Graham S Ogg

University of Oxford, Oxford, England, United Kingdom

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Publications (47)289.63 Total impact

  • Clinical Immunology 04/2014; · 3.77 Impact Factor
  • Clinical Immunology. 01/2014;
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    ABSTRACT: Activation of the group 2 innate lymphoid cell (ILC2) population leads to production of the classical type 2 cytokines, thus promoting type 2 immunity. Chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2), a receptor for prostaglandin D2 (PGD2), is expressed by human ILC2s. However, the function of CRTH2 in these cells is unclear. We sought to determine the role of PGD2 and CRTH2 in human ILC2s and compare it with that of the established ILC2 activators IL-25 and IL-33. The effects of PGD2, IL-25, and IL-33 on the cell migration, cytokine production, gene regulation, and receptor expression of ILC2s were measured with chemotaxis, ELISA, Luminex, flow cytometry, quantitative RT-PCR, and QuantiGene assays. The effects of PGD2 under physiologic conditions were evaluated by using the supernatant from activated mast cells. PGD2 binding to CRTH2 induced ILC2 migration and production of type 2 cytokines and many other cytokines. ILC2 activation through CRTH2 also upregulated the expression of IL-33 and IL-25 receptor subunits (ST2 and IL-17RA). The effects of PGD2 on ILC2s could be mimicked by the supernatant from activated human mast cells and inhibited by a CRTH2 antagonist. PGD2 is an important and potent activator of ILC2s through CRTH2 mediating strong proallergic inflammatory responses. Through IgE-mediated mast cell degranulation, these innate cells can also contribute to adaptive type 2 immunity; thus CRTH2 bridges the innate and adaptive pathways in human ILC2s.
    The Journal of allergy and clinical immunology 12/2013; · 12.05 Impact Factor
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    ABSTRACT: Type 2 innate lymphoid cells (ILC2s, nuocytes, NHC) require RORA and GATA3 for their development. We show that human ILC2s express skin homing receptors and infiltrate the skin after allergen challenge, where they produce the type 2 cytokines IL-5 and IL-13. Skin-derived ILC2s express the IL-33 receptor ST2, which is up-regulated during activation, and are enriched in lesional skin biopsies from atopic patients. Signaling via IL-33 induces type 2 cytokine and amphiregulin expression, and increases ILC2 migration. Furthermore, we demonstrate that E-cadherin ligation on human ILC2 dramatically inhibits IL-5 and IL-13 production. Interestingly, down-regulation of E-cadherin is characteristic of filaggrin insufficiency, a cardinal feature of atopic dermatitis (AD). ILC2 may contribute to increases in type 2 cytokine production in the absence of the suppressive E-cadherin ligation through this novel mechanism of barrier sensing. Using Rag1(-/-) and RORα-deficient mice, we confirm that ILC2s are present in mouse skin and promote AD-like inflammation. IL-25 and IL-33 are the predominant ILC2-inducing cytokines in this model. The presence of ILC2s in skin, and their production of type 2 cytokines in response to IL-33, identifies a role for ILC2s in the pathogenesis of cutaneous atopic disease.
    Journal of Experimental Medicine 12/2013; · 13.21 Impact Factor
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    ABSTRACT: Comprehensive antigenic characterization of a T cell population of unknown specificity is challenging. Existing MHC class I expression systems are limited by the practical difficulty of probing cell populations with an MHC class I peptide library and the cross-reactivity of T cells that are able to recognise many variants of an index peptide. Using emulsion PCR and emulsion in vitro transcription/translation of a random library of peptides conjugated to CD8-null HLA-A*0201 on beads, we probed HLA-A*0201-restricted T cells with specificity for influenza, CMV and EBV. We observed significant enrichment for sequences containing HLA-A2 anchors and correct viral fragments for all T cell populations. HLA bead display provides a novel approach to identify the specificity of T cells.
