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Aida S Hansen, Bettina B Bundgaard, Bjarne K Møller, Per Höllsberg
CD46 is a glycoprotein with important functions in innate and adaptive immune responses. Functionally different isoforms are generated by alternative splicing at exons 7-9 (BC and C isoforms) and exon 13 (CYT-1 and CYT-2 isoforms) giving rise to BC1, BC2, C1 and C2. We developed a novel real-time PCR assay that allows quantitative comparisons between these isoforms. Their relative frequency in CD4(+) T cells from 100 donors revealed a distribution with high interpersonally variability. Importantly, the distribution between the isoforms was not random and although splicing favoured inclusion of exon 8 (BC isoforms), exclusion of exon 8 (C isoforms) was significantly linked to exclusion of exon 13 (CYT-2 isoforms)...
October 14, 2016: Scientific Reports
Dineke Westra, Elena B Volokhina, Renate G van der Molen, Thea J A M van der Velden, Annelies Jeronimus-Klaasen, Joop Goertz, Valentina Gracchi, Eiske M Dorresteijn, Antonia H M Bouts, Mandy G Keijzer-Veen, Joanna A E van Wijk, Jaap A Bakker, Anja Roos, Lambert P van den Heuvel, Nicole C A J van de Kar
BACKGROUND: The role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS. METHODS: Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, αFH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS...
October 7, 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Daniela Viecceli, Mariana Pires Garcia, Laiana Schneider, Ana Paula Alegretti, Cristiano Kohler Silva, André Lucas Ribeiro, Claiton Viegas Brenol, Ricardo Machado Xavier
OBJECTIVES: To correlate the basal expression of complement regulatory proteins (CRPs) CD55, CD59, CD35, and CD46 in B-lymphocytes from the peripheral blood of a cohort of 10 patients with rheumatoid arthritis (RA) initiating treatment with rituximab (RTX) with depletion and time repopulation of such cells. METHODS: Ten patients with RA received two infusions of 1g of RTX with an interval of 14 days. Immunophenotypic analysis for the detection of CD55, CD59, CD35, and CD46 on B-lymphocytes was carried out immediately before the first infusion...
September 17, 2016: Revista Brasileira de Reumatologia
Michaela Frolikova, Natasa Sebkova, Lukas Ded, Katerina Dvorakova-Hortova
The acrosome reaction (AR) is a process of membrane fusion and lytic enzyme release, which enables sperm to penetrate the egg surroundings. It is widely recognized that specific sperm proteins form an active network prior to fertilization, and their dynamic relocation is crucial for the sperm-egg fusion. The unique presence of the membrane cofactor protein CD46 in the sperm acrosomal membrane was shown, however, its behaviour and connection with other sperm proteins has not been explored further. Using super resolution microscopy, we demonstrated a dynamic CD46 reorganisation over the sperm head during the AR, and its interaction with transmembrane protein integrins, which was confirmed by proximity ligation assay...
September 26, 2016: Scientific Reports
Qi Lv, Hui Ding, Zi-Quan Liu, Hong-Wei Gao, Bao-Guo Yu, Zhou-Wei Wu, Hao-Jun Fan, Shi-Ke Hou
OBJECTIVE: Human adenovirus type 55 (HAdV-55) has recently caused multiple outbreaks. This study examined polymorphisms in CD46 to determine their involvement in HAdV-55 infection. METHODS: A total of 214 study subjects infected with HAdV-55 were included in our study. The study subjects were divided into those with silent infections (n=91), minor infections (n=85), and severe infections (n=38). Ten single nucleotide polymorphisms (SNPs) from CD46 were examined...
September 20, 2016: Disaster Medicine and Public Health Preparedness
Sangeet Lal, Kah-Whye Peng, Michael B Steele, Nathan Jenks, Hong Ma, Gary Kohanbash, Joanna J Phillips, Corey Raffel
The modified Edmonston vaccine strain of measles virus (MV) has shown potent oncolytic efficacy against various tumor types and is being investigated in clinical trials. Our laboratory showed that MV effectively kills medulloblastoma tumor cells in both localized disease and when tumor cells are disseminated through cerebrospinal fluid (CSF). Although the safety of repeated intracerebral injection of modified MV in rhesus macaques has been established, the safety of administering MV into CSF has not been adequately investigated...
