Bernard P Mahon
Research interests
-
InterestsMesenchymal Stem Cells, Regenerative Medicine, Bordetella pertussis, Cellular Immunology, Immunomodulation, Regulatory T Cell, Vaccine
Publications
-
5.18Impact points
Mesenchymal stem cell inhibition of T-helper 17 cell- differentiation is triggered by cell-cell contact and mediated by prostaglandin E2 via the EP4 receptor.
European journal of immunology. 06/2011; 41(10):2840-51.
Mesenchymal stem cells (MSCs) inhibit T-cell activation and proliferation but their effects on individual T-cell-effector pathways and on memory versus naïve T cells remain unclear. MSC influence on the differentiation of naïve and memory CD4(+) T cells toward the Th17 phenotype was examined. CD4(+)... [more] Mesenchymal stem cells (MSCs) inhibit T-cell activation and proliferation but their effects on individual T-cell-effector pathways and on memory versus naïve T cells remain unclear. MSC influence on the differentiation of naïve and memory CD4(+) T cells toward the Th17 phenotype was examined. CD4(+) T cells exposed to Th17-skewing conditions exhibited reduced CD25 and IL-17A expression following MSC co-culture. Inhibition of IL-17A production persisted upon re-stimulation in the absence of MSCs. These effects were attenuated when cell-cell contact was prevented. Th17 cultures from highly purified naïve- and memory-phenotype responders were similarly inhibited. Th17 inhibition by MSCs was reversed by indomethacin and a selective COX-2 inhibitor. Media from MSC/Th17 co-cultures contained increased prostaglandin E2 (PGE2) levels and potently suppressed Th17 differentiation in fresh cultures. MSC-mediated Th17 inhibition was reversed by a selective EP4 antagonist and was mimicked by synthetic PGE2 and a selective EP4 agonist. Activation-induced IL-17A secretion by naturally occurring, effector-memory Th17 cells from a urinary obstruction model was also inhibited by MSC co-culture in a COX-dependent manner. Overall, MSCs potently inhibit Th17 differentiation from naïve and memory T-cell precursors and inhibit naturally-occurring Th17 cells derived from a site of inflammation. Suppression entails cell-contact-dependent COX-2 induction resulting in direct Th17 inhibition by PGE2 via EP4.
-
2.94Impact points
Allogeneic mesenchymal stem cells: agents of immune modulation.
Journal of cellular biochemistry. 03/2011; 112(8):1963-8.
Adult mesenchymal stem cells possess a remarkably diverse array of immunosuppressive characteristics. The capacity to suppress the regular processes of allogeneic rejection, have allowed the use of tissue mismatched cells as therapeutic approaches in regenerative medicine and as agents of immune dev... [more] Adult mesenchymal stem cells possess a remarkably diverse array of immunosuppressive characteristics. The capacity to suppress the regular processes of allogeneic rejection, have allowed the use of tissue mismatched cells as therapeutic approaches in regenerative medicine and as agents of immune deviation. This review describes recent advances in understanding the mechanistic basis of mesenchymal stromal or stem cells (MSC) interaction with innate immunity. Particular emphasis is placed on the effect of Toll-like receptor signalling on MSC and a hypothesis that innate immune signals induce a 'licensing switch' in MSC is put forward. The mechanisms underlying MSC suppression of T cell responses and induction of regulatory populations are surveyed. Conflicting data regarding the influence of MSC on B cell function are outlined and discussed. Finally the limits to MSC mediated immune modulation are discussed with reference to the future clinical application of novel cell therapies.
-
2.54Impact points
IL-17A induces CCL28, supporting the chemotaxis of IgE-secreting B cells.
International archives of allergy and immunology. 03/2011; 156(1):51-61.
