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Check point autoimmunity

Grażyna Korczak-Kowalska, Anna Stelmaszczyk-Emmel, Katarzyna Bocian, Ewelina Kiernozek, Nadzieja Drela, Joanna Domagała-Kulawik
Regulation of immune response was found to play an important role in the course of many diseases such as autoimmune diseases, allergy, malignancy, organ transplantation. The studies on immune regulation focus on the role of regulatory cells (Tregs, Bregs, regulatory myeloid cells) in these disorders. The number and function of Tregs may serve as a marker of disease activity. As in allergy, the depletion of Tregs is observed and the results of allergen-specific immunotherapy could be measured by an increase in the population of IL-10(+) regulatory cells...
May 3, 2017: Archivum Immunologiae et Therapiae Experimentalis
Yael Diesendruck, Itai Benhar
Drug resistance of tumor cells to chemotherapy is limiting the therapeutic efficacy of most anticancer drugs and represents a major obstacle in medical oncology. However, treatment of various human malignancies with biologics, mostly monoclonal antibodies (mAbs), is not limited by such chemoresistance mechanisms. However, other resistance or evasion mechanisms limit the efficacy to anticancer therapeutic mAbs that engage tumor-associated antigens on the surface of the malignant cells. Immune checkpoint blocking monoclonal antibodies are heralded as a promising therapeutic approach in clinical oncology...
January 2017: Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
Naohiro Ichino, Keisuke Osakabe, Keiko Sugimoto, Koji Suzuki, Hiroya Yamada, Hiroji Takai, Hiroko Sugiyama, Jun Yukitake, Takashi Inoue, Koji Ohashi, Tadayoshi Hata, Nobuyuki Hamajima, Toru Nishikawa, Senju Hashimoto, Naoto Kawabe, Kentaro Yoshioka
OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is a common debilitating condition in many industrialized countries that increases the risk of cardiovascular disease. The aim of this study was to derive a simple and accurate screening tool for the prediction of NAFLD in the Japanese population. METHODS: A total of 945 participants, 279 men and 666 women living in Hokkaido, Japan, were enrolled among residents who attended a health check-up program from 2010 to 2014...
January 2015: Rinsho Byori. the Japanese Journal of Clinical Pathology
Keiichi Fujiwara, Katsushi Seza, Yoshihiro Fukuda, Masayuki Nakano, Osamu Yokosuka
Autoimmune hepatitis (AIH) is generally regarded as a clinically and histologically "chronic" hepatitis. It often shows acute presentation like acute hepatitis without typical clinicopathological features of AIH, especially in a case of overlap with primary biliary cirrhosis (PBC). A 52-year-old man showed mild liver dysfunction for the first time at an annual medical check. Two months later, he showed jaundice, and laboratory tests revealed elevation of liver enzymes, hyperbilirubinemia and prolonged prothrombin time activity like acute liver failure...
December 2013: Clinical Journal of Gastroenterology
Matthew M K Chan, Richard F Kefford, Matteo Carlino, Arthur Clements, Nicholas Manolios
We report the acute onset of polyarticular inflammatory arthritis in 2 patients receiving the immune check-point inhibitor, pembrolizumab (MK-3475), anti-PD1 drug for metastatic melanoma after 14 and 11 months therapy, respectively. The first patient had severe tenosynovitis, synovitis, bone marrow edema, and myositis, whereas the second patient had predominantly synovitis and tenosynovitis. Good symptomatic control was obtained with bisphosphonates and salazopyrin, avoiding the use of T-cell immunosuppressants...
January 2015: Journal of Immunotherapy
S Franz, L E Muñoz, P Heyder, M Herrmann, M Schiller
Apoptosis of polymorphonuclear neutrophils (PMN) and subsequent 'silent' removal represents an important check-point for the resolution of inflammation. Failure in PMN clearance resulting in secondary necrosis-driven tissue damage has been implicated in conditions of chronic inflammation and autoimmunity. Apoptotic PMN undergo profound biophysical changes that warrant their efficient recognition and uptake by phagocytes before fading to secondary necrosis. In this study, we demonstrate that staurosporine (STS), a non-selective but potent inhibitor of cyclin-dependent kinase and protein kinase C, exerts a drastic impact on PMN apoptosis...