September 7, 2016: Human Gene Therapy. Clinical Development
Maximilian Richter, Kamola Saydaminova, Roma Yumul, Rohini Krishnan, Jing Liu, Eniko-Eva Nagy, Manvendra Singh, Zsuzsanna Izsvák, Roberto Cattaneo, Wolfgang Uckert, Donna Palmer, Philip Ng, Kevin G Haworth, Hans-Peter Kiem, Anja Ehrhardt, Thalia Papayannopoulou, André Lieber
Current protocols for hematopoietic stem/progenitor cell (HSPC) gene therapy, involving the transplantation of ex vivo genetically modified HSPCs, are complex and not without risk for the patient. We developed a new approach for in vivo HSPC transduction that does not require myeloablation and transplantation. It involves subcutaneous injections of G-CSF/AMD3100 to mobilize HSPCs from the bone marrow into the peripheral blood stream and the intravenous injection of an integrating, helper-dependent adenovirus (HD-Ad5/35++) vector system...
August 23, 2016: Blood
Wayne J Hawthorne, Andrew M Lew, Helen E Thomas
PURPOSE OF REVIEW: Despite the benefits of islet and pancreas allotransplantation, their widespread use in type 1 diabetes is limited because of the paucity of suitable donors. Porcine xenotransplantation offers an alternative, and advances in genetic modification of pigs have opened up new potential for its clinical use. This review outlines the barriers to successful islet xenotransplantation, and genetic modifications that have been tested to overcome these. RECENT FINDINGS: Islets from pigs lacking α1,3-galactosyltransferase, to prevent hyperacute rejection, are now used as a background strain for further genetic modifications...
October 2016: Current Opinion in Organ Transplantation
Ashrafali M Ismail, Ji Sun Lee, David W Dyer, Donald Seto, Jaya Rajaiya, James Chodosh
: Human adenoviruses (HAdVs) contain seven species (HAdV-A to -G), each associated with specific disease conditions. Among these, HAdV-D includes those viruses associated with epidemic keratoconjunctivitis (EKC), a severe ocular surface infection. The reasons for corneal tropism for some but not all HAdV-Ds are not known. The fiber protein is a major capsid protein; its C-terminal "knob" mediates binding with host cell receptors to facilitate subsequent viral entry. In a comprehensive phylogenetic analysis of HAdV-D capsid genes, fiber knob gene sequences of HAdV-D types associated with EKC formed a unique clade...
November 1, 2016: Journal of Virology
Whayoung Lee, Cassandra Long, Jagdeece Ramsoondar, David Ayares, David K C Cooper, Rizwan A Manji, Hidetaka Hara
BACKGROUND: Glutaraldehyde-fixed bioprosthetic heart valves (GBHVs) derived from wild-type (WT, genetically unmodified) pigs are widely used clinically for heart valve replacement. There is evidence that their failure is related to an immune response. The use of valves from genetically engineered pigs that do not express specific pig antigens may prolong GBHV survival. Our aims were to determine (i) expression of Gal and NeuGc on heart (aortic and pulmonary) valves and pericardium of WT, α1,3-galactosyltransferase gene knockout (GTKO) and GTKO/N-glycolylneuraminic acid gene-knockout (GTKO/NeuGcKO) pigs in comparison with three different commercially available GBHVs and (ii) to determine human antibody binding to these tissues...
September 2016: Xenotransplantation
Yujia Li, John B Johnson, Griffith D Parks
Many enveloped RNA viruses recruit host cell proteins during assembly as a mechanism to limit antiviral effects of complement. Using viruses which incorporated CD46 alone, CD55 alone or both CD46 and CD55, we addressed the role of these two host cell regulators in limiting complement-mediated neutralization of Parainfluenza virus 5 (PIV5). PIV5 incorporated functional forms of both CD55 and CD46 into virions. PIV5 containing CD55 was highly resistant to complement-mediated neutralization, whereas CD46-containing PIV5 was as sensitive to neutralization as virus lacking both regulators...