Atopic asthma is an allergic disease typically associated with T(H)2 cytokines. IL-17A is also associated with asthma, through the induction of chemokines. Mucosal CCL28 concentrations correlate with cellular recruitment to inflamed airways and support migration of IgA(+) B cells. Here, a link betwe... [more] Atopic asthma is an allergic disease typically associated with T(H)2 cytokines. IL-17A is also associated with asthma, through the induction of chemokines. Mucosal CCL28 concentrations correlate with cellular recruitment to inflamed airways and support migration of IgA(+) B cells. Here, a link between IL-17A, CCL28 and IgE-secreting B cell chemotaxis is examined. Primary human airway cells and the airway epithelial line A549 were used to characterize IL-17A receptor expression and the effect of IL-17A on CCL28 transcription and translation. B cells, differentiated to IgE+ cells ex vivo, were assessed for CCR10 surface expression and chemotaxis to CCL28 by flow cytometry, transwell migration and ELISpot. Human airway epithelium expressed both IL-17RA and IL-17RC, and was responsive to IL-17A stimulation. Cultured human IgE+ B cells expressed surface CCR10 and displayed CCR10-dependent chemotaxis towards recombinant CCL28. Enhanced levels of CCL28 were observed upon A549 cell incubation with IL-17A, and this up-regulation significantly increased the migration of IgE+ antibody-secreting B cells. The specificity of chemotaxis was confirmed by migration blockade in the presence of anti-CCL28 or anti-CCR10. This work identifies a novel chemokine for the migration of IgE+ B cells, in addition to characterizing induction of CCL28 by IL-17A. Taken together the results presented here propose a new role for IL-17A in the allergic airways, linking this cytokine with the recruitment of IgE+ antibody-secreting B cells, via the induction of CCL28. These observations justify further in vivo studies of larger cohorts.
-
2.37Impact points
A live, attenuated Bordetella pertussis vaccine provides long-term protection against virulent challenge in a murine model.
Clinical and vaccine immunology : CVI. 02/2011; 18(2):187-93.
Despite successful mass vaccination programs, whooping cough remains a significant cause of neonatal mortality. Immunity induced by current vaccines wanes in adolescence, requiring additional immunizations to prevent resurgence. There is a need for a new generation of vaccines capable of conferring ... [more] Despite successful mass vaccination programs, whooping cough remains a significant cause of neonatal mortality. Immunity induced by current vaccines wanes in adolescence, requiring additional immunizations to prevent resurgence. There is a need for a new generation of vaccines capable of conferring long-lasting immunity from birth. Recently, a live, attenuated whooping cough vaccine, BPZE1, has been developed. Here, an established murine immunization model was used to examine the induction and longevity of immunological memory. In this predictive model, BPZE1 conferred a level of protection against virulent bacterial challenge comparable to that conferred by recovery from prior infection, up to 1 year after immunization. One year after immunization with BPZE1, a pertussis-specific persistent response, with high levels of gamma interferon (IFN-γ), could be detected from spleen cells restimulated with inactivated Bordetella pertussis. BPZE1 induced low levels of interleukin-17 (IL-17) and no IL-10 or IL-5. BPZE1 immunization induced long-lasting, efficacious memory B-cell and specific antibody responses dominated by IgG2a, which were boosted by subsequent challenge. Finally, the antibody induced by BPZE1 was functionally relevant and could clear a virulent B. pertussis infection in antibody-deficient mice following passive transfer. This study suggests that BPZE1 is capable of conferring a high level of long-lived effective protection against virulent B. pertussis.
-
4.20Impact points
Immunological aspects of allogeneic mesenchymal stem cell therapies.
Human gene therapy. 12/2010; 21(12):1641-55.
Allogeneic mesenchymal stem or stromal cells (MSCs) are proposed as cell therapies for degenerative, inflammatory, and autoimmune diseases. The feasibility of allogeneic MSC therapies rests heavily on the concept that these cells avoid or actively suppress the immunological responses that cause reje... [more] Allogeneic mesenchymal stem or stromal cells (MSCs) are proposed as cell therapies for degenerative, inflammatory, and autoimmune diseases. The feasibility of allogeneic MSC therapies rests heavily on the concept that these cells avoid or actively suppress the immunological responses that cause rejection of most allogeneic cells and tissues. In this article the validity of the immune privileged status of allogeneic MSCs is explored in the context of recent literature. Current data that provide the mechanistic basis for immune modulation by MSCs are reviewed with particular attention to how MSCs modify the triggering and effector functions of innate and adaptive immunity. The ability of MSCs to induce regulatory dendritic and T-cell populations is discussed with regard to cell therapy for autoimmune disease. Finally, we examine the evidence for and against the immune privileged status of allogeneic MSCs in vivo. Allogeneic MSCs emerge as cells that are responsive to local signals and exert wide-ranging, predominantly suppressive, effects on innate and adaptive immunity. Nonetheless, these cells also retain a degree of immunogenicity in some circumstances that may limit MSC longevity and attenuate their beneficial effects. Ultimately successful allogeneic cell therapies will rely on an improved understanding of the parameters of MSC-immune system interactions in vivo.
