Benjamin Owens
Experienced experimental immunologist working on translational projects across murine and human systems.
Currently supported by an Oxford - UCB Pharma Postdoctoral Fellowship.
Particular interests in: Immune Regulation; Dendritic cell biology; Chronic inflammation; Intestinal mucosal immunology; Stromal immunology and the Stromal / Innate immune interface.
Currently managing several pre-clinical research projects:
- Phenotypic alterations of human intestinal stromal cells during chronic inflammation
- Novel innate immune functions of intestinal stromal cells
- Role of microRNAs in the regulation of dendritic cell function
- Development and optimisation of 3D culture models of the human intestine
I am interested in the development of novel therapeutics for chronic inflammatory disorders and am active in the industrial biopharmaceutical and entrepreneurial biotech environment, in addition to academia.
Co-founder & Chairman of the Stromal Immunology Group:
www.stroma.org.uk
Oxford Page: http://www.expmedndm.ox.ac.uk/benjamin-owens
More information on my LinkedIn page: http://uk.linkedin.com/in/bmjowens
Phone: +44 1865 220 663
Address: Translational Gastroenterology Unit
Experimental Medicine Division
Nuffield Department of Medicine
University of Oxford
Level 5, John Radcliffe Hospital
Oxford, OX3 9DU
Currently supported by an Oxford - UCB Pharma Postdoctoral Fellowship.
Particular interests in: Immune Regulation; Dendritic cell biology; Chronic inflammation; Intestinal mucosal immunology; Stromal immunology and the Stromal / Innate immune interface.
Currently managing several pre-clinical research projects:
- Phenotypic alterations of human intestinal stromal cells during chronic inflammation
- Novel innate immune functions of intestinal stromal cells
- Role of microRNAs in the regulation of dendritic cell function
- Development and optimisation of 3D culture models of the human intestine
I am interested in the development of novel therapeutics for chronic inflammatory disorders and am active in the industrial biopharmaceutical and entrepreneurial biotech environment, in addition to academia.
Co-founder & Chairman of the Stromal Immunology Group:
www.stroma.org.uk
Oxford Page: http://www.expmedndm.ox.ac.uk/benjamin-owens
More information on my LinkedIn page: http://uk.linkedin.com/in/bmjowens
Phone: +44 1865 220 663
Address: Translational Gastroenterology Unit
Experimental Medicine Division
Nuffield Department of Medicine
University of Oxford
Level 5, John Radcliffe Hospital
Oxford, OX3 9DU
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Papers by Benjamin Owens
In this study we examined the innate immune capacity of primary human intestinal stromal cells (iSCs). CD90+ iSCs isolated from human colonic mucosa expressed a wide array of innate immune receptors and functionally responded to stimulation with bacterial ligands. iSCs also sensed infection with live Salmonella typhimurium, rapidly expressing IL-1 family cytokines via a RIPK2/p38MAPK-dependent signaling process. In addition to responding to innate immune triggers, primary iSCs exhibited a capacity for bacterial uptake, phagocytosis, and antigen processing, although to a lesser extent than professional APCs.
Thus CD90+ iSCs represent an abundant population of “non-professional” innate immune effector cells of the human colonic mucosa and likely play an important adjunctive role in host defense and immune regulation at this site.
miR-29 expression was upregulated in human dendritic cells (DCs) in response to NOD2 signals, and miR-29 regulated the expression of multiple immune mediators. In particular, miR-29 downregulated interleukin-23 (IL-23) by targeting IL-12p40 directly and IL-23p19 indirectly, likely via reduction of ATF2.
DSS-induced colitis was worse in miR-29-deficient mice and was associated with elevated IL-23 and T helper 17 signature cytokines in the intestinal mucosa. Crohn’s disease (CD) patient DCs expressing NOD2 polymorphisms failed to induce miR-29 upon pattern recognition receptor stimulation and showed enhanced release of IL-12p40 on exposure to adherent invasive E. coli. Therefore, we suggest that loss of miR-29-mediated immunoregulation in CD DCs might contribute to elevated IL-23 in this disease.