October 2016: Virology
Natalya Belousova, Galina Mikheeva, Chiyi Xiong, Loren J Stagg, Mihai Gagea, Patricia S Fox, Roland L Bassett, John E Ladbury, Michael B Braun, Thilo Stehle, Chun Li, Victor Krasnykh
Unique molecular properties of species D adenoviruses (Ads)-the most diverse yet underexplored group of Ads-have been used to develop improved gene vectors. The low seroprevalence in humans of adenovirus serotype 43 (Ad43), an otherwise unstudied species D Ad, identified this rare serotype as an attractive new human gene therapy vector platform. Thus, in this study we wished to assess biological properties of Ad43 essential to its vectorization. We found that (1) Ad43 virions do not bind blood coagulation factor X and cause low random transduction upon vascular delivery; (2) they clear host tissues more quickly than do traditionally used Ad5 vectors; (3) Ad43 uses CD46 as primary receptor; (4) Ad43 can use integrins as alternative primary receptors...
July 23, 2016: Oncotarget
Konrad Fischer, Simone Kraner-Scheiber, Björn Petersen, Beate Rieblinger, Anna Buermann, Tatiana Flisikowska, Krzysztof Flisikowski, Susanne Christan, Marlene Edlinger, Wiebke Baars, Mayuko Kurome, Valeri Zakhartchenko, Barbara Kessler, Elena Plotzki, Izabela Szczerbal, Marek Switonski, Joachim Denner, Eckhard Wolf, Reinhard Schwinzer, Heiner Niemann, Alexander Kind, Angelika Schnieke
Xenotransplantation from pigs could alleviate the shortage of human tissues and organs for transplantation. Means have been identified to overcome hyperacute rejection and acute vascular rejection mechanisms mounted by the recipient. The challenge is to combine multiple genetic modifications to enable normal animal breeding and meet the demand for transplants. We used two methods to colocate xenoprotective transgenes at one locus, sequential targeted transgene placement - 'gene stacking', and cointegration of multiple engineered large vectors - 'combineering', to generate pigs carrying modifications considered necessary to inhibit short to mid-term xenograft rejection...
2016: Scientific Reports
R Sakai, A Maeda, R Matsuura, H Eguchi, P Lo, H Hasuwa, M Ikawa, K Nakahata, M Zenitani, T Yamamichi, S Umeda, H Okuyama, S Miyagawa
BACKGROUND: The purpose of this study was to produce molecules that can precisely regulate the complement and coagulation system and to assess the expression of such molecules in transgenic animals. METHODS: The CTDM gene, which is composed of the delta-1-99 amino acid (aa) C1-INH, EGF domain 4-6 of thrombomoduline (TM), short consensus repeat (SCR) 2-4 of DAF(CD55), and SCR 2-4 of MCP(CD46) was established. The codon usage for expression in mammals was adopted...
May 2016: Transplantation Proceedings
Inger S Nijhof, Tineke Casneuf, Jeroen van Velzen, Berris van Kessel, Amy E Axel, Khaja Syed, Richard W J Groen, Mark van Duin, Pieter Sonneveld, Monique C Minnema, Sonja Zweegman, Christopher Chiu, Andries C Bloem, Tuna Mutis, Henk M Lokhorst, A Kate Sasser, Niels W C J van de Donk
The anti-CD38 monoclonal antibody daratumumab is well tolerated and has high single agent activity in heavily pretreated relapsed and refractory multiple myeloma (MM). However, not all patients respond, and many patients eventually develop progressive disease to daratumumab monotherapy. We therefore examined whether pretreatment expression levels of CD38 and complement-inhibitory proteins (CIPs) are associated with response and whether changes in expression of these proteins contribute to development of resistance...