-
6.38Impact points
Allogeneic mesenchymal stem cells prevent allergic airway inflammation by inducing murine regulatory T cells.
Allergy. 11/2010; 66(4):523-31.
Adult bone marrow-derived mesenchymal stem cells (MSC) possess potent immune modulatory effects which support their possible use as a therapy for immune-mediated disease. MSC induce regulatory T cells (T(reg)) in vitro although the in vivo relevance of this is not clear. This study addressed the hyp... [more] Adult bone marrow-derived mesenchymal stem cells (MSC) possess potent immune modulatory effects which support their possible use as a therapy for immune-mediated disease. MSC induce regulatory T cells (T(reg)) in vitro although the in vivo relevance of this is not clear. This study addressed the hypothesis that adult bone marrow derived-MSC would prevent the pathology associated with allergen-driven airway inflammation, and sought to define the effector mechanism. The influence of allogeneic MSC was examined in a model system where T(reg) induction is essential to prevent pathology. This was tested using a combination of a model of ovalbumin-driven inflammation with allogeneic MSC cell therapy. Systemic administration of allogeneic MSC protected the airways from allergen-induced pathology, reducing airway inflammation and allergen-specific IgE. MSC were not globally suppressive but induced CD4(+) FoxP3(+) T cells and modulated cell-mediated responses at a local and systemic level, decreasing IL-4 but increasing IL-10 in bronchial fluid and from allergen re-stimulated splenocytes. Moderate dose cyclophosphamide protocols were used to differentially ablate T(reg) responses; under these conditions the major beneficial effect of MSC therapy was lost, suggesting induction of T(reg) as the key mechanism of action by MSC in this model. In spite of the elimination of T(reg) , a significant reduction in airway eosinophilia persisted in those treated with MSC. These data demonstrate that MSC induce T(reg) in vivo and reduce allergen-driven pathology. Multiple T(reg) dependent and independent mechanisms of therapeutic action are employed by MSC.
-
4.08Impact points
Attenuated Bordetella pertussis vaccine strain BPZE1 modulates allergen-induced immunity and prevents allergic pulmonary pathology in a murine model.
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 02/2010; 40(6):933-41.
Virulent Bordetella pertussis, the causative agent of whooping cough, exacerbates allergic airway inflammation in a murine model of ovalbumin (OVA) sensitization. A live genetically attenuated B. pertussis mucosal vaccine, BPZE1, has been developed that evokes full protection against virulent challe... [more] Virulent Bordetella pertussis, the causative agent of whooping cough, exacerbates allergic airway inflammation in a murine model of ovalbumin (OVA) sensitization. A live genetically attenuated B. pertussis mucosal vaccine, BPZE1, has been developed that evokes full protection against virulent challenge in mice but the effect of this attenuated strain on the development of allergic responses is unknown. To assess the influence of attenuated B. pertussis BPZE1 on OVA priming in a murine model of allergic airway inflammation. Mice were challenged with virulent or attenuated strains of B. pertussis, and sensitized to allergen (OVA) at the peak of bacterial carriage. Subsequently, airway pathology, local inflammation and OVA-specific immunity were examined. In contrast to virulent B. pertussis, live BPZE1 did not exacerbate but reduced the airway pathology associated with allergen sensitization. BPZE1 immunization before allergen sensitization did not have an adjuvant effect on allergen specific IgE but resulted in a statistically significant decrease in airway inflammation in tissue and bronchoalveolar lavage fluid. BPZE1 significantly reduced the levels of OVA-driven IL-4, IL-5 and IL-13 but induced a significant increase in IFN-gamma in response to OVA re-stimulation. These data demonstrate that, unlike virulent strains, the candidate attenuated B. pertussis vaccine BPZE1 does not exacerbate allergen-driven airway pathology. BPZE1 may represent an attractive T-helper type 1 promoting vaccine candidate for eradication of whooping cough that is unlikely to promote atopic disease.
-
0.62Impact points
Zinc and silver glass polyalkenoate cements: an evaluation of their antibacterial nature.
Bio-medical materials and engineering. 01/2010; 20(2):99-106.
