Bristol Institute for Transfusion science

Bristol, United Kingdom

Bristol Institute for Transfusion science

Bristol, United Kingdom
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Kumpel B.M.,Bristol Institute for Transfusion science | Manoussaka M.S.,St George's, University of London
Vox Sanguinis | Year: 2012

During pregnancy, women are tolerant of their semi-allogeneic fetus whilst not being immunosuppressed and indeed readily form alloantibodies. This 'Immunological Paradox of Pregnancy' may be explained by an understanding of placental anatomy and immunology. Trophoblast cells form the interface between the fetus and maternal tissues and blood and escape allorecognition because they lack classical human leucocyte antigen (HLA) class I and II molecules. Local immunoregulation, or tolerance, in the decidua is mediated partly by HLA-G+ extravillous trophoblasts (EVT) that invade the tissue and prevent killing by maternal natural killer cells, cytotoxic T cells and macrophages. Placental hormones orchestrate the composition and regulatory function of maternal immune cells. In contrast, syncytiotrophoblast cells at the surface of chorionic villi, in contact with maternal blood, maintain a state of mild maternal systemic immunity via activation of innate immunity and skewing towards humoral immunity. This enables maintenance of a healthy immune system in pregnant women and robust protective antibody responses to pathogens whilst enabling survival of the fetus. However, this has the unfortunate consequence that pregnant women readily form alloantibodies to incompatible alloantigens on fetal red cells, platelets and leucocytes if fetomaternal haemorrhage (FMH) occurs. The antibodies are initially low affinity but after re-immunization with further FMH become functionally effective, high-titre IgG. © 2011 The Author(s). Vox Sanguinis © 2011 International Society of Blood Transfusion.

Diamanti P.,Bristol Institute for Transfusion science | Diamanti P.,University of Bristol | Cox C.V.,Bristol Institute for Transfusion science | Cox C.V.,University of Bristol | And 3 more authors.
Blood | Year: 2013

Approximately 20% of children with acute lymphoblastic leukemia (ALL) relapse because of failure to eradicate the disease. Current drug efficacy studies focus on reducing leukemia cell burden. However, if drugs have limited effects on leukemia-initiating cells (LICs), then these cells may expand and eventually cause relapse. Parthenolide (PTL) has been shown to cause apoptosis of LIC in acute myeloid leukemia. In the present study, we assessed the effects of PTL on LIC populations in childhood ALL. Apoptosis assays demonstrated that PTL was effective against bulk B- and T-ALL cells, whereas the CD34 +/CD19-, CD34+/CD7-, and CD34 - subpopulations were more resistant. However, functional analyses revealed that PTL treatment prevented engraftment of multiple LIC populations in NOD/LtSz-scid IL-2Rγc-null mice. PTL treatment of mice with established leukemias from low- and high-risk patients resulted in survival and restoration of normal murine hemopoiesis. In only 3 cases, disease progression was significantly slowed in mice engrafted with CD34+/CD19 - or CD34+/CD7- and CD34- cells, but was not prevented, demonstrating that individual LIC populations within patients have different responses to therapy. These observations indicate that PTL may have therapeutic potential in childhood ALL and provide a basis for developing effective therapies that eradicate all LIC populations to prevent disease progression and reduce relapse. © 2013 by The American Society of Hematology.

Daniels G.,International Blood Group Reference Laboratory | Daniels G.,Bristol Institute for Transfusion science
Human Blood Groups: 3rd edition | Year: 2013

Human Blood Groups is a comprehensive and fully referenced text covering both the scientific and clinical aspects of red cell surface antigens, including: serology, inheritance, biochemistry, molecular genetics, biological functions and clinical significance in transfusion medicine. Since the last edition, seven new blood group systems and over 60 new blood group antigens have been identified. All of the genes representing those systems have now been cloned and sequenced. This essential new information has made the launch of a third edition of Human Blood Groups, now in four colour, particularly timely. This book continues to be an essential reference source for all those who require clinical information on blood groups and antibodies in transfusion medicine and blood banking. © 2013 Geoff Daniels.