August 18, 2016: Blood
Kandis Wright, Rachel Dziuk, Payal Mital, Gurvinder Kaur, Jannette M Dufour
Xenotransplantation has vast clinical potential but is limited by the potent immune responses generated against xenogeneic tissue. Immune-privileged Sertoli cells (SC) survive xenotransplantation long-term (>90 days) without immunosuppression, making SC an ideal model to identify xenograft survival mechanisms. Xenograft rejection includes the binding of natural and induced antibodies, and activation of complement cascade. Using an in vitro cytotoxicity assay, where cells were cultured with human serum and complement, we demonstrated neonatal pig SC (NPSC) are resistant to complement mediated cell lysis and express complement inhibitory factors, membrane cofactor protein (MCP; CD46) and decay accelerating factor (DAF; CD55) at significantly higher levels than neonatal pig islets (NPI), non-immune privileged controls...
June 14, 2016: Cell Transplantation
Valeriy V Lyzogubov, Puran S Bora, Xiaobo Wu, Leah E Horn, Ryan de Roque, Xeniya V Rudolf, John P Atkinson, Nalini S Bora
In the mouse, membrane cofactor protein (CD46), a key regulator of the alternative pathway of the complement system, is only expressed in the eye and on the inner acrosomal membrane of spermatozoa. We noted that although Cd46(-/-) mice have normal systemic alternative pathway activating ability, lack of CD46 leads to dysregulated complement activation in the eye, as evidenced by increased deposition of C5b-9 in the retinal pigment epithelium (RPE) and choroid. A knockout of CD46 induced the following cardinal features of human dry age-related macular degeneration (AMD) in 12-month-old male and female mice: accumulation of autofluorescent material in and hypertrophy of the RPE, dense deposits in and thickening of Bruch's membrane, loss of photoreceptors, cells in subretinal space, and a reduction of choroidal vessels...
August 2016: American Journal of Pathology
M S Park, S K Kim, T W Lee, S H Lee, J Y Moon, C G Ihm, Y H Kim, S W Kang, K H Jeong, J-H Chung
OBJECTIVES: CD46 molecule (complement regulatory protein [CD46]), known as a human cell surface receptor, plays an important role in complement and T-cell regulation for organ transplantation. This study was performed to evaluate the association of promoter polymorphism (rs2796267, -496 A/G) of the CD46 gene with acute renal allograft rejection (AR), late acute rejection (LAR), and graft loss (GL) in Korean patients. METHODS: A total of 334 patients with kidney transplants were recruited...
April 2016: Transplantation Proceedings
S L Hulin-Curtis, H Uusi-Kerttula, R Jones, L Hanna, J D Chester, A L Parker
Ovarian cancer accounts for >140 000 deaths globally each year. Typically, disease is asymptomatic until an advanced, incurable stage. Although response to cytotoxic chemotherapy is frequently observed, resistance to conventional platinum-based therapies develop rapidly. Improved treatments are therefore urgently required. Virotherapy offers great potential for ovarian cancer, where the application of local, intraperitoneal delivery circumvents some of the limitations of intravenous strategies. To develop effective, adenovirus (Ad)-based platforms for ovarian cancer, we profiled the fluid and cellular components of patient ascites for factors known to influence adenoviral transduction...
July 2016: Cancer Gene Therapy
Sze Jing Tang, Shufang Luo, Jia Xin Jessie Ho, Phuong Thao Ly, Eling Goh, Xavier Roca
Here we present a detailed analysis of the alternative splicing regulation of human CD46, which generates different isoforms with distinct functions. CD46 is a ubiquitous membrane protein that protects host cells from complement and plays other roles in immunity, autophagy, and cell adhesion. CD46 deficiency causes an autoimmune disorder, and this protein is also involved in pathogen infection and cancer. Before this study, the mechanisms of CD46 alternative splicing remained unexplored even though dysregulation of this process has been associated with autoimmune diseases...
July 1, 2016: Journal of Biological Chemistry
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