A biofilm is an accumulation of micro-organisms and their extracellular products forming a structured community on a surface. Biofilm formation on medical devices has severe health consequences as bacteria growing in this lifestyle are tolerant to both host defence mechanisms and antibiotic therapie... [more] A biofilm is an accumulation of micro-organisms and their extracellular products forming a structured community on a surface. Biofilm formation on medical devices has severe health consequences as bacteria growing in this lifestyle are tolerant to both host defence mechanisms and antibiotic therapies. However, silver and zinc ions inhibit the attachment and proliferation of immature biofilms. The objective of this study is to evaluate whether silver and zinc ions eluted from novel glass polyalkenoate cement (GPC) coatings have the ability to inhibit Methicillin-resistant Staphylococcus aureus (MRSA) in vivo. A silver and zinc-containing GPC coating was synthesised, deposited onto Ti6Al4V discs and placed in a specified amount of analytical water for 1, 7 and 30 days. The resulting elutes were collected and Atomic absorption spectroscopy was used to measure ion release. The elutes were injected into Galleria mellonella larvae infected with MRSA and the antibacterial properties of these elutes were evaluated in vivo. The majority of the zinc and silver ions were released within the first 24 h; this corresponded with the greatest degree of protection observed in infected larvae. Results were compared to a conventional in vitro model where identical elutes were incubated with MRSA on nutrient agar. These results were consistent with those observed in the larval model, demonstrating a reduction in bacterial viability when co-cultured with elutes for 2 h. This work confirms the promise of the Galleria mellonella as a model for the assessment of antimicrobial agents and demonstrates the capacity of novel silver and zinc-containing GPCs to retard the colonisation of MRSA.
-
3.26Impact points
AAV-2 induces cell mediated immune responses directed against multiple epitopes of the capsid protein VP1.
The Journal of general virology. 08/2009;
Adeno-associated virus serotype 2 (AAV-2) has been developed as a gene therapy vector. Antibody and cell-mediated immune responses to AAV-2 or AAV-2 transfected cells may confound the therapeutic use of such vectors in the clinic. In the most detailed examination of AAV-2 immunity in humans to date,... [more] Adeno-associated virus serotype 2 (AAV-2) has been developed as a gene therapy vector. Antibody and cell-mediated immune responses to AAV-2 or AAV-2 transfected cells may confound the therapeutic use of such vectors in the clinic. In the most detailed examination of AAV-2 immunity in humans to date, cell mediated and humoral immune responses to AAV-2 were characterised in a panel of healthy blood donors. The extent of AAV-2 specific antibody in humans was determined by examination of circulating AAV-2 specific total IgG levels in plasma from 45 normal donors. 41 donors were seropositive and the responses were dominated by IgG1 and IgG2 subclasses. Conversely, AAV-2 specific IgG3 levels were consistently low in all donors, suggesting evasion of complement activation by AAV-2. The virus induced a cell mediated recall response in nearly half of the population sampled. In vitro re-stimulation with AAV-2 of peripheral blood mononuclear cell (PBMC) cultures from 16 donors elicited gamma interferon (IFN-gamma) (10 donors), interleukin-10 (IL-10) (8 donors) and interleukin-13 (IL-13) (4 donors). Using a series of overlapping peptides derived from the sequence of the VP1 viral capsid protein, a total of 59 candidate T cell epitopes were identified. HLA characterisation of donors revealed that the population studied included diverse haplotypes, but that at least 16 epitopes were recognised by multiple donors and could be regarded as immunodominant. These data indicate that robust immunological memory is established to AAV-2 and the diversity of sequences recognised is likely to render standard modification of the AAV-2 capsid unfeasible.
-
2.37Impact points
A live attenuated Bordetella pertussis candidate vaccine does not cause disseminating infection in IFN-{gamma} receptor knockout mice.
Clinical and vaccine immunology : CVI. 08/2009;
Bordetella pertussis, is the cause of whooping cough and responsible for 300,000 infant deaths per annum. Current vaccines require six months to confer optimal immunity to infants, the population at highest risk. Recently, an attenuated strain of B. pertussis (BPZE1) has been developed to be used as... [more] Bordetella pertussis, is the cause of whooping cough and responsible for 300,000 infant deaths per annum. Current vaccines require six months to confer optimal immunity to infants, the population at highest risk. Recently, an attenuated strain of B. pertussis (BPZE1) has been developed to be used as a low-cost, live, intra-nasal, single-dose vaccine for newborns. Pre-clinical proof of concept has been established, however, it is necessary to evaluate the safety of BPZE1, especially in immunodeficient models, prior to human clinical trials. Here, the preclinical safety of BPZE1 was examined in well characterized murine models. Immunocompetent and IFN-gamma receptor knockout mice were challenged by aerosol with either virulent B. pertussis or BPZE1. Both strains colonised the lung at equal levels, but inflammation was only associated with carriage of virulent bacteria. Virulent bacteria disseminated to the liver of IFN-gammaR deficient mice, resulting in atypical pathology. In contrast, attenuated BPZE1 did not disseminate in either immunocompetent or immunodeficient mice and did not induce atypical pathology. In neonatal challenge models, virulent B. pertussis infection resulted in significant mortality of both immunodeficient and immunocompetent mice, whereas no mortality was observed for any neonatal mice challenged with BPZE1. BPZE1 was shown to elicit strong IFN-gamma responses in mice, equivalent to virulent BPSM, also inducing IgG2a, a process requiring Th1 cytokines in mice. These data indicate that a live attenuated whooping cough vaccine candidate shows no signs of disseminating infection in preclinical models but rather evokes an immunological profile associated with optimal protection against disease.