January 2015: Clinical and Experimental Immunology
Isabella Sanseverino, Cristina Purificato, Barbara Varano, Lucia Conti, Sandra Gessani, M Cristina Gauzzi
Dendritic cells (DC) are an attractive target for therapeutic manipulation of the immune system to enhance insufficient immune responses, such those occurring in cancer, or to dampen dangerous responses in allergic and autoimmune diseases. Main goal of this study was to manipulate human monocyte-derived DC (MDDC) function by silencing STAT3, since this transcription factor plays a key role as a negative regulator of immune surveillance, and is strongly involved in inflammation. STAT3 silencing did not affect the immunophenotype of both immature and toll-like receptor (TLR) ligand-matured DC...
July 2014: Immunobiology
Eun-Ji Yang, Jennifer Lee, Seon-Young Lee, Eun-Kyung Kim, Young-Mee Moon, Young Ok Jung, Sung-Hwan Park, Mi-La Cho
Epigallocatechin-3-gallate (EGCG) is a green tea polyphenol exerting potent anti-oxidant and anti-inflammatory effects by inhibiting signaling and gene expression. The objective of the study was to evaluate the effect of EGCG on interleukin (IL)-1 receptor antagonist knockout (IL-1RaKO) autoimmune arthritis models. IL-1RaKO arthritis models were injected intraperitoneally with EGCG three times per week after the first immunization. EGCG decreased the arthritis index and showed protective effects against joint destruction in the IL-1RaKO arthritis models...
2014: PloS One
Kerstin Berer, Marina Boziki, Gurumoorthy Krishnamoorthy
Myelin-specific, pro-inflammatory TH17 cells are widely regarded as the drivers of experimental autoimmune encephalomyelitis (EAE), an animal model for Multiple sclerosis (MS). The factors, responsible for the generation and maintenance of TH17 cells as well as their participation in the pathogenic cascade leading to the demyelinating disease, have been studied extensively. However, how these harmful autoreactive cells are controlled in vivo remains unclear. By comparing TCR transgenic mice on a disease susceptible and a disease resistant genetic background, we show here that pathogenic TH17 cells are sequestered within the intestine of spontaneous EAE resistant B10...
2014: PloS One
Dorottya Kövesdi, Adrienn Angyal, Krisztina Huber, Dániel Szili, Gabriella Sármay
The importance of the BCR and TLR9 in autoimmunity and in the production of auto-antibodies is well established but the underlying molecular mechanism still needs to be determined. Here, we aim to characterize the BCR-TLR9 cross-talk by its effect on T-bet, as T-bet is activated and regulated by both receptors and has an important role in class-switching to pathological IgG2a in mice. Using primary mouse B cells, we demonstrate that T-bet expression is synergistically elevated by the cross-talk between the BCR and TLR9...
March 2014: European Journal of Immunology
Hodaya Prinz-Hadad, Tehila Mizrachi, Michal Irony-Tur-Sinai, Tatyana B Prigozhina, Alexandra Aronin, Talma Brenner, Michal Dranitzki-Elhalel
BACKGROUND: Multiple sclerosis (MS) is a, T cell-mediated autoimmune disease, the management of which remains challenging. The recently described fusion protein, Fn14·TRAIL, combining the extracellular domain of Fn14 (capable of blocking the pro-inflammatory TWEAK ligand) fused to the extracellular domain of the TRAIL ligand (capable of sending apoptotic signals through its receptors on activated inflammatory cells) was designed to modulate the immune system as an anti-inflammatory agent...
2013: Journal of Neuroinflammation
Michal Lotem, Sharon Merims, Steven Frank, Inna Ospovat, Tamar Peretz
Ipilimumab (Yervoy) is a monocLonal antibody designed to block cytotoxic T cell antigen 4 (CTLA-4), an inhibitory receptor of T lymphocytes. This drug is the first to receive US FDAs approval for advanced stage malignant melanoma in the last 13 years. So far, no survival benefit was achieved for this patient group with single drug or combination chemo- and chemo-immunotherapy. In phase II and III trials, up to 15% of patients had melanoma regressions, with a decreased hazard ratio of death of 0.72 compared to the standard chemotherapy with Dacarbazine...
October 2012: Harefuah
David W Scott, Ai-Hong Zhang, Yan Su
The essence of the adaptive immune system is self tolerance, which is maintained by various central and peripheral check points. However, the tolerance mechanisms can be broken in autoimmune disease conditions due to genetic predisposition and environmental triggers. As a consequence, a patient's tissue is attacked by his/her own adaptive immune system. An ideal therapy for autoimmune diseases should include methods to re-establish tolerance to the underpinning autoantigen(s). During the last 15 years our lab has been dedicated to developing a novel B-cell gene therapy approach for antigen-specific tolerance induction...