Homeostatic lymphoid tissue organogenesis proceeds via exquisitely controlled spatiotemporal interactions between hematopoietic lymphoid tissue inducer populations and multiple subsets of non-hematopoietic stromal cells. However, it is becoming clear that in a range of inflammatory contexts, ectopic or tertiary lymphoid organs (TLOs) can develop inappropriately under pathological stress.
Here we summarise the role of stromal cells in the development of homeostatic lymphoid tissue, and assess emerging evidence that suggests a critical role for stromal involvement in the TLO development associated with chronic infections and inflammation.
Leishmania donovani is an intracellular protozoan parasite of mammalian phagocytes, capable of establishing a persistent and life-threatening infection in man. Associated with profound immunopathology and chronic immune suppression, visceral leishmaniasis is endemic to some of the world’s most resource-poor regions. There is no vaccine and current therapeutic options are limited by parasite resistance, high toxicity and prohibitive costs. As such, a deeper understanding of the immunological mechanisms underlying this disease is critical for the development of effective novel interventions.
Phenotypic and functional analysis of CD11chi conventional dendritic cell subsets (cDCs) revealed widespread alterations as a result of chronic infection in the murine spleen. cDCs displayed a limited capacity for costimulatory molecule expression and pro-inflammatory cytokine production ex vivo. Instead, the preferential production of the immunoregulatory cytokines IL-10 and IL-27 led to the establishment of an auto- regulatory cytokine cascade, modulating cDC function and limiting their capacity to direct effector T cell polarisation in vitro.
2
Conditional in vivo ablation of CD11c+ cells during chronic infection suggested a key role for DCs in the maintenance of pathology and parasite persistence in the spleen, whilst adoptive transfer approaches revealed for the first time that IL-10+IL-27+ cDCs facilitated the expansion of IL-10 producing Th1 cells in vivo and significantly contributed to the progression of disease.
Taken together, this study reveals a paradoxical capacity for cDCs to suppress effective immune responses during chronic parasitic infection and highlights novel immunoregulatory mechanisms associated with this neglected tropical disease.
Here, we have shown in mice that administration of the broad-spectrum RTKI sunitinib maleate (Sm) blocked the vascular remodeling and progressive splenomegaly associated with experimental visceral leishmaniasis. Furthermore, Sm treatment restored the integrity of the splenic microarchitecture. Although restoration of splenic architecture was accompanied by an increase in the frequency of IFN-γ+CD4+ T cells, Sm treatment alone was insufficient to cause a reduction in tissue parasite burden. However, preconditioning by short-term Sm treatment proved to be successful as an adjunct therapy, increasing the frequency of IFN-γ+ and IFN-γ+TNF+CD4+ T cells, enhancing NO production by splenic macrophages, and providing dose-sparing effects when combined with a first-line immune-dependent anti-leishmanial drug.
We propose, therefore, that RTKIs may prove clinically useful as agents to restore immune competence before the administration of chemo- or immunotherapeutic drugs in the treatment of visceral leishmaniasis or other diseases involving lymphoid tissue remodeling, including cancer.
Safe, cheap and effective adjunct therapies preventing the development of, or reducing the mortality from, severe malaria could have considerable and rapid public health impact. Oral activated charcoal (oAC) is a safe and well tolerated treatment for acute poisoning, more recently shown to have significant immunomodulatory effects in man. In preparation for possible efficacy trials in human malaria, we sought to determine whether oAC would i) reduce mortality due to experimental cerebral malaria (ECM) in mice, ii) modulate immune and inflammatory responses associated with ECM, and iii) affect the pharmacokinetics of parenteral artesunate in human volunteers.