-
3.01Impact points
Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4(+)CD25(High)forkhead box P3(+) regulatory T cells.
Clinical and experimental immunology. 03/2009;
Summary Adult human mesenchymal stromal or stem cells (MSC) can differentiate into a variety of cell types and are candidate cellular therapeutics in regenerative medicine. Surprisingly, these cells also display multiple potent immunomodulatory capabilities, including allosuppression, making allogen... [more] Summary Adult human mesenchymal stromal or stem cells (MSC) can differentiate into a variety of cell types and are candidate cellular therapeutics in regenerative medicine. Surprisingly, these cells also display multiple potent immunomodulatory capabilities, including allosuppression, making allogeneic cell therapy a possibility. The exact mechanisms involved in regulatory T cell induction by allogeneic human MSC was examined, using purified CD4(+) populations and well-characterized bone marrow-derived adult human MSC. Allogeneic MSC were shown to induce forkhead box P3 (FoxP3)(+) and CD25(+) mRNA and protein expression in CD4(+) T cells. This phenomenon required direct contact between MSC and purified T cells, although cell contact was not required for MSC induction of FoxP3 expression in an unseparated mononuclear cell population. In addition, through use of antagonists and neutralizing antibodies, MSC-derived prostaglandins and transforming growth factor (TGF)-beta1 were shown to have a non-redundant role in the induction of CD4(+)CD25(+)FoxP3(+) T cells. Purified CD4(+)CD25(+) T cells induced by MSC co-culture expressed TGF-beta1 and were able to suppress alloantigen-driven proliferative responses in mixed lymphocyte reaction. These data clarify the mechanisms of human MSC-mediated allosuppression, supporting a sequential process of regulatory T cell induction involving direct MSC contact with CD4(+) cells followed by both prostaglandin E(2) and TGF-beta1 expression. Overall, this study provides a rational basis for ongoing clinical studies involving allogeneic MSC.
-
2.87Impact points
A possible role for protein synthesis, extracellular signal-regulated kinase, and brain-derived neurotrophic factor in long-term spatial memory retention in the water maze.
Behavioral neuroscience. 08/2008; 122(4):805-15.
Hippocampal protein synthesis is dependent upon a number of different molecular and cellular mechanisms that act together to make previously labile memories more stable and resistant to disruption. Both brain-derived neurotrophic factor (BDNF) and extracellular signal-regulated kinase (ERK) are know... [more] Hippocampal protein synthesis is dependent upon a number of different molecular and cellular mechanisms that act together to make previously labile memories more stable and resistant to disruption. Both brain-derived neurotrophic factor (BDNF) and extracellular signal-regulated kinase (ERK) are known to play an important role in protein synthesis-dependent memory consolidation, via the mitogen-activated protein-kinase (MAP-K) signaling pathway during the transcription phase of protein synthesis. The current study investigates the influence of protein synthesis inhibition (PSI) by cycloheximide on spatial learning and memory. In an initial experiment, the authors utilized two doses of cycloheximide (0.5 mg/kg and 1.0 mg/kg, intraperitoneally) to determine the dose at which long-term (>24 hours) memories are impaired. A second experiment was designed to investigate the effect of PSI on the formation of cue-platform associations in the watermaze, and on BDNF and ERK expression in the hippocampus. At the higher dose (1.0 mg/kg) cycloheximide resulted in impaired retention of the water maze. BDNF and ERK expression was also down-regulated in animals injected with this dose of cycloheximide. Our results demonstrate a role of protein synthesis in spatial memory retention, along with a possible relationship between protein synthesis and hippocampal BDNF/ERK expression.
