Publications
76 results found
Wilcox CR, Holder E, Jones CE, 2017, Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
At birth, neonates are particularly vulnerable to infection and transplacental transfer of immunoglobulin G (IgG) from mother to fetus provides crucial protection in the first weeks of life. Transcytosis of IgG occurs via binding with the neonatal Fc receptor (FcRn) in the placental synctiotrophoblast. As maternal vaccination becomes an increasingly important strategy for the protection of young infants, improving our understanding of transplacental transfer and the factors that may affect this will become increasingly important, especially in low-income countries where the burden of morbidity and mortality is highest. This review highlights factors of relevance to maternal vaccination that may modulate placental transfer—IgG subclass, glycosylation of antibody, total maternal IgG concentration, maternal disease, infant gestational age, and birthweight—and outlines the conflicting evidence and questions that remain regarding the complexities of these relationships. Furthermore, the intricacies of the Ab–FcRn interaction remain poorly understood and models that may help address future research questions are described.
Rice T, Kampmann B, Holder B, 2017, One size fits all? Antibody avidity measurement against multiple antigens in maternal vaccination studies, Virulence, Vol: 8, Pages: 1066-1068, ISSN: 2150-5608
Grant CR, Holder BS, Liberal R, et al., 2017, Immunosuppressive drugs affect interferon (IFN)-γ and programmed cell death 1 (PD-1) kinetics in patients with newly diagnosed autoimmune hepatitis., Clinical and Experimental Immunology, Vol: 189, Pages: 71-82, ISSN: 1365-2249
Autoimmune hepatitis (AIH) is characterized by overwhelming effector immune responses associated with defective regulatory T cells (Tregs ). Several lines of evidence indicate CD4 as the main effectors involved in autoimmune liver damage. Herein we investigate the in-vitro effects of prednisolone, 6-mercaptopurine, cyclosporin, tacrolimus, mycophenolic acid (MPA) and rapamycin, immunosuppressive drugs (ISDs) used in AIH treatment, on the expression of proinflammatory cytokines, co-inhibitory molecules and ability to proliferate of CD4(+) CD25(-) cells, isolated from the peripheral blood of treatment-naive patients with AIH. We note that in healthy subjects (HS) following polyclonal stimulation and in the absence of ISDs, the expression of interferon (IFN)-γ, interleukin (IL)-17 and tumour necrosis factor (TNF)-α by CD4 effectors peaks at 48 h and decreases at 96 h to reach baseline levels. In contrast, in AIH the expression of all these proinflammatory cytokines continue rising between 48 and 96 h. Levels of programmed cell death-1 (PD-1), T cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) and cytotoxic T lymphocyte antigen-4 (CTLA-4) increase over 96-h culture both in HS and AIH, although with faster kinetics in the latter. Exposure to ISDs contains IFN-γ and PD-1 expression in AIH, where control over CD4(+) CD25(-) cell proliferation is also noted upon exposure to MPA. Treatment with tacrolimus and cyclosporin render CD4(+) CD25(-) cells more susceptible to Treg control. Collectively, our data indicate that in treatment-naive patients with AIH, all ISDs restrain T helper type 1 (Th1) cells and modulate PD-1 expression. Furthermore, they suggest that tacrolimus and cyclosporin may ameliorate effector cell responsiveness to Tregs .
Holder BS, Jones T, Sancho Shimizu V, et al., 2016, Macrophage exosomes induce placental inflammatory cytokines: a novel mode of maternal-placental messaging, Traffic, Vol: 17, Pages: 168-178, ISSN: 1600-0854
During pregnancy, the placenta forms the interface between mother and fetus. Highly controlled regulation of trans-placental trafficking is therefore essential for the healthy development of the growing fetus. Extracellular vesicle-mediated transfer of protein and nucleic acids from the human placenta into the maternal circulation is well documented; the possibility that this trafficking is bi-directional has not yet been explored but could affect placental function and impact on the fetus. We hypothesized that the ability of the placenta to respond to maternal inflammatory signals is mediated by the interaction of maternal immune cell exosomes with placental trophoblast. Utilizing the BeWo cell line and whole placental explants, we demonstrated that the human placenta internalizes macrophage-derived exosomes in a time- and dose-dependent manner. This uptake was via clathrin-dependent endocytosis. Furthermore, macrophage exosomes induced release of proinflammatory cytokines by the placenta. Taken together, our data demonstrates that exosomes are actively transported into the human placenta and that exosomes from activated immune cells modulate placental cytokine production. This represents a novel mechanism by which immune cells can signal to the placental unit, potentially facilitating responses to maternal inflammation and infection, and thereby preventing harm to the fetus.
