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Horsnell W.G.C.,University of Cape Town | Vira A.,University of Cape Town | Kirstein F.,University of Cape Town | Mearns H.,University of Cape Town | And 14 more authors.
Mucosal Immunology | Year: 2011

Nippostrongylus brasiliensis infections generate pulmonary pathologies that can be associated with strong TH2 polarization of the host's immune response. We present data demonstrating N. brasiliensis-driven airway mucus production to be dependent on smooth muscle cell interleukin 4 receptor-α (IL-4Rα) responsiveness. At days 7 and 10 post infection (PI), significant airway mucus production was found in IL-4Rα /lox control mice, whereas global knockout (IL-4Rα /) and smooth muscle-specific IL-4Rα- deficient mice (SM-MHC Cre IL-4Rα /lox) showed reduced airway mucus responses. Furthermore, interleukin (IL)-13 and IL-5 cytokine production in SM-MHC Cre IL-4Rα /lox mice was impaired along with a transient reduction in T-cell numbers in the lung. In vitro treatment of smooth muscle cells with secreted N. brasiliensis excretory-secretory antigen (NES) induced IL-6 production. Decreased protein kinase C (PKC)-dependent smooth muscle cell proliferation associated with cell cycle arrest was found in cells stimulated with NES. Together, these data demonstrate that both IL-4Rα and NES-driven responses by smooth muscle cells make important contributions in initiating TH2 responses against N. brasiliensis infections. © 2011 Society for Mucosal Immunology.

Powley L.,Histocompatibility and Immunogenetics Research Group | Powley L.,University College London | Brown C.,Colindale Center | Melis A.,Europdonor Foundation | And 4 more authors.
Bone Marrow Transplantation | Year: 2016

In cord blood (CB) transplantation, virtual 6/6 HLA matches, whereby the donor-recipient mismatch is identical to the CB noninherited maternal Ag (NIMA), have similar outcomes to inherited 6/6 matches. In the UK-British Bone Marrow Registry (BBMR), 4707 of the total 21 020 CB donors have the NIMA defined. Retrospective searches of these donors, for 1-3 NIMA matches, identified a virtual 6/6 match for 31.4% of 274 European Caucasoid (EC) and 25.4% of 67 other ethnicity (OE) patients. Patients weighing ≤50 kg were also evaluated for a single graft with adequate cell dose. In 125 EC patients, 6/6 HLA matches were identified for 24.0% and virtual 6/6 matches were identified for a further 21.6%. The remaining EC patients had a 5/6 (30.4%) or a 4/6 (22.4%) match. In OE patients, 6/6 HLA matches were identified for 9.3% and virtual 6/6 matches were identified for a further 18.7%. The remaining OE patients had a 5/6 (30.2%) or a 4/6 (37.2%) match. Searches were also performed using the 26 735 Bone Marrow Donors Worldwide CB with defined NIMA and yielded comparable increases. Considering NIMA as permissible mismatches in donor selection therefore increased the availability of a 6/6 match in this cohort. © 2016 Macmillan Publishers Limited.

Horsnell W.G.C.,University of Cape Town | Darby M.G.,University of Cape Town | Hoving J.C.,University of Cape Town | Nieuwenhuizen N.,University of Cape Town | And 11 more authors.
PLoS Pathogens | Year: 2013

In this study, B cell function in protective TH2 immunity against N. brasiliensis infection was investigated. Protection against secondary infection depended on IL-4Rα and IL-13; but not IL-4. Protection did not associate with parasite specific antibody responses. Re-infection of B cell-specific IL-4Rα-/- mice resulted in increased worm burdens compared to control mice, despite their equivalent capacity to control primary infection. Impaired protection correlated with reduced lymphocyte IL-13 production and B cell MHC class II and CD86 surface expression. Adoptive transfer of in vivo N. brasiliensis primed IL-4Rα expressing B cells into naïve BALB/c mice, but not IL-4Rα or IL-13 deficient B cells, conferred protection against primary N. brasiliensis infection. This protection required MHC class II compatibility on B cells suggesting cognate interactions by B cells with CD4+ T cells were important to co-ordinate immunity. Furthermore, the rapid nature of these protective effects by B cells suggested non-BCR mediated mechanisms, such as via Toll Like Receptors, was involved, and this was supported by transfer experiments using antigen pulsed Myd88-/- B cells. These data suggest TLR dependent antigen processing by IL-4Rα-responsive B cells producing IL-13 contribute significantly to CD4+ T cell-mediated protective immunity against N. brasiliensis infection. © 2013 Horsnell et al.