June 2012: Infectious Disorders Drug Targets
A Vossenkämper, P M K Lutalo, J Spencer
Systemic lupus erythematosus (SLE) and Sjögren's syndrome are autoimmune disorders which are characterized by a disturbed B cell homeostasis which leads ultimately to dysfunction of various organs. One of the B cell subsets that appear in abnormal numbers is the population of transitional B cells, which is increased in the blood of patients with SLE and Sjögren's syndrome. Transitional B cells are newly formed B cells. In mice, transitional B cells undergo selection checks for unwanted specificity in the bone marrow and the spleen in order to eliminate autoreactive B cells from the circulating naive B cell population...
January 2012: Clinical and Experimental Immunology
Xiang-Yang Wang, Daming Zuo, Devanand Sarkar, Paul B Fisher
INTRODUCTION: The incidence of melanoma continues to rise, and prognosis in patients with metastatic melanoma remains poor. The cytotoxic T-lymphocyte antigen-4 (CTLA-4) serves as one of the primary immune check points and downregulates T-cell activation pathways. Enhancing T-cell activation by antibody blockade of CTLA-4 provides a new approach to overcome tumor-induced immune tolerance. Recently, anti-CTLA-4 therapy demonstrated significant clinical benefits in patients with metastatic melanoma, which led to the approval of ipilimumab by the FDA in early 2011...
December 2011: Expert Opinion on Pharmacotherapy
A Bizzocchi, G Genoni, A Petri, F Prodam, M Negro, S Bellone, G Bona
The 22q11.2 microdeletion produces many syndromes, characterized by similar phenotypical features. The most known syndromes are: the DiGeorge syndrome, the velocardiofacial syndrome, the conotruncal anomaly face syndrome. The hallmark features are represented by cardiac anomalies, palate defects, immune and cognitive deficiencies, facial dysmorphisms. Less common disorders include: genito-urinary abnormalities, visual defects, autoimmune disorders and pituitary anomalies, being the last represented by growth hormone and/or insulin growth factor-I deficiency...
December 2011: Minerva Pediatrica
Maki Nakayama
Type 1 diabetes is a T-cell-mediated autoimmune disease against pancreatic beta cells. T cells target various antigens such as insulin, chromogranin A, glutamic acid decarboxylase and islet-specific glucose-6-phosphatase catalytic subunit-related protein. Elimination of insulin dramatically prevents diabetes in the non-obese diabetic (NOD) mouse model and response to insulin occurs prior to that to other antigens. These findings suggest that insulin is a target antigen at the early stage of the disease and is likely to be essential to cause anti-islet autoimmunity in NOD mice...
November 2011: Diabetes/metabolism Research and Reviews
Mi-Oh Roh, Chan-Hee Jung, Bo-Yeon Kim, Ji-Oh Mok, Chul-Hee Kim
Few studies were performed to evaluate the prevalence of latent autoimmune diabetes in adults (LADA) and the difference of chronic complications between LADA, T1DM, and T2DM in Korean. The aim of this study is to establish the prevalence of LADA in a diabetic clinic of Soonchunhyang University hospital and to compare the phenotypic characteristics according to DM classification based on positivity of glutamic acid decarboxylase antibodies (GADA). Also, another important point concerns the occurrence of diabetes chronic microvascular complications in LADA...
April 2013: Acta Diabetologica
Haiying Liu, Yunfeng Liu, Luxia Wang, Dexing Xu, Bingliang Lin, Renqian Zhong, Sitang Gong, Mauro Podda, Pietro Invernizzi
BACKGROUND: Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by the presence of anti-mitocondrial autoantibodies (AMA) which has an essential role also for diagnosis. In addition, also some anti-nuclear antibodies (ANA) have been shown to be highly specific PBC. The purpose of this study was to assess the prevalence of PBC among the adults referring hospital for annual health check-up in Southern China by screening sera for PBC-specific autoantibodies. METHODS: AMA and ANA were screened in 8,126 adults (mean age 44 ± 15 years, 48% females) by indirect immunofluorenscence (IIF)...
2010: BMC Gastroenterology
Natalia V Giltiay, Yi Lu, David Allman, Trine N Jørgensen, Xiaoxia Li
The transitional stage is a key check-point for elimination of autoreactive B cells in the periphery. This selection process requires fine regulation of signals received through BCR and B cell activating factor (BAFF) receptor. We previously identified the adaptor molecule Act1 as a negative regulator of BAFF-mediated signaling. Deficiency of Act1 in mice results in peripheral B cell hyperplasia and development of autoimmunity. In this study, we demonstrate that Act1 plays a critical role in the regulation of transitional B cell survival and maturation...
July 1, 2010: Journal of Immunology: Official Journal of the American Association of Immunologists
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