    Journal of immunological methods 12/2013; · 2.35 Impact Factor
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    ABSTRACT: Dengue viral infections are the commonest mosquito borne viral infection in the world, affecting more than 100 countries and 390 million individuals annually. Currently, there are no effective antiviral drugs or an effective vaccine to prevent infection. A main hurdle in developing a safe and effective vaccine has been our poor understanding of the complex nature of the protective immune response in acute dengue infection and the presence of four dengue virus (DV) serotypes that are highly homologous. The role of DV specific T cells in the pathogenesis of severe clinical disease in not clear. It has been speculated that highly cross reactive T cells for the previous infecting heterologous DV serotype, which produce pro-inflammatory cytokines, contribute to disease pathogenesis. These cross reactive T cells are believed to be suboptimal in clearing the infection with the current DV-serotype. However, other studies have shown that cross-reactive DV-specific T cells are absent or present in very low frequency during acute infection, appearing only during the convalescent period in the majority of patients. Furthermore, significant apoptosis of T cells occurs in severe acute clinical disease. Overall therefore, it is unclear what role T cells play in contributing to disease pathogenesis during acute dengue infection. Existing data have been complicated by cross-reactivity in T cells assays. These findings can now be re-evaluated in the light of novel technologies to identify serotype-specific T cell responses.
    Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 10/2013; · 3.12 Impact Factor
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    ABSTRACT: Several studies have shown that serum IL-10, IFNgamma and MIF are elevated in patients in severe dengue (SD) and could be used as potential biomarkers. We proceeded to determine if these cytokines could be used as biomarkers in a large cohort of adult dengue patients with varying severity of dengue infection. Serum IL-10 levels were determined in 259 of whom 40 had severe dengue infection. Serum IFNgamma andIFNalpha levels were done in 78 and MIF levels were done in 65 patients with acute dengue infection. Clinical features and laboratory investigations were undertaken during the febrile and critical phase. We found that serum IL-10 levels were significantly higher (p = 0.001) in patients with SD, when compared to those with non SD. Serum IL-10 levels significantly and inversely correlated with white cell counts (R = -0.23, p = 0.0002) and lymphocyte counts (R = -0.29, p < 0.0001) but significantly and positively correlated with aspartate tranaminase levels (R = 0.16, p = 0.01) and alanine transaminase levels (R = 0.22, p = 0.007). However, IL-10 levels did not have a good predictive value in discriminating those who were likely to develop SD (AUC = 0.66). Serum IFNgamma levels were also significantly higher (p = 0.04) in patients with SD when compared to non SD. There was no difference (p = 0.34) in serum IFNalpha levels and serum MIF levels (p = 0.15) in patients with SD and non SD. Although serum IL-10 was significantly elevated in patients with SD it had a poor discriminatory value in identifying those with SD and non SD and therefore, is unsuitable to be used as a robust biomarker in this cohort.
    BMC Infectious Diseases 07/2013; 13(1):341. · 3.03 Impact Factor
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    ABSTRACT: Although peptides are well recognised biological molecules in vivo, their selection from libraries is challenging because of relative low affinity whilst in linear conformation. We hypothesized that multiplexed peptides and DNA on the surface of beads would provide a platform for enhanced avidity and the selection of relevant peptides from a library (ORBIT bead display). Using human immunodeficiency virus (HIV-1) gp120 as a target, we identify peptides that inhibit HIV-1 replication in vitro through blocking of protein:protein interaction with the co-receptor CCR5. The bead display approach has many potential applications for probing biological systems and for drug lead development.