Hewitt P.E.,Colindale Center | Davison K.,NHSBT HPA Epidemiology Team | Howell D.R.,NHSBT HPA Epidemiology Team | Taylor G.P.,NHSBT HPA Epidemiology Team
Transfusion | Year: 2013

Background Leukoreduction of blood components was introduced in the United Kingdom during 1998. Human T-lymphotropic virus (HTLV) screening of blood donations was introduced in 2002. NHS Blood and Transplant conducted an HTLV lookback on blood components issued before 2002. A proportion of included components were nonleukoreduced, although the majority were subject to white blood cell reduction measures. Study Design and Methods A standard lookback was conducted on untested cellular blood components from donors later confirmed to be HTLV positive, for the 4 to 5 years before 2002, and on the last tested negative donation from donors who had seroconverted. Results A total of 437 red blood cell and platelet components were included and an outcome was reported for 84% of these. Just over half of identified recipients were dead at the time of lookback; blood samples for testing were obtained from 77% of identified living recipients. HTLV infection was confirmed in seven recipients, but one was discounted as not transfusion transmitted. Conclusion Although numbers are small, our results provide evidence of the efficacy of leukoreduction in reducing the likelihood of HTLV transmission through transfusion of cellular blood components. The HTLV-positive rate in recipients of leukoreduced components was 3.7%, a reduction of 93% compared with nonleukoreduced components. Importantly, the one infected recipient of a leukoreduced component had existing risk factors for HTLV infection. HTLV lookback was much less efficient in identifying infected recipients than was hepatitis virus C lookback. © 2013 American Association of Blood Banks.

Win N.,Tooting Center | Lee E.,Colindale Center | Needs M.,Tooting Center | Chia L.-W.,St. Georges Hospital | Stasi R.,St. Georges Hospital
Transfusion Medicine | Year: 2012

Background: Hyperhaemolytic transfusion reaction (HHTR) has been well described in patients with sickle cell disease (SCD). It is characterised by a decrease in haemoglobin concentration to levels below those before transfusion and a fall in the absolute reticulocyte count. As red blood cells (RBC) alloantibodies are typically not detected in post-transfusion samples in acute forms of HHTR, we have previously proposed that both the transfused and autologous RBCs cells (HbSS/reticulocytes) are destroyed by activated macrophages. Case reports: We report a patient with SCD who presented with vaso-occlusive sickle cell crisis and developed a severe HHTR attributable to anti-Fy3. In addition to the usual supportive measures, the patient was treated with intravenous immunoglobulin (IVIG) and steroids. Serum ferritin levels were measured as an aspecific marker of macrophage activation. Results: Steroids and IVIG were effective in managing HHTR. Ferritin levels were high at the time of haemolysis, (>10000 μg L -1) whereas recovery and cessation of haemolysis correlated with a decrease in ferritin levels. Conclusion: Serum ferritin values >10 000 μg L -1 are considered pathognomic for conditions characterised by abnormal macrophage activation. In our case, serum ferritin levels correlate well with the disease activity and clinical response. This further supports our previous proposal that the activated macrophages play an important role in HHTR. Serum ferritin is a nonspecific marker of inflammation. A rapid specific bio-marker to measure the activity of macrophages in SCD in HHTR is desirable, and this area warrants further investigation. © 2012 The Authors. Transfusion Medicine © 2012 British Blood Transfusion Society.

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