Anstee D.J.,Bristol Institute for Transfusion science
Vox Sanguinis | Year: 2011

Antigens of 23 of the 30 human blood group systems are defined by the amino acid sequence of red cell membrane proteins. The antigens of DI, RH, RHAG, MNS, GE and CO systems are carried on blood group-active proteins (Band 3, D and CE polypeptides, RhAG, Glycophorins A and B, Glycophorins C and D and Aquaporin 1, respectively) which are expressed at high levels (>-200-000 copies/red cell). These major proteins contribute to essential red cell functions either directly as membrane transporters and by providing linkage to the underlying red cell skeleton or by facilitating the membrane assembly of the protein complexes involved in these processes. The proteins expressing antigens of the remaining 17 blood group systems are much less abundant (<-20-000 copies/red cell) and their functional importance for the circulating red cell is largely unknown. Human gene knock-outs (null phenotypes) have been described for many of these minor blood group-active proteins, but only absence of Kx glycoprotein has been clearly linked with pathology directly related to the function of circulating red cells. Recent evidence suggesting the normal quality control system for glycoprotein synthesis is altered during the latter stages of red cell production raises the possibility that many of these low abundance blood group-active proteins are vestigial. In sickle cell disease and polycythaemia vera, elevated Lutheran glycoprotein expression may contribute to pathology. Dyserythropoiesis with reduced antigen expression can result from mutations in the erythroid transcription factors GATA-1 and EKLF. © 2010 The Author(s). Vox Sanguinis © 2010 International Society of Blood Transfusion.

Flatt F. J.F.,Bristol Institute for Transfusion science | Bawazir M. W.M.,Bristol Institute for Transfusion science | Bawazir M. W.M.,University of Bristol | Bruce L.J.,Bristol Institute for Transfusion science
Frontiers in Physiology | Year: 2014

Stored blood components are a critical life-saving tool provided to patients by health services worldwide. Red cells may be stored for up to 42 days, allowing for efficient blood bank inventory management, but with prolonged storage comes an unwanted side-effect known as the "storage lesion", which has been implicated in poorer patient outcomes. This lesion is comprised of a number of processes that are inter-dependent. Metabolic changes include a reduction in glycolysis and ATP production after the first week of storage. This leads to an accumulation of lactate and drop in pH. Longer term damage may be done by the consequent reduction in anti-oxidant enzymes, which contributes to protein and lipid oxidation via reactive oxygen species. The oxidative damage to the cytoskeleton and membrane is involved in increased vesiculation and loss of cation gradients across the membrane. The irreversible damage caused by extensive membrane loss via vesiculation alongside dehydration is likely to result in immediate splenic sequestration of these dense, spherocytic cells. Although often overlooked in the literature, the loss of the cation gradient in stored cells will be considered in more depth in this review as well as the possible effects it may have on other elements of the storage lesion. It has now become clear that blood donors can exhibit quite large variations in the properties of their red cells, including microvesicle production and the rate of cation leak. The implications for the quality of stored red cells from such donors is discussed. © 2014 Flatt, Bawazir and Bruce.

Betin V.M.S.,University of Bristol | Singleton B.K.,Bristol Institute for Transfusion science | Parsons S.F.,Bristol Institute for Transfusion science | Anstee D.J.,Bristol Institute for Transfusion science | Lane J.D.,University of Bristol
Autophagy | Year: 2013

Wholesale depletion of membrane organelles and extrusion of the nucleus are hallmarks of mammalian erythropoiesis. Using quantitative EM and fluorescence imaging we have investigated how autophagy contributes to organelle removal in an ex vivo model of human erythroid differentiation. We found that autophagy is induced at the polychromatic erythroid stage, and that autophagosomes remain abundant until enucleation. This stimulation of autophagy was concomitant with the transcriptional upregulation of many autophagy genes: of note, expression of all ATG8 mammalian paralog family members was stimulated, and increased expression of a subset of ATG4 family members (ATG4A and ATG4D) was also observed. Stable expression of dominant-negative ATG4 cysteine mutants (ATG4BC74A; ATG4DC144A) did not markedly delay or accelerate differentiation of human erythroid cells; however, quantitative EM demonstrated that autophagosomes are assembled less efficiently in ATG4B C74A-expressing progenitor cells, and that cells expressing either mutant accumulate enlarged amphisomes that cannot be degraded. The appearance of these hybrid autophagosome/endosome structures correlated with the contraction of the lysosomal compartment, suggesting that the actions of ATG4 family members (particularly ATG4B) are required for the control of autophagosome fusion with late, degradative compartments in differentiating human erythroblasts. © 2013 Landes Bioscience.

