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Genetics and immune therapy

Lotte Vosmar Denning
PIDs are heterogeneous disorders caused by hereditary genetic defects of the immune system. The immune system normally helps the body fight off infections by germs/'micro-organisms' such as bacteria, viruses, fungi and protozoa. Because the immune systems do not work properly, people with PIDs are more prone than other people to infections. When PIDs are left undiagnosed or misdiagnosed, the immune system remains defective, often leading to illness, disability, permanent organ damage or even death. Too often infections are treated while missing the underlying cause...
October 2017: Journal of Family Medicine and Primary Care
Vasiliki Triantafillou, Alan D Workman, Michael A Kohanski, Noam A Cohen
Bitter (T2R) and sweet taste (T1R) receptors have emerged as regulators of upper airway immune responses. Genetic variation of these taste receptors additionally confers susceptibility to infection and has been implicated in severity of disease in chronic rhinosinusitis (CRS). Ongoing taste receptor research has identified a variety of biologically active compounds that activate T1R and T2R receptors, increasing our understanding of not only additional receptor isoforms and their function but also how receptor function may contribute to the pathophysiology of CRS...
2018: Frontiers in Cellular and Infection Microbiology
Priyadarsini Kumar, Kewa Gao, Chuwang Wang, Christopher Pivetti, Lee Lankford, Diana Farmer, Aijun Wang
Hemophilia A (HA) is an X-linked recessive disorder caused by mutations in the factor VIII ( FVIII) gene leading to deficient blood coagulation. The current standard of care is frequent infusions of plasma-derived FVIII or recombinant B-domain-deleted FVIII (BDD-FVIII). While this treatment is effective, many patients eventually develop FVIII inhibitors that limit the effectiveness of the infused FVIII. As a monogenic disorder, HA is an ideal target for gene or cell-based therapy. Several studies have investigated allogeneic stem cell therapy targeting in utero or postnatal treatment of HA but have not been successful in completely correcting HA...
January 2018: Cell Transplantation
Max D Wellenstein, Karin E de Visser
Owing to their tremendous diversity and plasticity, immune cells exert multifaceted functions in tumor-bearing hosts, ranging from anti-tumor to pro-tumor activities. Tumor immune landscapes differ greatly between and within cancer types. Emerging evidence suggests that genetic aberrations in cancer cells dictate the immune contexture of tumors. Here, we review the current understanding of the mechanisms whereby common drivers of tumorigenesis modulate the tumor immune milieu. We discuss these findings in the context of clinical observations and examine how cancer-cell-intrinsic properties can be exploited to maximize the benefit of immunomodulatory therapies...
March 20, 2018: Immunity
Jason Chesney, Yoannis Imbert-Fernandez, Sucheta Telang, Mary Baum, Smita Ranjan, Mostafa Fraig, Nicolas Batty
Talimogene laherparepvec is a genetically modified herpes simplex virus type 1-based oncolytic immunotherapy for the local treatment of unresectable subcutaneous and nodal tumors in patients with melanoma recurrent after initial surgery. We report on two patients with melanoma who, after progression on numerous systemic therapies, derived clinical benefit from talimogene laherparepvec in an expanded-access protocol (, NCT02147951). Intralesional talimogene laherparepvec (day 1, ≤4 ml 10 PFU/ml; after 3 weeks, ≤4 ml 10 PFU/ml every 2 weeks) was administered until complete response, no injectable tumors, progressive disease, or intolerance occurred...
March 21, 2018: Melanoma Research
Nicola Silvestris, Oronzo Brunetti, Rosamaria Pinto, Daniela Petriella, Antonella Argentiero, Livia Fucci, Stefania Tommasi, Katia Danza, Simona De Summa
OBJECTIVES: Adenosquamous cancer of pancreas (ASCP) is a rare variant of pancreatic adenocarcinoma (PDAC). It is characterized by poor prognosis and lacks of literature data supporting the choice of systemic therapies. The role of immunotherapy for this malignancy is still unknown. In this study, we evaluated any differences between immune-related genes of PDAC and its adenosquamous variant with the aim to characterize these histothistotypes and eventually identify potential biomarkers useful for an immune-therapy approach in ASCP...
March 21, 2018: Expert Opinion on Therapeutic Targets
Cynthia Louis, Chris Burns, Ian Wicks
The pathogenesis of autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is driven by genetic predisposition and environmental triggers that lead to dysregulated immune responses. These include the generation of pathogenic autoantibodies and aberrant production of inflammatory cytokines. Current therapies for RA and other autoimmune diseases reduce inflammation by targeting inflammatory mediators, most of which are innate response cytokines, resulting in generalized immunosuppression...