Methods/Principal Findings
We found that oAC provided significant protection against P. berghei ANKA-induced ECM, increasing overall survival time compared to untreated mice (p<0.0001; hazard ratio 16.4; 95% CI 6.73 to 40.1). Protection from ECM by oAC was associated with reduced numbers of splenic TNF+ CD4+ T cells and multifunctional IFNγ+TNF+ CD4+ and CD8+ T cells. Furthermore, we identified a whole blood gene expression signature (68 genes) associated with protection from ECM. To evaluate whether oAC might affect current best available anti-malarial treatment, we conducted a randomized controlled open label trial in 52 human volunteers (ISRCTN NR. 64793756), administering artesunate (AS) in the presence or absence of oAC. We demonstrated that co-administration of oAC was safe and well-tolerated. In the 26 subjects further analyzed, we found no interference with the pharmacokinetics of parenteral AS or its pharmacologically active metabolite dihydroartemisinin.
Conclusions/Significance
oAC protects against ECM in mice, and does not interfere with the pharmacokinetics of parenteral artesunate. If future studies succeed in establishing the efficacy of oAC in human malaria, then the characteristics of being inexpensive, well-tolerated at high doses and requiring no sophisticated storage would make oAC a relevant candidate for adjunct therapy to reduce mortality from severe malaria, or for immediate treatment of suspected severe malaria in a rural setting.
In this study we examined the innate immune capacity of primary human intestinal stromal cells (iSCs). CD90+ iSCs isolated from human colonic mucosa expressed a wide array of innate immune receptors and functionally responded to stimulation with bacterial ligands. iSCs also sensed infection with live Salmonella typhimurium, rapidly expressing IL-1 family cytokines via a RIPK2/p38MAPK-dependent signaling process. In addition to responding to innate immune triggers, primary iSCs exhibited a capacity for bacterial uptake, phagocytosis, and antigen processing, although to a lesser extent than professional APCs.
Thus CD90+ iSCs represent an abundant population of “non-professional” innate immune effector cells of the human colonic mucosa and likely play an important adjunctive role in host defense and immune regulation at this site.
miR-29 expression was upregulated in human dendritic cells (DCs) in response to NOD2 signals, and miR-29 regulated the expression of multiple immune mediators. In particular, miR-29 downregulated interleukin-23 (IL-23) by targeting IL-12p40 directly and IL-23p19 indirectly, likely via reduction of ATF2.
DSS-induced colitis was worse in miR-29-deficient mice and was associated with elevated IL-23 and T helper 17 signature cytokines in the intestinal mucosa. Crohn’s disease (CD) patient DCs expressing NOD2 polymorphisms failed to induce miR-29 upon pattern recognition receptor stimulation and showed enhanced release of IL-12p40 on exposure to adherent invasive E. coli. Therefore, we suggest that loss of miR-29-mediated immunoregulation in CD DCs might contribute to elevated IL-23 in this disease.
Homeostatic lymphoid tissue organogenesis proceeds via exquisitely controlled spatiotemporal interactions between hematopoietic lymphoid tissue inducer populations and multiple subsets of non-hematopoietic stromal cells. However, it is becoming clear that in a range of inflammatory contexts, ectopic or tertiary lymphoid organs (TLOs) can develop inappropriately under pathological stress.
Here we summarise the role of stromal cells in the development of homeostatic lymphoid tissue, and assess emerging evidence that suggests a critical role for stromal involvement in the TLO development associated with chronic infections and inflammation.
Leishmania donovani is an intracellular protozoan parasite of mammalian phagocytes, capable of establishing a persistent and life-threatening infection in man. Associated with profound immunopathology and chronic immune suppression, visceral leishmaniasis is endemic to some of the world’s most resource-poor regions. There is no vaccine and current therapeutic options are limited by parasite resistance, high toxicity and prohibitive costs. As such, a deeper understanding of the immunological mechanisms underlying this disease is critical for the development of effective novel interventions.
