant International: Official Journal of the European Society for Organ Transplantation
https://www.readbyqxmd.com/read/27849166/first-in-human-study-in-healthy-subjects-with-fr104-a-pegylated-monoclonal-antibody-fragment-antagonist-of-cd28
#17
Nicolas Poirier, Gilles Blancho, Maryvonne Hiance, Caroline Mary, Tim Van Assche, Jos Lempoels, Steven Ramael, Weirong Wang, Virginie Thepenier, Cecile Braudeau, Nina Salabert, Regis Josien, Ian Anderson, Ian Gourley, Jean-Paul Soulillou, Didier Coquoz, Bernard Vanhove
FR104 is a monovalent pegylated Fab' Ab, antagonist of CD28, under development for treatment of transplant rejection and autoimmune diseases. In contrast to CD80/86 antagonists (CTLA4-Ig), FR104 selectively blunts CD28 costimulation while sparing CTLA-4 and PD-L1 coinhibitory signals. In the present work, FR104 has been evaluated in a first-in-human study to evaluate the safety, pharmacokinetics, pharmacodynamics, and potency of i.v. administrations in healthy subjects. Sixty-four subjects were randomly assigned to four single ascending dose groups, two double dose groups and four single ascending dose groups challenged with keyhole limpet hemocyanin...
December 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27843587/life-threatening-colitis-and-complete-response-with-ipilimumab-in-a-patient-with-metastatic-braf-mutant-melanoma-and-rheumatoid-arthritis
#18
Francisco Aya, Lydia Gaba, Ivan Victoria, Aranzazu Fernandez-Martinez, Virginia Ruiz-Esquide, Estela Pineda, Monica Tosca, Margarita Viladot, Veronica Pereira, Josep Malvehy, Aleix Prat, Ana Arance
Immune checkpoint inhibitors, such as ipilimumab (an anti-CTLA4 antibody), have become a commonly used therapy in cancer. To date, safety data of patients with underlying autoimmune disease is limited. We present a case of a patient with rheumatoid arthritis who was diagnosed of a BRAF-mutant metastatic melanoma. The patient was treated with ipilimumab and presented with high-grade colitis requiring immunosuppressors. Despite of the immune-related adverse event, no exacerbation of the rheumatoid arthritis was observed and the patient achieved a complete response...
2016: ESMO Open
https://www.readbyqxmd.com/read/27832379/immunogenetics-of-igg4-related-aip
#19
Masao Ota, Takeji Umemura, Shigeyuki Kawa
Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis characterized by high serum IgG4 concentration and a variety of complicating extra-pancreatic lesions. AIP has the features of a complex disease that is caused by multifactorial genes. However, the genetic factors underlying AIP have not been elucidated conclusively. Association studies by the candidate-gene approach and genome-wide association studies (GWAS) have revealed several susceptibility genes for AIP, including HLA DRB1*04:05-DQB1*04:01, FCRL3, CTLA4, and KCNA3, albeit in small-scale analyses...
November 11, 2016: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/27824586/persistently-curly-hair-phenotype-with-the-use-of-nivolumab-for-squamous-cell-lung-cancer
#20
Constantin A Dasanu, Scott M Lippman, Steven C Plaxe
Increasing use of programmed cell death protein 1/programmed cell death protein 1 ligand inhibition for the treatment of patients with various malignancies such as advanced lung cancer, kidney cancer, and melanoma has resulted in valuable clinical responses, along with the occurrence of new and often puzzling side effects. Known cutaneous effects of CTLA4 and programmed cell death protein 1/programmed cell death protein 1 ligand inhibitors include generalized pruritus, vitiligo, maculopapular lesions, and lichenoid skin eruptions...
October 18, 2016: Journal of Oncology Pharmacy Practice
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