    Scientific Reports 01/2013; 3:3030. · 2.93 Impact Factor
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    ABSTRACT: Elevated IL-10 has been shown to be associated with severe dengue infection (DI). We proceeded to investigate the role of IL-10 in the pathogenesis of acute DI. Ex vivo and cultured IFNγ ELISpot assays for dengue virus (DENV) NS3 protein and non dengue viral proteins were carried out in 26 patients with acute DI (16 with dengue haemorrhagic fever) and 12 healthy dengue seropositive individuals from Sri Lanka. DENV serotype specific (SS) responses were determined by using a panel of SS peptides. Serum IL-10 level were significantly higher (p = 0.02) in those who did not have in vitro responses to DENV-SS peptides (mean 144.2 pg/ml) when compared to those who responded (mean 75.7 pg/ml). DENV-NS3 specific ex vivo IFNγ ELISpot responses were also significantly lower (p = 0.0001) in those who did not respond to DENV-SS peptides (mean 42 SFU/million PBMCs) when compared to those who responded to DENV-SS peptides (mean 1024 SFU/million PBMCs). Serum IL-10 levels correlated significantly (p = 0.03) and inversely (Spearmans R = -0.45) with ex vivo DENV-NS3 specific responses but not with ex vivo non DENV specific responses (Spearmans R = -014, p = 0.52). Blockage of IL-10 in vitro significantly increased (p = 0.04) the ex vivo IFNγ ELISpot DENV-NS3 specific responses but had no effect on responses to non DENV proteins. IL-10 appears to contribute to the pathogenesis of acute dengue infections by inhibiting DENV-specific T cell responses, which can be restored by blocking IL-10.
    PLoS Neglected Tropical Diseases 01/2013; 7(9):e2409. · 4.57 Impact Factor
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    ABSTRACT: BACKGROUND: The WHO guidelines were revised recently to identify patients with severe dengue (SD) early. We proceeded to determine the usefulness of the warning signs in the new WHO guidelines in predicting SD and we have also attempted to define other simple laboratory parameters that could be useful in predicting SD. METHODS: Clinical and laboratory parameters were recorded in 184 patients in 2011, with confirmed dengue viral infections, admitted to a medical ward in two tertiary care hospitals in Colombo, Sri Lanka. RESULTS: We found that the presence of 5 or more dengue warning signs were significantly (p = 0.02) associated with the development of SD (odds ratio 5.14, 95% CI = 1.312 to 20.16). The AST levels were significantly higher (p = 0.0001) in patients with abdominal pain (mean 243.5, SD +/- 200.7), when compared to those who did not have abdominal pain (mean 148.5, SD +/- 218.6). Lymphocyte counts <1,500 cells/mm3 were significantly (p = 0.005) associated with SD (odds ratio 3.367, 95% CI 1.396 to 8.123). High AST levels were also significantly associated (p < 0.0001) with SD (odds ratio 27.26, 95% CI 1.632 to 455.2). Platelet counts <20,000cells/mm3, were again significantly associated (p < 0.001) with severe disease (odds ratio 1.632 to 455.2, 95% CI 3.089 to 14.71). The PCR was positive in 26/84 of the patients and we found that the infecting serotype was DEN-1 in all 26 patients. CONCLUSIONS: The presence of 5 or more warning signs appears to be a predictor of SD. Lymphocyte counts <1,500 cells/mm3, platelet counts <20,000/mm3 and raised AST levels were associated with SD and could be used to help identify patients who are likely to develop SD.
    BMC Research Notes 11/2012; 5(1):645.
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    ABSTRACT: Atopic eczema and psoriasis are common skin diseases. While it is well established that the pathogenesis of these diseases varies, both are characterized by impairment in epidermal barrier function and abnormal IL-17 expression in the skin and peripheral blood. Recent findings indicated that filaggrin is essential during barrier formation and its insufficiency underlies the pathogenesis of atopic eczema. Filaggrin downregulation has also been reported in psoriasis. It is clear that Th1/Th2 bias influences expression of the protein, but an analysis of the effects of interleukin-17 (IL-17) on the expression of the protein and profilaggrin-processing enzymes has not yet been reported. In addition, the effect of the cytokine on components of functional epidermal barrier, tight junctions and adhesion/desmosomal proteins, has not been elucidated. Keratinocytes were exposed to interleukin-17A, and microarray analysis was performed. Filaggrin protein level was assessed by western blot. We have observed a significant decrease in profilaggrin mRNA level in interleukin-17A-exposed cultures (P = 0.008). Expression of processing enzymes was also altered, indicating an indirect effect of the cytokine on filaggrin production/degradation. Moreover, expression of many genes involved in cellular adhesion was also decreased. A significant downregulation of filaggrin at the protein level was detected by western blot in immortal and primary keratinocytes. Gene ontology analysis indicated changes in keratinization, epidermal differentiation and formation of the cornified envelope. We conclude that IL-17A downregulates the expression of filaggrin and genes important for cellular adhesion which could affect epidermal barrier formation. This effect potentially contributes to barrier dysfunction and could become a possible therapeutic target.
