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Immunological tolerance

Avishai Shemesh, Aleksandra Kugel, Naama Steiner, Michal Yezersky, Dan Tirosh, Avishay Edri, Omri Teltsh, Benyamin Rosental, Eyal Sheiner, Eitan Rubin, Kerry S Campbell, Angel Porgador
NKp44 and NKp30 splice variant profiles have been shown to promote diverse cellular functions. Moreover, microenvironment factors such as TGF-β, IL-15 and IL-18 are able to influence both NKp44 and NKp30 splice variant profiles, leading to cytokine-associated profiles. Placenta and cancerous tissues have many similarities; both are immunologically privileged sites and both share immune tolerance mechanisms to support tissue development. Therefore, we studied the profiles of NKp44 and NKp30 splice variants in these states by comparing (i) decidua from pregnancy disorder and healthy gestation and (ii) matched normal and cancer tissue...
September 27, 2016: Oncotarget
S Kanda, K Goto, H Shiraishi, E Kubo, A Tanaka, H Utsumi, K Sunami, S Kitazono, H Mizugaki, H Horinouchi, Y Fujiwara, H Nokihara, N Yamamoto, H Hozumi, T Tamura
BACKGROUND: The human IgG4 monoclonal antibody nivolumab targets programmed cell death-1 (PD-1) and promotes antitumor response by blocking the interaction of PD-1 with its ligands. This single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients who had stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible...
October 20, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Wataru Obara, Takashi Karashima, Kazuyoshi Takeda, Renpei Kato, Yoichiro Kato, Mitsugu Kanehira, Ryo Takata, Keiji Inoue, Toyomasa Katagiri, Taro Shuin, Yusuke Nakamura, Tomoaki Fujioka
PURPOSE: Through genome-wide expression profile analysis, hypoxia-inducible protein 2 (HIG2) has previously been identified as an oncoprotein involved in development/progression of renal cell carcinoma (RCC). We subsequently identified a highly immunogenic HLA-A*0201/0206-restricted epitope peptide (HIG2-9-4) corresponding to a part of HIG2 and applied it as a therapeutic vaccine. We conducted a phase I clinical trial using the HIG2-9-4 peptide for patients with advanced RCC. MATERIALS AND METHODS: Nine patients having HLA-A*0201 or HLA-A*0206 with metastatic or unresectable RCC after failure of the cytokine and/or tyrosine kinase inhibitor therapies were enrolled in this study...
October 18, 2016: Cancer Immunology, Immunotherapy: CII
Neil H Segal, Theodore F Logan, F Stephen Hodi, David F McDermott, Ignacio Melero, Omid Hamid, Henrik Schmidt, Caroline Robert, Vanna Chiarion-Sileni, Paolo A Ascierto, Michele Maio, Walter J Urba, Tara C Gangadhar, Satyendra Suryawanshi, Jaclyn Neely, Maria Jure-Kunkel, Suba Krishnan, Holbrook E Kohrt, Mario Sznol, Ronald Levy
PURPOSE: Urelumab is an agonist antibody to CD137 with potential application as an immuno-oncology therapeutic. Data were analyzed to assess safety, tolerability, and pharmacodynamic activity of urelumab, including the dose selected for ongoing development in patients with advanced solid tumors and lymphoma. PATIENTS AND METHODS: Three hundred and forty-six patients with advanced cancers who had progressed after standard treatment received at least one dose of urelumab in one of three dose-escalation, monotherapy studies...
October 18, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Perparim Limani, Michael Linecker, Philipp Kron, Panagiotis Samaras, Bernhard Pestalozzi, Roger Stupp, Alexander Jetter, Philipp Dutkowski, Beat Müllhaupt, Andrea Schlegel, Claude Nicolau, Jean-Marie Lehn, Henrik Petrowsky, Bostjan Humar, Rolf Graf, Pierre-Alain Clavien
BACKGROUND: Solid tumors, such as hepato-pancreato-biliary cancer, develop tumor hypoxia with tumor growth. Despite advances in surgery, a majority of these patients are in an unresectable condition. At this stage standard cytotoxic chemotherapy regimens are applied with limited success. Novel biological treatment options based on an antiangiogenic mechanism of action neglect other hypoxia mediated mechanisms (e.g. epithelial-mesenchymal transition, Warburg effect, and immunological response) leading to an increased invasiveness with a poor outcome...
October 19, 2016: BMC Cancer
Gemma Amo, José A Cornejo-García, Jesus M García-Menaya, Concepcion Cordobes, M J Torres, Gara Esguevillas, Cristobalina Mayorga, Carmen Martinez, Natalia Blanca-Lopez, Gabriela Canto, Alfonso Ramos, Miguel Blanca, José A G Agúndez, Elena García-Martín
The high-affinity IgE receptor (Fcε RI) is a heterotetramer of three subunits: Fcε RIα, Fcε RIβ, and Fcε RIγ (αβγ2) encoded by three genes designated as FCER1A, FCER1B (MS4A2), and FCER1G, respectively. Recent evidence points to FCERI gene variability as a relevant factor in the risk of developing allergic diseases. Because Fcε RI plays a key role in the events downstream of the triggering factors in immunological response, we hypothesized that FCERI gene variants might be related with the risk of, or with the clinical response to, selective (IgE mediated) non-steroidal anti-inflammatory (NSAID) hypersensitivity...