Liberal R, Grant CR, Holder BS, et al., 2015, In autoimmune liver disease defective regulatory T cell responsiveness to IL-2 results in low IL-10 production and impaired suppression, 66th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: WILEY-BLACKWELL, Pages: 364A-364A, ISSN: 0270-9139
Donaldson B, Jain P, Holder BS, et al., 2015, What determines uptake of pertussis vaccine in pregnancy? A cross sectional survey in an ethnically diverse population of pregnant women in London, Vaccine, Vol: 33, Pages: 5822-5828, ISSN: 1873-2518
Liberal R, Grant CR, Holder BS, et al., 2015, In autoimmune hepatitis type 1 or the autoimmune hepatitis-sclerosing cholangitis variant defective regulatory T-cell responsiveness to IL-2 results in low IL-10 production and impaired suppression, Hepatology, Vol: 62, Pages: 863-875, ISSN: 0270-9139
Defective immune regulation plays a permissive role enabling effector cells to initiate and perpetuate tissue damage, eventually resulting in autoimmune disease. Numerical and functional regulatory T‐cell (Treg) impairment has been previously reported in autoimmune liver disease (AILD; including autoimmune hepatitis and autoimmune sclerosing cholangitis ASC). However, in these early reports, Tregs were phenotypically defined as CD4+CD25+ or CD4+CD25high cells. In the current study, we reexamined phenotypic and functional properties of Tregs by adopting a more refined definition of these cells that also includes negativity or low level of expression of CD127. We studied 43 AILD patients and 22 healthy subjects (HSs) and found that CD4+CD25+CD127− Tregs were decreased in the former. This decrease was more marked in patients with active disease than in those in remission. In AILD, Treg frequencies correlated inversely with parameters of disease activity and were not affected by immunosuppressive treatment. We also document, for the first time, that, in AILD, bona‐fide Tregs produce less interleukin (IL)−10 and are impaired in their ability to suppress CD4+CD25− target cell proliferation, a feature that in HSs, but not in AILDs, is dependent, at least in part, on IL‐10 secretion. Decreased IL‐10 production by Tregs in AILD is linked to poor responsiveness to IL‐2 and phospho signal transducer and activator of transcription 5 up‐regulation. Conclusion: Tregs are numerically impaired in AILD, this impairment being more prominent during active disease. Notably, defective IL‐10 production, resulting from low Treg responsiveness to IL‐2, contributes to Treg functional impairment. (Hepatology 2015;62:863–875)
Grant CR, Liberal R, Holder BS, et al., 2015, EFFECT OF IMMUNOSUPPRESSIVE DRUGS ON THE KINETICS OF CO-INHIBITORY MOLECULE EXPRESSION AND PRO-INFLAMMATORY CYTOKINE PRODUCTION BY EFFECTOR T CELLS IN AUTOIMMUNE HEPATITIS, 50th International Liver Congress of the European-Association-for-the-Study-of-the-Liver, Publisher: ELSEVIER SCIENCE BV, Pages: S807-S808, ISSN: 0168-8278
Grant CR, Liberal R, Holder BS, et al., 2014, Effect of immunosuppressive drugs on the kinetics of co-inhibitory molecule expression and pro-inflammatory cytokine production by effector T cells in autoimmunity, Publisher: WILEY-BLACKWELL, Pages: 125-125, ISSN: 0019-2805
Holder BS, Grant CR, Liberal R, et al., 2014, Retinoic acid stabilizes antigen-specific regulatory T-cell function in autoimmune hepatitis type 2, JOURNAL OF AUTOIMMUNITY, Vol: 53, Pages: 26-32, ISSN: 0896-8411
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- Citations: 27