    Experimental Dermatology 02/2012; 21(2):104-10. · 3.58 Impact Factor
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    Danuta Gutowska-Owsiak, Graham S Ogg
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    ABSTRACT: It is now clear that the epidermis has an active role in local immune responses in the skin. Keratinocytes are involved early in inflammation by providing first-line innate mechanisms and, in addition, can contribute to adaptive immune responses that may be associated with clinical disease. Moreover, keratinocytes are capable of enhancing and shaping the outcome of inflammation in response to stimuli and promoting particular types of immune bias. Through understanding the underlying mechanisms, the role of keratinocytes in disease pathogenesis will be further defined, which is likely to lead to the identification of potential targets for prophylactic or therapeutic intervention.
    Journal of Investigative Dermatology 01/2012; 132(3 Pt 2):940-8. · 6.19 Impact Factor
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    ABSTRACT: The occurrence of dengue haemorrhagic fever (DHF) is thought to result from a complex interplay between the virus, host genetics and host immune factors. Existing published data are not consistent, in part related to relatively small sample sizes. We set out to determine possible associations between dengue virus (DEN-V) NS3 specific T cells and cytokine and chemokine levels and the pathogenesis of severe disease in a large cohort of individuals with DHF. By using ex vivo IFNγ ELISpot assays we determined DENV-NS3 specific responses in patients with varying severity of DHF. Other cytokines produced by DENV-NS3 specific T cells were determined by using multiple bead array analysis (MBAA). We also determined the serum cytokine levels using MBAA, lymphocyte subsets and Annexin V expression of lymphocytes in patients with varying severity of DHF. Of the 112 DHF patients studied, 29 developed shock. Serum IL-10 and IP-10 levels positively and significantly correlated with T cell apoptosis while IL-10 levels inversely correlated with T cell numbers. In contrast, TGFß showed a very significant (P<0.0001) and positive correlation (Spearman's R = 0.65) with the platelet counts, consistent with platelet release. We found that whilst patients with severe dengue had lower total T cell numbers, the DV-NS3 specific T cells persisted and produced high levels of IFNγ but not TNFα, IL-3, IL-13, IL-2, IL-10 or IL-17. Our data suggest that serum IL-10, TNFα and TGFβ differentially associate with dengue disease severity.
    PLoS ONE 01/2012; 7(11):e50387. · 3.73 Impact Factor
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    ABSTRACT: PGD(2) exerts a number of proinflammatory responses through a high-affinity interaction with chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and has been detected at high concentrations at sites of allergic inflammation. Because cysteinyl leukotrienes (cysLTs) are also produced during the allergic response, we investigated the possibility that cysLTs may modulate the response of human Th2 cells to PGD(2). PGD(2) induced concentration-dependent Th2 cytokine production in the absence of TCR stimulation. Leukotrienes D(4) and E(4) (LTE(4)) also stimulated the cytokine production but were much less active than PGD(2). However, when combined with PGD(2), cysLTs caused a greater than additive enhancement of the response, with LTE(4) being most effective in activating Th2 cells. LTE(4) enhanced calcium mobilization in response to PGD(2) in Th2 cells without affecting endogenous PGD(2) production or CRTH2 receptor expression. The effect of LTE(4) was inhibited by montelukast but not by the P2Y(12) antagonist methylthioadenosine 5'-monophosphate. The enhancing effect was also evident with endogenous cysLTs produced from immunologically activated mast cells because inhibition of cysLT action by montelukast or cysLT synthesis by MK886, an inhibitor of 5-lipoxygenase-activating protein, reduced the response of Th2 cells to the levels produced by PGD(2) alone. These findings reveal that cysLTs, in particular LTE(4), have a significant proinflammatory impact on T cells and demonstrate their effects on Th2 cells are mediated by a montelukast-sensitive receptor.