-
2.47Impact points
BMP4 induces an epithelial-mesenchymal transition-like response in adult airway epithelial cells.
Growth factors (Chur, Switzerland). 03/2008; 26(1):12-22.
Bone morphogenetic proteins (BMPs) are critical morphogens and play key roles in epithelial-mesenchymal transitions (EMTs) during embryogenesis. BMP4 is required for early mesoderm formation and also regulates morphogenesis and epithelial cell differentiation in developing lungs. While, BMP signalli... [more] Bone morphogenetic proteins (BMPs) are critical morphogens and play key roles in epithelial-mesenchymal transitions (EMTs) during embryogenesis. BMP4 is required for early mesoderm formation and also regulates morphogenesis and epithelial cell differentiation in developing lungs. While, BMP signalling pathways are activated during lung inflammation in adult mice, the role of BMPs in adult lungs remains unclear. We hypothesised that BMPs are involved in remodelling processes in adult lungs and investigated effects of BMP4 on airway epithelial cells. BEAS-2B cell growth decreased in the presence of BMP4. Cells acquired a mesenchymal-like morphology with downregulation of adherens junction proteins and increased cell motility. Changes in extracellular matrix-related gene expression occurred with BMP4 treatment including upregulation of collagens, fibronectin and tenascin C. We conclude that the activity of BMP4 in EMT during development is recapitulated in adult airway epithelial cells and suggest that this activity may contribute to inflammation and fibrosis in vivo.
-
2.91Impact points
Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation.
Immunology letters. 02/2008; 115(1):50-8.
Mesenchymal stem cells (MSC) possess a wide range of immunosuppressive functions. Among these is the ability to inhibit CD4+ T cell proliferation. Dendritic cells (DC) play a role in initiating cell-mediated immunity; however, the immunosuppressive influence of MSC on professional antigen presenting... [more] Mesenchymal stem cells (MSC) possess a wide range of immunosuppressive functions. Among these is the ability to inhibit CD4+ T cell proliferation. Dendritic cells (DC) play a role in initiating cell-mediated immunity; however, the immunosuppressive influence of MSC on professional antigen presenting cells remains unclear. DC exposed to TNF-alpha and cultured with murine MSC failed to show regular upregulation of maturation markers. Similarly, the presence of MSC abrogated the capacity of ovalbumin-pulsed DC to support antigen specific CD4+ T cell proliferation, or for DC to display an MHC class II- peptide complex recognizable by specific antibody. Interestingly, culture of MSC with DC resulted in reduced expression of CCR7 by DC following stimulation. Likewise, DC matured in the presence of MSC, showed significantly less migration to CCL19. In contrast, murine MSC prevented loss of expression of the tissue anchoring protein E-cadherin by DC. Modulation of DC maturation and function was not permanent and could be restored after removal of MSC. These data demonstrate that MSC modulate the three cardinal features of DC maturation, providing the first demonstration of MSC interference with DC migration.
-
3.01Impact points
Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells.
Clinical and experimental immunology. 09/2007; 149(2):353-63.
The ability of mesenchymal stem cells (MSC) to suppress alloresponsiveness is poorly understood. Herein, an allogeneic mixed lymphocyte response was used as a model to investigate the mechanisms of MSC-mediated immunomodulation. Human MSC are demonstrated to express the immunosuppressive cytokines h... [more] The ability of mesenchymal stem cells (MSC) to suppress alloresponsiveness is poorly understood. Herein, an allogeneic mixed lymphocyte response was used as a model to investigate the mechanisms of MSC-mediated immunomodulation. Human MSC are demonstrated to express the immunosuppressive cytokines hepatocyte growth factor (HGF), interleukin (IL)-10 and transforming growth factor (TGF)-beta1 at concentrations that suppress alloresponses in vitro. MSC also express cyclooxygenase 1 and 2 and produce prostaglandin E2 constitutively. Blocking studies with indomethacin confirmed that prostaglandins contribute to MSC-mediated allosuppression. The proinflammatory cytokine interferon (IFN)-gamma did not ablate MSC inhibition of alloantigen-driven proliferation but up-regulated HGF and TGF-beta1. IFN-gamma also induced expression of indoleamine 2,3, dioxygenase (IDO), involved in tryptophan catabolism. Use of an antagonist, 1-methyl-L-tryptophan, restored alloresponsiveness and confirmed an IDO contribution to IFN-gamma-induced immunomodulation by MSC. Addition of the tryptophan catabolite kynurenine to mixed lymphocyte reactions (MLR), blocked alloproliferation. These findings support a model where IDO exerts its effect through the local accumulation of tryptophan metabolites rather than through tryptophan depletion. Taken together, these data demonstrate that soluble factors, or products derived from MSC, modulate immune responses and suggest that MSC create an immunosuppressive microenvironment capable of modulating alloresponsiveness even in the presence of IFN-gamma.