Holder B, Jones T, Okala S, et al., 2014, UPTAKE OF MACROPHAGE EXOSOMES BY THE HUMAN PLACENTA., International-Federation-of-Placenta-Associations (IFPA)/EPG Meeting, Publisher: W B SAUNDERS CO LTD, Pages: A59-A59, ISSN: 0143-4004
Grant CR, Liberal R, Holder BS, et al., 2014, Dysfunctional CD39<SUP>POS</SUP> Regulatory T Cells and Aberrant Control of T-Helper Type 17 Cells in Autoimmune Hepatitis, HEPATOLOGY, Vol: 59, Pages: 1007-1015, ISSN: 0270-9139
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- Citations: 128
Grant CR, Liberal R, Holder BS, et al., 2013, In autoimmune hepatitis low expression of CD39 by regulatory T-cells is associated with decreased ATP hydrolysis and impaired control over Th17 cells, 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases, Publisher: WILEY-BLACKWELL, Pages: 566A-566A, ISSN: 0270-9139
Burl S, Holder BS, Lo BKM, et al., 2013, Optimisation of a functional mycobacterial growth-inhibition assay to improve its suitability for infant TB vaccine studies, JOURNAL OF IMMUNOLOGICAL METHODS, Vol: 394, Pages: 121-124, ISSN: 0022-1759
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- Citations: 6
Grant CR, Liberal R, Holder BS, et al., 2013, DEFECTIVE CD39 EXPRESSION BY Tregs IN AUTOIMMUNE HEPATITIS PREVENTS SUPPRESSION OF IL17 PRODUCTION AND IS ASSOCIATED WITH IMPAIRED ATP-HYDROLYSIS, International Liver Congress / 48th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: S385-S385, ISSN: 0168-8278
Liberal R, Grant CR, Holder BS, et al., 2013, PHENOTYPIC CHARACTERISATION OF CD4 EFFECTOR IMMUNE RESPONSES IN CHILDHOOD AUTOIMMUNE LIVER DISEASE, International Liver Congress / 48th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: S389-S390, ISSN: 0168-8278
Liberal R, Grant CR, Holder BS, et al., 2013, PHENOTYPIC AND FUNCTIONAL PLASTICITY OF CD4<SUP>pos</SUP>CD25<SUP>high</SUP>CD127<SUP>pos</SUP> AND CD4<SUP>pos</SUP>CD25<SUP>high</SUP>CD127<SUP>neg</SUP> T CELLS IN AUTOIMMUNE HEPATITIS, International Liver Congress / 48th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: S389-S389, ISSN: 0168-8278
Liberal R, Grant CR, Holder BS, et al., 2012, In autoimmune sclerosing cholangitis and autoimmune hepatitis a high proportion of circulating T and B lymphocytes express the gut-homing integrin α4β7, 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: WILEY-BLACKWELL, Pages: 721A-721A, ISSN: 0270-9139
Grant CR, Liberal R, Holder BS, et al., 2012, CD39<SUP>+</SUP>CD4<SUP>+</SUP> T cells display a pro-inflammatory signature in patients with autoimmune hepatitis, 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: WILEY-BLACKWELL, Pages: 992A-993A, ISSN: 0270-9139
Holder BS, Grant CR, Liberal R, et al., 2012, Retinoic acid restores CD25 expression and boosts suppressive function of antigen-specific regulatory T cells in autoimmune hepatitis, 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: WILEY-BLACKWELL, Pages: 196A-197A, ISSN: 0270-9139
Grant C, Liberal R, Holder BS, et al., 2012, Immune cell CD39 and CD73 expression in autoimmune hepatitis and health, European Congress of Immunology, Publisher: WILEY-BLACKWELL, Pages: 502-502, ISSN: 0019-2805
Grant C, Liberal R, Holder BS, et al., 2012, CD39<SUP>+</SUP> CD4+T cells display a pro-inflammatory signature in patients with autoimmune hepatitis, European Congress of Immunology, Publisher: WILEY-BLACKWELL, Pages: 497-497, ISSN: 0019-2805
Holder BS, Grant CR, Liberal R, et al., 2012, Retinoic acid restores CD25 expression and boosts suppressive function of antigen-specific regulatory T cells in autoimmune hepatitis, European Congress of Immunology, Publisher: WILEY-BLACKWELL, Pages: 123-123, ISSN: 0019-2805