    The Journal of Immunology 12/2011; 188(2):694-702. · 5.52 Impact Factor
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    ABSTRACT: Streptococcus pneumoniae is an encapsulated bacterium that causes significant global morbidity and mortality. There is emerging evidence that T cells contribute to the immunity that protects humans from S. pneumoniae-associated disease. However, no T-cell epitopes have been identified as yet in this bacterium and there are no data that address the functional nature of T cells specific for pneumococcal-derived epitopes. We sought to define T-cell epitopes in the conserved serine/threonine kinase, found in S. pneumoniae (StkP) and to investigate specific interferon γ (IFN-γ) production resulting from such T-cell activation in healthy donors. We were able to detect the activation of T cells in response to pneumococcal whole-cell antigen or StkP-derived peptides in all 15 individuals. We found that the majority of the T-cell responses were directed against the extracellular, penicillin-binding protein and serine/threonine kinase-associated domains. We proceeded to characterize the immunodominant epitope in detail and observed HLA-DRB1(*) 1501 restriction. This is the first study that has identified T-cell responses to peptides derived from a protein from S. pneumoniae and has shown that in healthy adults, specific T cells have rapid IFN-γ production compatible with effector cell differentiation. The use of such T-cell epitopes will aid in the future monitoring of T-cell responses to both S. pneumoniae infection and vaccination in humans.
    FEMS Immunology & Medical Microbiology 11/2010; 60(2):113-22. · 2.68 Impact Factor
  • The Journal of infection 06/2010; · 4.13 Impact Factor
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    ABSTRACT: Allergen immunotherapy presents an opportunity to define mechanisms of induction of clinical tolerance in humans. Significant progress has been made in our understanding of changes in T cell responses during immunotherapy, but existing work has largely been based on functional T cell assays. HLA-peptide-tetrameric complexes allow the tracking of antigen-specific T-cell populations based on the presence of specific T-cell receptors and when combined with functional assays allow a closer assessment of the potential roles of T-cell anergy and clonotype evolution. We sought to develop tools to facilitate tracking of antigen-specific T-cell populations during wasp-venom immunotherapy in people with wasp-venom allergy. We first defined dominant immunogenic regions within Ves v 5, a constituent of wasp venom that is known to represent a target antigen for T-cells. We next identified HLA-DRB1*1501 restricted epitopes and used HLA class II tetrameric complexes alongside cytokine responses to Ves v 5 to track T-cell responses during immunotherapy. In contrast to previous reports, we show that there was a significant initial induction of IL-4 producing antigen-specific T-cells within the first 3-5 weeks of immunotherapy which was followed by reduction of circulating effector antigen-specific T-cells despite escalation of wasp-venom dosage. However, there was sustained induction of IL-10-producing and FOXP3 positive antigen-specific T cells. We observed that these IL-10 producing cells could share a common precursor with IL-4-producing T cells specific for the same epitope. Clinical tolerance induction in humans is associated with dynamic changes in frequencies of antigen-specific T-cells, with a marked loss of IL-4-producing T-cells and the acquisition of IL-10-producing and FOXP3-positive antigen-specific CD4+ T-cells that can derive from a common shared precursor to pre-treatment effector T-cells. The development of new approaches to track antigen specific T-cell responses during immunotherapy can provide novel insights into mechanisms of tolerance induction in humans and identify new potential treatment targets.