-
2.91Impact points
IFN-gamma and TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells.
Immunology letters. 07/2007; 110(2):91-100.
Murine mesenchymal stem cells (MSC) have the ability to inhibit allogeneic immune responses. Two different mechanisms, either cell contact-dependent or independent, have been proposed to account for this immunosuppression. The focus of this study was to elucidate the involvement of soluble suppressi... [more] Murine mesenchymal stem cells (MSC) have the ability to inhibit allogeneic immune responses. Two different mechanisms, either cell contact-dependent or independent, have been proposed to account for this immunosuppression. The focus of this study was to elucidate the involvement of soluble suppressive factors secreted by murine MSC in an inflammatory setting, and their role in MSC immunomodulation. In a non-inflammatory environment, bone marrow derived murine MSC constitutively expressed low levels of COX-2, PGE-2, TGF-beta1 and HGF, but not IL-10, PD-1, PD-L1 or PD-L2. These MSC were able to significantly reduce alloantigen driven proliferation in mixed lymphocyte reactions as well as mitogen driven proliferation. The pro-inflammatory cytokines IFN-gamma and TNF-alpha did not ablate MSC mediated immunosuppression. MSC expression of PGE-2, IDO and PD-L1 was differentially regulated by these cytokines. COX-2 and PGE-2 expression by MSC were upregulated by both IFN-gamma and TNF-alpha, and using a biochemical inhibitor this was shown to have an essential, non-redundant role in modulating alloantigen-driven proliferation. However, the surface expression of PD-L1 was induced by IFN-gamma but not TNF-alpha and similarly functional IDO expression was only induced by IFN-gamma stimulation. Blocking studies using neutralising antibodies and biochemical antagonists revealed that while PD-L1 induction was not essential, IDO expression was a prerequisite for IFN-gamma mediated MSC immunomodulation. These data demonstrate that murine MSC expression of immunomodulatory factors dramatically changes in a pro-inflammatory environment and that IFN-gamma in particular has an important role in regulating MSC immunomodulatory factor expression.
-
4.21Impact points
gammadelta T cells regulate the early inflammatory response to bordetella pertussis infection in the murine respiratory tract.
Infection and immunity. 04/2006; 74(3):1837-45.
The role of gammadelta T cells in the regulation of pulmonary inflammation following Bordetella pertussis infection was investigated. Using a well-characterized murine aerosol challenge model, inflammatory events in mice with targeted disruption of the T-cell receptor delta-chain gene (gammadelta TC... [more] The role of gammadelta T cells in the regulation of pulmonary inflammation following Bordetella pertussis infection was investigated. Using a well-characterized murine aerosol challenge model, inflammatory events in mice with targeted disruption of the T-cell receptor delta-chain gene (gammadelta TCR-/- mice) were compared with those in wild-type animals. Early following challenge with B. pertussis, gammadelta TCR-/- mice exhibited greater pulmonary inflammation, as measured by intra-alveolar albumin leakage and lesion histomorphometry, yet had lower contemporaneous bacterial lung loads. The larger numbers of neutrophils and macrophages and the greater concentration of the neutrophil marker myeloperoxidase in bronchoalveolar lavage fluid from gammadelta TCR-/- mice at this time suggested that differences in lung injury were mediated through increased leukocyte trafficking into infected alveoli. Furthermore, flow cytometric analysis found the pattern of recruitment of natural killer (NK) and NK receptor+ T cells into airspaces differed between the two mouse types over the same time period. Taken together, these findings suggest a regulatory influence for gammadelta T cells over the early pulmonary inflammatory response to bacterial infection. The absence of gammadelta T cells also influenced the subsequent adaptive immune response to specific bacterial components, as evidenced by a shift from a Th1 to a Th2 type response against the B. pertussis virulence factor filamentous hemagglutinin in gammadelta TCR-/- mice. The findings are relevant to the study of conditions such as neonatal B. pertussis infection and acute respiratory distress syndrome where gammadelta T cell dysfunction has been implicated in the inflammatory process.