Liberal R, Grant CR, Holder BS, et al., 2012, The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9/tim-3 pathway, HEPATOLOGY, Vol: 56, Pages: 677-686, ISSN: 0270-9139
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- Citations: 102
Grant CR, Liberal R, Holder B, et al., 2012, LOW CD39 EXPRESSION MARKS SEVERE REGULATORY T CELL IMPAIRMENT IN PATIENTS WITH AUTOIMMUNE SCLEROSING CHOLANGITIS, Publisher: B M J PUBLISHING GROUP, Pages: A119-A119, ISSN: 0017-5749
Longhi MS, Liberal R, Holder B, et al., 2012, Inhibition of Interleukin-17 Promotes Differentiation of CD25<SUP>-</SUP> Cells Into Stable T Regulatory Cells in Patients With Autoimmune Hepatitis, GASTROENTEROLOGY, Vol: 142, Pages: 1526-+, ISSN: 0016-5085
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- Citations: 81
Holder BS, Tower CL, Abrahams VM, et al., 2012, Syncytin 1 in the human placenta, PLACENTA, Vol: 33, Pages: 460-466, ISSN: 0143-4004
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- Citations: 35
Holder BS, Tower CL, Forbes K, et al., 2012, Immune cell activation by trophoblast-derived microvesicles is mediated by syncytin 1, IMMUNOLOGY, Vol: 136, Pages: 184-191, ISSN: 0019-2805
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- Citations: 70
Holder BS, Tower CL, Jones CJP, et al., 2012, Heightened Pro-Inflammatory Effect of Preeclamptic Placental Microvesicles on Peripheral Blood Immune Cells in Humans, BIOLOGY OF REPRODUCTION, Vol: 86, ISSN: 0006-3363
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- Citations: 68
Menzies FM, Khan AH, Higgins CA, et al., 2012, The chemokine receptor CCR2 is not required for successful initiation of labor in mice., Biol Reprod, Vol: 86
Chemokine-driven neutrophil and monocyte recruitment into the uterus and cervix has been proposed to initiate labor. Chemokines that bind CXCR2 direct neutrophil migration and are induced during labor in humans. The chemokine CCL2, induced in the uterus by endocrine and mechanical signals, has been proposed to drive CCR2-dependent monocyte homing to the uterus to contribute to the initiation of labor. However, no direct evidence indicates that chemokines or their receptors play indispensable roles in labor-associated inflammation, and the impact of leukocyte infiltration on labor is unclear. Here, we have quantified expression of the principal monocyte- and neutrophil-attracting chemokines in the uteri of term pregnant (Day 18) and laboring wild-type mice. None of the neutrophil attractants we assayed were up-regulated with labor. Strikingly, however, Ccl2 was markedly increased, and this was concomitant with increased expression of Ccr2, the myeloid marker Itgam (also known as Cd11b), the monocyte/macrophage marker Emr1 (also known as F4/80). Moreover, in CCR2-deficient mice, this labor-associated increase in Itgam and Emr1 was not seen, consistent with the monocyte-trafficking defects that exist in these animals. Nonetheless, laboring CCR2-deficient and wild-type uteri showed similarly enhanced expression of the myometrial activation markers Gja1 and Oxtr (commonly known as connexin 43 and oxytocin receptor, respectively), and CCR2-deficient mice had gestation lengths, litter sizes, and fetal and placental weights no different from those of their wild-type counterparts. Thus, whereas labor is associated with an inflammatory response in gestational tissues, CCR2-dependent leukocyte recruitment into the mouse uterus is dispensable for the initiation of successful labor.
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