    PLoS ONE 01/2010; 5(6):e11028. · 3.73 Impact Factor
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    ABSTRACT: In Sri Lanka, varicella zoster virus (VZV) is typically acquired during adulthood with significant associated disease morbidity and mortality. T cells are believed to be important in the control of VZV replication and in the prevention of reactivation. The relationship between viral load, disease severity and cellular immune responses in primary VZV infection has not been well studied. We used IFNgamma ELISpot assays and MHC class II tetramers based on VZV gE and IE63 epitopes, together with quantitative real time PCR assays to compare the frequency and phenotype of specific T cells with virological and clinical outcomes in 34 adult Sri Lankan individuals with primary VZV infection. Viral loads were found to be significantly higher in patients with moderate to severe infection compared to those with mild infection (p<0.001) and were significantly higher in those over 25 years of age (P<0.01). A significant inverse correlation was seen between the viral loads and the ex vivo IFNgamma ELISpot responses of patients (P<0.001, r = -0.85). VZV-specific CD4+ T cells expressed markers of intermediate differentiation and activation. Overall, these data show that increased clinical severity in Sri Lankan adults with primary VZV infection associates with higher viral load and reduced viral specific T cell responses.
    PLoS ONE 02/2008; 3(11):e3789. · 3.73 Impact Factor
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    ABSTRACT: Open reading frame 63 of varicella-zoster Virus (VZV) encodes an immediate early (IE) phosphoprotein (IE63) that is believed to be important for viral infectivity and establishing latency. Evidence suggests that VZV-specific T cells are crucial in the control of viral replication; however, data addressing the existence of IE63 protein-specific CD4+ T cells are limited. Using IFN-gamma immunosorbent assays, we identified high frequencies of responses to overlapping peptides spanning the IE63 protein both ex vivo and after in vitro restimulation in healthy VZV-seropositive individuals. We identified a commonly recognised epitope, restricted by HLA-DRB1*1501, which was naturally processed and presented by keratinocytes. We proceeded to investigate the frequency and phenotype of the epitope-specific CD4+ T cells using HLA class II tetrameric complexes. Epitope-specific CD4+ T cells were detectable ex vivo and showed a mixed central and effector-memory differentiation phenotype, with a significant proportion showing evidence of recent activation and rapid effector function. In summary these data implicate persistent low-level or recurrent VZV antigen exposure in healthy immune donors and are compatible with a role for IE63-specific CD4+ T cells in the control of viral reactivation.
    European Journal of Immunology 01/2008; 37(12):3393-403. · 4.97 Impact Factor
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    ABSTRACT: The ability of human keratinocytes to present antigen to T cells is controversial and, indeed, it has been suggested that keratinocytes may promote T cell hyporesponsiveness. Furthermore, it is unclear whether keratinocytes can process antigen prior to MHC class I and class II presentation. We tested the ability of keratinocytes to induce functional responses in epitope-specific CD4+ and CD8+ memory T cells using peptides, protein and recombinant expression vectors as sources of antigen. Keratinocytes were able to efficiently process and present protein antigen to CD4+ T cells, resulting in cytokine secretion (Th1 and Th2). This interaction was dependent on keratinocyte expression of HLA class II and ICAM-1, which could be induced by IFN-gamma. In addition, keratinocytes could present virally encoded or exogenous peptide to CD8+ T cells, resulting in T cell cytokine production and target cell lysis. Finally, T cell lines grown using keratinocytes as stimulators showed no loss of function. These findings demonstrate that keratinocytes are able to efficiently process and present antigen to CD4+ and CD8+ memory T cells and induce functional responses. The findings have broad implications for the pathogenesis of cutaneous disease and for transcutaneous drug or vaccine delivery.
    European Journal of Immunology 07/2007; 37(6):1485-93. · 4.97 Impact Factor

Publication Stats

3k Citations
289.63 Total Impact Points

Institutions

  • 2006–2014
    • University of Oxford
      • MRC Human Immunology Unit
      Oxford, England, United Kingdom
  • 1998–2013
    • Oxford University Hospitals NHS Trust
      • Nuffield Department of Medicine
      Oxford, England, United Kingdom
  • 2010–2012
    • NIHR Oxford Biomedical Research
      Oxford, England, United Kingdom
  • 2002–2004
    • University College London
      Londinium, England, United Kingdom
    • Institute of Genetics and Molecular Medicine
      Edinburgh, Scotland, United Kingdom