Daniels G.,Bristol Institute for Transfusion science | van der Schoot C.E.,Sanquin Research at CLB | Olsson M.L.,Lund University
Vox Sanguinis | Year: 2011

The fourth International Society of Blood Transfusion (ISBT) workshop on molecular blood group genotyping was held in 2010, with a feedback meeting at the ISBT Congress in Berlin, Germany. Fifty laboratories participated, 17 more than in 2008. Six samples were distributed. Samples 1-3 were DNA samples for all red cell blood group tests available to the participants. Of the 46 laboratories that tested these samples, 37 obtained completely correct results, although the extent of testing varied considerably. Sample 4, also a DNA sample, was an Rh problem in which RHDΨ and RHCE*ceCF were present, but the participants were only informed that the donor's red cells typed as positive with some monoclonal anti-D. Of the 42 laboratories that participated in this exercise, seven performed the sequencing necessary to obtain the correct result. Samples 5 and 6 were plasma samples from RhD-negative pregnant women, for foetal RhD testing. These were sent to 25 laboratories, and two incorrect results were reported. Overall, the level of accuracy was about equal to that of the previous workshop. The main conclusion for the last two workshops can be reiterated: with greater care and attention to detail, very high standards could be set for molecular blood group genotyping. © 2011 The Author(s). Vox Sanguinis © 2011 International Society of Blood Transfusion.

Mankelow T.J.,Bristol Institute for Transfusion science | Griffiths R.E.,Bristol Institute for Transfusion science | Trompeter S.,University College London | Flatt J.F.,Bristol Institute for Transfusion science | And 3 more authors.
Blood | Year: 2015

During maturation to an erythrocyte, a reticulocyte must eliminate any residual organelles andreduce itssurface area andvolume. Hereweshowthis involves anovel processwhereby large, intact, inside-out phosphatidylserine (PS)-exposed autophagic vesicles are extruded. Cell surface PS is awell-characterized apoptotic signal initiating phagocytosis. In peripheral blood from patients after splenectomy or in patients with sickle cell disease (SCD), the number of circulating red cells exposing PS on their surface is elevated. We show that in these patientsPS is presentonthe cell surfaceof red cells inlarge (∼1.4 mm) discrete areas corresponding to autophagic vesicles. The autophagic vesicles found on reticulocytes are identical to those observed on red cells from splenectomized individuals and patients with SCD. Our data suggest the increased thrombotic risk associated with splenectomy, and patients with hemoglobinopathies is a possible consequence of increased levels of circulating mature reticulocytes expressing inside-out PS-exposed autophagic vesicles because of asplenia. © 2015 by The American Society of Hematology.

Daniels G.,Bristol Institute for Transfusion science | Daniels G.,New York Blood Center | Reid M.E.,Bristol Institute for Transfusion science | Reid M.E.,New York Blood Center
Transfusion | Year: 2010

Since the first issue of TRANSFUSION in 1961, there has been a tremendous expansion in not only the number of blood group antigens identified but also in our knowledge of their biochemical basis, function, and more recently, associated DNA changes. As certain techniques became available, our ability to discover and elucidate blood group antigens and appreciate their contribution to biology became possible. In particular, Western blotting, monoclonal antibodies, cloning, and polymerase chain reaction-based assays have led to an explosion of our knowledge base. The study of blood groups has had a significant effect on human genetics where they serve as useful markers in genetic linkage analyses. Indeed blood groups have provided several "firsts" in certain aspects of genetics. Blood group-null phenotypes, as natural human knockouts, have provided valuable insights into the importance of red blood cell membrane components. This review summarizes key aspects of the discovery of blood groups; the inconsistent terminology that has arisen; and the contribution of blood groups to genetics, safe transfusion, transplantation, evolution, and biology. © 2009 American Association of Blood Banks.

Anstee D.J.,Bristol Institute for Transfusion science
Blood | Year: 2010

The relative contribution of founder effects and natural selection to the observed distribution of human blood groups has been debated since blood group frequencies were shown to differ between populations almost a century ago. Advances in our understanding of the migration patterns of early humans from Africa to populate the rest of the world obtained through the use of Y chromosome and mtDNA markers do much to inform this debate. There are clear examples of protection against infectious diseases from inheritance of polymorphisms in genes encoding and regulating the expression of ABH and Lewis antigens in bodily secretions particularly in respect of Helicobacter pylori, norovirus, and cholera infections. However, available evidence suggests surviving malaria is the most significant selective force affecting the expression of blood groups. Red cells lacking or having altered forms of blood group-active molecules are commonly found in regions of the world in which malaria is endemic, notably the Fy(a-b-) phenotype and the S-s- phenotype in Africa and the Ge- and SAO phenotypes in South East Asia. Founder effects provide a more convincing explanation for the distribution of the D- phenotype and the occurrence of hemolytic disease of the fetus and newborn in Europe and Central Asia.© 2010 by The American Society of Hematology.

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