Phenotypic and functional analysis of CD11chi conventional dendritic cell subsets (cDCs) revealed widespread alterations as a result of chronic infection in the murine spleen. cDCs displayed a limited capacity for costimulatory molecule expression and pro-inflammatory cytokine production ex vivo. Instead, the preferential production of the immunoregulatory cytokines IL-10 and IL-27 led to the establishment of an auto- regulatory cytokine cascade, modulating cDC function and limiting their capacity to direct effector T cell polarisation in vitro.
2
Conditional in vivo ablation of CD11c+ cells during chronic infection suggested a key role for DCs in the maintenance of pathology and parasite persistence in the spleen, whilst adoptive transfer approaches revealed for the first time that IL-10+IL-27+ cDCs facilitated the expansion of IL-10 producing Th1 cells in vivo and significantly contributed to the progression of disease.
Taken together, this study reveals a paradoxical capacity for cDCs to suppress effective immune responses during chronic parasitic infection and highlights novel immunoregulatory mechanisms associated with this neglected tropical disease.
Here, we have shown in mice that administration of the broad-spectrum RTKI sunitinib maleate (Sm) blocked the vascular remodeling and progressive splenomegaly associated with experimental visceral leishmaniasis. Furthermore, Sm treatment restored the integrity of the splenic microarchitecture. Although restoration of splenic architecture was accompanied by an increase in the frequency of IFN-γ+CD4+ T cells, Sm treatment alone was insufficient to cause a reduction in tissue parasite burden. However, preconditioning by short-term Sm treatment proved to be successful as an adjunct therapy, increasing the frequency of IFN-γ+ and IFN-γ+TNF+CD4+ T cells, enhancing NO production by splenic macrophages, and providing dose-sparing effects when combined with a first-line immune-dependent anti-leishmanial drug.
We propose, therefore, that RTKIs may prove clinically useful as agents to restore immune competence before the administration of chemo- or immunotherapeutic drugs in the treatment of visceral leishmaniasis or other diseases involving lymphoid tissue remodeling, including cancer.
Safe, cheap and effective adjunct therapies preventing the development of, or reducing the mortality from, severe malaria could have considerable and rapid public health impact. Oral activated charcoal (oAC) is a safe and well tolerated treatment for acute poisoning, more recently shown to have significant immunomodulatory effects in man. In preparation for possible efficacy trials in human malaria, we sought to determine whether oAC would i) reduce mortality due to experimental cerebral malaria (ECM) in mice, ii) modulate immune and inflammatory responses associated with ECM, and iii) affect the pharmacokinetics of parenteral artesunate in human volunteers.
Methods/Principal Findings
We found that oAC provided significant protection against P. berghei ANKA-induced ECM, increasing overall survival time compared to untreated mice (p<0.0001; hazard ratio 16.4; 95% CI 6.73 to 40.1). Protection from ECM by oAC was associated with reduced numbers of splenic TNF+ CD4+ T cells and multifunctional IFNγ+TNF+ CD4+ and CD8+ T cells. Furthermore, we identified a whole blood gene expression signature (68 genes) associated with protection from ECM. To evaluate whether oAC might affect current best available anti-malarial treatment, we conducted a randomized controlled open label trial in 52 human volunteers (ISRCTN NR. 64793756), administering artesunate (AS) in the presence or absence of oAC. We demonstrated that co-administration of oAC was safe and well-tolerated. In the 26 subjects further analyzed, we found no interference with the pharmacokinetics of parenteral AS or its pharmacologically active metabolite dihydroartemisinin.
Conclusions/Significance
oAC protects against ECM in mice, and does not interfere with the pharmacokinetics of parenteral artesunate. If future studies succeed in establishing the efficacy of oAC in human malaria, then the characteristics of being inexpensive, well-tolerated at high doses and requiring no sophisticated storage would make oAC a relevant candidate for adjunct therapy to reduce mortality from severe malaria, or for immediate treatment of suspected severe malaria in a rural setting.