2018: Frontiers in Immunology
Theresa L Wampler Muskardin, Timothy B Niewold
The type I interferon pathway has been implicated in the pathogenesis of a number of rheumatic diseases, including systemic lupus erythematosus, Sjögren syndrome, myositis, systemic sclerosis, and rheumatoid arthritis. In normal immune responses, type I interferons have a critical role in the defence against viruses, yet in many rheumatic diseases, large subgroups of patients demonstrate persistent activation of the type I interferon pathway. Genetic variations in type I interferon-related genes are risk factors for some rheumatic diseases, and can explain some of the heterogeneity in type I interferon responses seen between patients within a given disease...
March 21, 2018: Nature Reviews. Rheumatology
Michael Loesche, Kamyar Farahi, Kimberly Capone, Steven Fakharzadeh, Andrew Blauvelt, Kristina Callis Duffin, Samuel E DePrimo, Ernesto J Muñoz-Elías, Carrie Brodmerkel, Bidisha Dasgupta, Marc Chevrier, Kevin Smith, Joseph Horwinski, Amanda Tyldsley, Elizabeth A Grice
BACKGROUND: Plaque psoriasis, a chronic inflammatory disease primarily affecting the skin, is thought to have a multifactorial etiology, including innate immune system dysregulation, environmental triggers, and genetic susceptibility. PURPOSE: We sought to further understand the role of skin microbiota in psoriasis pathogenesis, as well as their response to therapy. We systematically analyzed dynamic microbiota colonizing psoriasis lesions and adjacent nonlesional skin in 114 patients prior to and during ustekinumab treatment in a Phase 3b clinical trial...
March 17, 2018: Journal of Investigative Dermatology
Muhammad Naveed, Lei Han, Ghulam Jilany Khan, Sufia Yasmeen, Reyaj Mikrani, Muhammad Abbas, Li Cunyu, Zhou Xiaohui
Congestive heart failure (CHF) is a complicated pathophysiological syndrome, leading cause of hospitalization as well as mortalities in developed countries wherein an irregular function of the heart leads to the insufficient blood supply to the body organs. It is an accumulative slackening of various complications including myocardial infarction (MI), coronary heart disease (CAD), hypertension, valvular heart disease (VHD) and cardiomyopathy; its hallmarks include hypertrophy, increased interstitial fibrosis and loss of myocytes...
March 14, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Anna S Berghoff, Priscilla K Brastianos
Brain metastases (BMs) reflect an area of high clinical need, as up to 40% of patients with metastatic cancer will develop this morbid and highly fatal complication. Historically, treatment strategies have relied on local approaches including radiosurgery, whole-brain radiotherapy, and neurosurgical resection. Recently, targeted and immune-modulating therapies have shown promising responses and have been introduced in the clinical management of patients with BMs. Recent improvements in genomic technologies have enriched our understanding of BMs and have demonstrated that BMs present with significant genetic divergence from the originating primary tumor, such that potentially targetable genetic alterations are detected only in the BMs...
February 2018: Seminars in Neurology
Tory P Johnson, Avindra Nath
PURPOSE OF REVIEW: The immune system serves a critical role in protecting the host against various pathogens. However, under circumstances, once triggered by the infectious process, it may be detrimental to the host. This may be as a result of nonspecific immune activation or due to a targeted immune response to a specific host antigen. In this opinion piece, we discuss the underlying mechanisms that lead to such an inflammatory or autoimmune syndrome affecting the nervous system. We examine these hypotheses in the context of recent emerging infections to provide mechanistic insight into the clinical manifestations and rationale for immunomodulatory therapy...
March 14, 2018: Current Opinion in Neurology
Junya Kitadani, Toshiyasu Ojima, Hiromitsu Iwamoto, Hirotaka Tabata, Mikihito Nakamori, Masaki Nakamura, Keiji Hayata, Masahiro Katsuda, Masayasu Miyajima, Hiroki Yamaue
Clinical application of dendritic cell (DC) vaccine therapy is hindered by the need for a large quantity of DCs generated from peripheral blood monocytes of the patient. We investigated whether genetically modified human induced pluripotent stem cell (iPSC)-derived dendritic cells (hiPSDCs) expressing carcinoembryonic antigen (CEA) could induce CEA-specific cytotoxic T cells in a human model and whether genetically modified mouse iPSDCs (miPSDCs) expressing CEA showed an actual antitumor effect using a CEA transgenic mouse model...