-
2.91Impact points
Inflammation of the respiratory tract is associated with CCL28 and CCR10 expression in a murine model of allergic asthma.
Immunology letters. 04/2006; 103(2):92-100.
Mouse models and in vitro cell culture were used to examine airway expression of the mucosal chemokine CCL28. Low levels of constitutively expressed mRNA were observed in transformed murine epithelial cells, but high levels could be induced by stimulation. Cytokines that signal through NF-kappaB, in... [more] Mouse models and in vitro cell culture were used to examine airway expression of the mucosal chemokine CCL28. Low levels of constitutively expressed mRNA were observed in transformed murine epithelial cells, but high levels could be induced by stimulation. Cytokines that signal through NF-kappaB, including IL-1beta and TNF-alpha or via JAK-STAT pathway including oncostatin M induced CCL28 in airway epithelial cells in vitro. Immunohistochemistry of murine airway tissue revealed that constitutive expression of CCL28 protein in vivo was low and not ubiquitous. However, abundant expression was detected in epithelia and lymphoid aggregates following allergic sensitization and challenge with ovalbumin. This was accompanied by increased detection of cells expressing CCR10 protein and mRNA in inflamed airways. Taken together, these data support a role for CCL28 in contributing to allergen driven airway pathologies, show that proinflammatory cytokines can induce this signal and suggest a role for CCR10 expressing cells in airway inflammation.
-
2.70Impact points
IL-1beta and TNF-alpha induce increased expression of CCL28 by airway epithelial cells via an NFkappaB-dependent pathway.
Cellular immunology. 01/2006; 238(2):87-96.
CCL28 is a mucosal chemokine that attracts eosinophils and T cells via the receptors CCR3 and CCR10. Consequently, it is a candidate mediator of the pathology associated with asthma. This study examined constitutive and induced expression of CCL28 by A549 human airway epithelial-like cells. Real-tim... [more] CCL28 is a mucosal chemokine that attracts eosinophils and T cells via the receptors CCR3 and CCR10. Consequently, it is a candidate mediator of the pathology associated with asthma. This study examined constitutive and induced expression of CCL28 by A549 human airway epithelial-like cells. Real-time RT-PCR and ELISA of cultured cells and supernatants revealed constitutive levels of CCL28 expression to be low, whereas IL-1beta and TNF-alpha, induced significantly increased expression. Observations from induced sputum and human airway biopsies supported this. Signal transduction studies revealed that IL-1beta and TNF-alpha stimulation induced NFkappaB phosphorylation in A549 cells, but antagonist inhibition of NFkappaB p50-p65 phosphorylation correlated with marked reduction of IL-1beta or TNF-alpha induced CCL28 expression. Together these studies imply a role for CCL28 in the orchestration of airway inflammation, and suggest that CCL28 is one link between microbial insult and the exacerbation of pathologies such as asthma, through an NFkappaB-dependent mechanism.
-
3.26Impact points
Novel mechanism of immunosuppression by influenza virus haemagglutinin: selective suppression of interleukin 12 p35 transcription in murine bone marrow-derived dendritic cells.
The Journal of general virology. 08/2005; 86(Pt 7):1885-90.
Infection with influenza virus strongly predisposes an individual to bacterial superinfection, which is often the significant cause of morbidity and mortality during influenza epidemics. Little is known about the immunomodulating properties of the virus that lead to this phenomenon, but the effect o... [more] Infection with influenza virus strongly predisposes an individual to bacterial superinfection, which is often the significant cause of morbidity and mortality during influenza epidemics. Little is known about the immunomodulating properties of the virus that lead to this phenomenon, but the effect of the viral components on the development of immune dendritic cells (DCs) may prove vital. In this study, activation of and cytokine secretion by bacterial lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells (BMDCs) following treatment with the influenza virus major antigen haemagglutinin (HA) were examined. HA selectively inhibits the release of LPS-induced interleukin 12 (IL12) p70, which is independent of IL10 secretion. Suppression occurs at the transcriptional level, with selective inhibition of p35- and not p40-subunit mRNA expression. The downregulation of IL12 p70 by influenza HA is a novel and unexplored pathway that may be relevant in the predisposition to bacterial superinfection associated with influenza virus infections.
Following (7)
-
Philip Dix
National University of Ireland, Maynooth -
Noel B Murphy
National University of Ireland, Maynooth -
Elizabeth Ryan
University College Dublin -
Lydia Lynch
Harvard University -
Brian J Sheahan
University College Dublin