2016: Frontiers in Pharmacology
Gregory P Kalemkerian
Small cell lung cancer (SCLC) is a high-grade neuroendocrine tumor characterized by rapid growth, early metastatic spread, and initial responsiveness to therapy. Although the incidence of SCLC is declining, it remains one of the common causes of cancer-related mortality. Initial evaluation of patients with SCLC should focus on determining the extent of disease and the ability of the patient to tolerate specific therapy. Positron emission tomography (PET) can improve the accuracy of staging and treatment planning in many patients...
October 2016: Seminars in Respiratory and Critical Care Medicine
Ana Brotons-Canto, Nekane Martín-Arbella, Carlos Gamazo, Juan M Irache
Allergic diseases constitute one of the most common causes of chronic illness in developed countries. The main mechanism determining allergy is an imbalance between Th1 and Th2 response towards Th2. Areas covered: This review describes the mechanisms underlying the natural tolerance to food components and the development of an allergic response in sensitized individuals. Furthermore, therapeutic approaches proposed to manage these abnormal immunologic responses food are also presented and discussed. Expert opinion: In the past, management of food allergies has consisted of the education of patients to avoid the ingestion of the culprit food and to initiate the therapy (e...
October 12, 2016: Expert Opinion on Drug Delivery
Kaili Zhang, Ying Wang, Weiyuan Ma, Zhigang Hu, Pengxin Zhao
Hashimoto thyroiditis (HT) is a common autoimmune disease. Genistein is an isoflavone with immunomodulatory functions in various diseases. In this double-blind, randomized, placebo-controlled clinical study, we investigated the effects of genistein on patients with HT. A total of 218 patients were recruited. Genistein treated patients had a significant increased T4, fT4 levels, as well as reduction in serum TSH, TPOAb and TgAb levels, compared with those receiving placebo. Furthermore, Th1 related cytokine IFN-γ and IL-2 changes after genistein treatment suggest the immune modulating effect of genistein is mediated through regulating the function of Th1 cells...
October 4, 2016: Immunobiology
Herman Waldmann, Duncan Howie, Stephen Cobbold
A major goal of immunosuppressive therapies is to harness immune tolerance mechanisms so as to minimize unwanted side effects associated with protracted immunosuppressive therapy. Antibody blockade of lymphocyte coreceptor and costimulatory pathways in mice has demonstrated the principle that both naive and primed immune systems can be reprogrammed toward immunological tolerance. Such tolerance can involve the amplification of activity of regulatory T cells, and is maintained through continuous recruitment of such cells through processes of infectious tolerance...
August 2016: Microbiology Spectrum
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
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
Tue Kruse Rasmussen
Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are lifelong diseases with increased mortality and chronic pains. They are both characterized by immunological imbalances causing the immune system attack and destroy the bodies own tissues (called autoimmune disease). The best treatment, we are currently able to offer these patients, cause significant side-effects and can not prevent significant loss of quality of life. At the heart of the disease mechanisms in RA and SLE are subsets of immune cells called T and B cells...
October 2016: Danish Medical Journal
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
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
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
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
Kulkanya Chokephaibulkit, Chukiat Sirivichayakul, Usa Thisyakorn, Chitsanu Pancharoen, Mark Boaz, Alain Bouckenooghe, Emmanuel Feroldi
BACKGROUND: A single dose of live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) was shown to be immunogenic and well tolerated when given either as a booster to formalin-inactivated Japanese encephalitis (JE)-vaccine (mouse brain-derived vaccine [MBDV])-primed 2-5-year-olds, or as a primary vaccination to JE-vaccine-naïve 12-24-month-old toddlers in Thailand. A 5-year follow-up assessment of immune response persistence over time was conducted. METHODS: Four additional visits (at 2, 3, 4, and 5years) for immunologic assessments were added to the original 12-month open-label crossover study, in which 100 healthy children aged 2-5years with a history of two-dose primary vaccination with MBDV (according to the Thai Expanded Program for Immunization schedule), and 200 healthy JE-vaccine-naïve 12-24-month-old toddlers, were randomized 1:1 to receive JE-CV, containing ⩾4 log10 plaque forming units, 1month before or after hepatitis A control vaccine...
September 26, 2016: Vaccine
Periklis Dousdampanis, Kostantina Trigka, Athanasia Mouzaki
Kidney transplantation is recognised as the most effective treatment for patients with end-stage renal disease (ESRD). Kidney transplantation continues to face several challenges including long-term graft and patient survival, and the side effects of immunosuppressive therapy. The tendency in kidney transplantation is to avoid the side effects of immunosuppresants and induce immune tolerance. Regulatory T-cells (Tregs) contribute to self-tolerance, tolerance to alloantigen and transplant tolerance, mainly by suppressing the activation and function of reactive effector T-cells...
September 24, 2016: World Journal of Transplantation
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