March 15, 2018: Scientific Reports
Marina Chiara Garassino, Byoung-Chul Cho, Joo-Hang Kim, Julien Mazières, Johan Vansteenkiste, Hervé Lena, Jesus Corral Jaime, Jhanelle E Gray, John Powderly, Christos Chouaid, Paolo Bidoli, Paul Wheatley-Price, Keunchil Park, Ross A Soo, Yifan Huang, Catherine Wadsworth, Phillip A Dennis, Naiyer A Rizvi
BACKGROUND: Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR-/ALK-), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1...
March 12, 2018: Lancet Oncology
David Michalovich, Sergey Nejentsev
Activated PI3 kinase delta syndrome (APDS) is a primary immunodeficiency caused by dominant mutations that increase activity of phosphoinositide-3-kinase δ (PI3Kδ). APDS can be caused by mutations in the PIK3CD gene that encodes PI3Kδ catalytic subunit p110δ (APDS1) or mutations in the PIK3R1 gene that encodes regulatory subunit p85α (APDS2). APDS research advanced rapidly after the initial discovery in 2013. More than 200 APDS patients have been identified around the world. Multiple novel APDS mutations were reported and molecular mechanisms leading to PI3Kδ activation have been elucidated...
2018: Frontiers in Immunology
Jahnavi Aluri, Maya Gupta, Aparna Dalvi, Snehal Mhatre, Manasi Kulkarni, Gouri Hule, Mukesh Desai, Nitin Shah, Prasad Taur, Ramprasad Vedam, Manisha Madkaikar
Major histocompatibility complex (MHC) class II deficiency is a rare autosomal recessive form of primary immunodeficiency disorder (PID) characterized by the deficiency of MHC class II molecules. This deficiency affects the cellular and humoral immune response by impairing the development of CD4+ T helper (Th) cells and Th cell-dependent antibody production by B cells. Affected children typically present with severe respiratory and gastrointestinal tract infections. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy available for treating these patients...
2018: Frontiers in Immunology
Yongchang Lai, Zhijian Zhao, Tao Zeng, Xiongfa Liang, Dong Chen, Xiaolu Duan, Guohua Zeng, Wenqi Wu
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC), and is frequently accompanied by the genetic features of von Hippel-Lindau (VHL) loss. VHL loss increases the expression of hypoxia-inducible factors (HIFs) and their targets, including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF). The primary treatment for metastatic RCC (mRCC) is molecular-targeted therapy, especially anti-angiogenic therapy...
2018: Cancer Cell International
Zahra Akbari, Mohammad Taheri, Abdorreza Jafari, Arezou Sayad
INTRODUCTION: Multiple sclerosis (MS) is a heterogeneous disease with an unknown etiology. Both genetic and environmental factors lead to MS disease. Recent studies have revealed the inhibitory role of T regulatory cells in the MS disease. Forkhead box P3 (FOXP3) gene is a transcript of the CD4+CD25+FOXP3 and T regulatory cells that is recently introduced as a factor in determining the lineage of immune cells. Based on these assumptions we investigate the expression of this gene in the peripheral blood of fifty MS patients in comparison to fifty controls...
February 27, 2018: Human Antibodies
Bani Ahluwalia, Luiza Moraes, Maria K Magnusson, Lena Öhman
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract with a multifactorial pathophysiology. Full comprehension of IBD pathology is still out of reach and, therefore, treatment is far from ideal. Nevertheless, components involved in IBD pathogenesis including environmental, genetic, microbial, and immunological factors are continuously being investigated and the improved knowledge contributes to the development of new therapies. In this article we review the aspects of the immunopathogenesis of IBD, with focus on mucosal immunity, and discuss mechanisms of action for current and emerging biological therapies...
March 9, 2018: Scandinavian Journal of Gastroenterology
Marissa Penna-Martinez, Natalie Filmann, Dimitra Bogdanou, Firouzeh Shoghi, Sabine Huenecke, Ralf Schubert, Eva Herrmann, Ulrike Koehl, Eystein S Husebye, Klaus Badenhoop
OBJECTIVES: On the basis of the immunomodulatory actions of vitamin D (VD), we investigated the effects of high-dose VD therapy over a 3 mo period on the immune response in patients with Addison's disease (AD). METHODS: This randomized, controlled, crossover trial included 13 patients with AD who received either cholecalciferol (4000 IU/d) for 3 mo followed by 3 mo placebo oil or the sequential alternative placebo followed by verum. Glucocorticoid replacement doses remained stable...
December 2, 2017: Nutrition
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