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Introduction
My Current research interests focus on the further understanding of immune modulation mediated by mesenchymal stromal cells (MSC). To address this question, we utilise sophisticated humanised models of inflammatory disease including graft versus host disease and lung inflammation and fibrotic associated diseases. The overall goal is to optimise MSC therapy for the treatment of inflammatory disorders.
Additional affiliations
January 2015 - October 2015
December 2011 - present
April 2009 - December 2011
Publications
Publications (78)
Enhancing mesenchymal stromal cell (MSC) therapeutic efficacy through licensing with proinflammatory cytokines is now well established. We have previously shown that macrophage migration inhibitory factor (MIF)‐licensed MSCs exerted significantly enhanced therapeutic efficacy in reducing inflammation in house dust mite (HDM)‐driven allergic asthma....
High level expression of the pro‐inflammatory cytokine macrophage migration inhibitory factor (MIF) has been associated with severe asthma. The role of MIF and its functional promotor polymorphism in innate immune training is currently unknown. Using novel humanized CATT7 MIF mice, this study is the first to investigate the effect of MIF on bone ma...
Mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (EVs) have emerged as innovative therapeutic agents for the treatment of sepsis and acute respiratory distress syndrome (ARDS). Although their potential remains undisputed in pre-clinical models, this has yet to be translated to the clinic. In this review, we focused on the rol...
Macrophage migration inhibitory factor (MIF) expression is controlled by a functional promoter polymorphism, where the number of tetranucleotide repeats (CATTn) corresponds to the level of MIF expression. To examine the role of this polymorphism in a pre‐clinical model of allergic asthma, novel humanized MIF mice with increasing CATT repeats (CATT5...
Mesenchymal Stromal Cells (MSCs) have attracted attention as a cell-based therapy due to their
immunomodulatory and immunoregulatory properties. MSCs have been investigated in clinical trials for the
treatment of a variety of inflammatory conditions, such as Acute Respiratory Distress Syndrome (ARDS).
Studies have shown that MSCs require activation...
Mesenchymal stromal cell (MSC) therapy has seen increased attention as a possible option to treat a number of inflammatory conditions including COVID-19 acute respiratory distress syndrome (ARDS). As rates of obesity and metabolic disease continue to rise worldwide, increasing proportions of patients treated with MSC therapy will be living with obe...
Fasciola hepatica is a trematode worm that causes fascioliasis, a neglected tropical disease in humans and livestock. To gain insight into the host-parasite interactions that facilitate infection, we have investigated the immunomodulatory properties of the parasite's tegumental coat (FhTeg), a major antigen source that is sloughed off and renewed e...
Mucosal Associated Invariant T cells are a population of innate T cells, which express the invariant T cell receptor (TCR) alpha chain Va7.2 and are capable of robust rapid cytokine secretion, producing a milieu of cytokines including IFN-gamma; and IL-17. MAIT cells have been reported in multiple human tissues including the gut, periphery and skin...
Severe viral pneumonia is a significant cause of morbidity and mortality globally, whether due to outbreaks of endemic viruses, periodic viral epidemics, or the rarer but devastating global viral pandemics. While limited anti-viral therapies exist, there is a paucity of direct therapies to directly attenuate viral pneumonia-induced lung injury, and...
Recent clinical trials of mesenchymal stromal cell (MSC) therapy for various inflammatory conditions have highlighted the significant benefit to patients who respond to MSC administration. Thus, there is strong interest in investigating MSC therapy in acute inflammatory lung conditions, such as acute respiratory distress syndrome (ARDS). Unfortunat...
Cell-based therapy for the treatment of inflammatory disorders has focused on the application of mesenchymal stromal cells (MSCs) and multipotent adult progenitor cells (MAPCs). Despite the recent positive findings in industry-sponsored clinical trials of MSCs and MAPCs for graft vs host disease (GvHD), cell therapy is efficacious in some but not a...
Recent advances in cell based therapies for lung diseases and critical illnesses offer significant promise. Despite encouraging preclinical results, the translation of efficacy to the clinical settings have not been successful. One of the possible reasons for this is the lack of understanding of the complex interaction between mesenchymal stromal c...
Immunosuppressive ability in human MSC donors has been shown to be variable and may be a limiting factor in MSC therapeutic efficacy in vivo. The importance of cytokine activation of mesenchymal stromal cells (MSCs) to facilitate their immunosuppressive function is well established. This study sought to further understand the interactions between M...
Background
Despite increased interest in MSC-based cell therapies for the acute respiratory distress syndrome (ARDS), clinical investigations have not yet been successful and understanding of the potential in vivo mechanisms of MSC actions in ARDS remain limited. ARDS is driven by an acute severe innate immune dysregulation, often characterised by...
Acute graft versus host disease (aGvHD) is an allogeneic T cell mediated disease which manifests as a severe inflammatory disease affecting multiple organs including the liver, skin, lungs and gastrointestinal tract. Existing prophylactic and therapeutic approaches in aGvHD include the use of cyclosporine A (CyA), however the currently approved CyA...
Growing evidence demonstrates that human mesenchymal stromal cells (MSCs) modify their in vivo anti-inflammatory actions depending on the specific inflammatory environment encountered. Understanding this better is crucial to refine MSC-based cell therapies for lung and other diseases. Using acute exacerbations of cystic fibrosis (CF) lung disease a...
Rapid progress is occurring in understanding the mechanisms underlying mesenchymal stromal cell (MSC)-based cell therapies (MSCT). However, the results of clinical trials, while demonstrating safety, have been varied in regard to efficacy. Recent data from different groups have shown profound and significant influences of the host inflammatory envi...
Lymphodepletion strategies are used in the setting of transplantation (including bone marrow, hematopoietic cell, and solid organ) to create space or to prevent allograft rejection and graft versus host disease. Following lymphodepletion, there is an excess of IL-7 available, and T cells that escape depletion respond to this cytokine undergoing acc...
Indomethacin does not impair interferon-γ (IFN-γ) production by T cells following anti-thymocyte globulin (ATG) administration. ATG was administered on days 0 and 3 followed by intraperitoneal (IP) injection of 30 µg Indomethacin (Indo) on days 4, 5, and 6. Spleens were harvested on day 7 and examined for the production of IFN-γ. Indo had no effect...
100 mg/kg anti-thymocyte globulin (ATG) administered intraperitoneal (IP) depletes T cells in vivo. 50 or 100 mg/kg ATG was administered on days 0 and 3 either IP or intravenous (IV). Spleens and lymph nodes were harvested on day 7, and the number of T cells was enumerated by flow cytometry. 100 mg/kg ATG administered IP was the optimal dose and ro...
Multipotent adult progenitor cells (MAPC) suppress IL-7-induced interferon-γ (IFN-γ) production by T cells in vivo. Recombinant IL-7 conjugated to M25 or PBS was administered intraperitoneal (IP) on days 0, 2, and 4. 1 × 106 MAPC were administered IP or intravenous (IV) on day 1. Spleens (A) and lymph nodes (B) were harvested on day 5. Bar graphs d...
Allotransplantation is the most common treatment for end stage kidney, liver, lung, and heart disease. In order to accommodate the allograft, the recipient must be immune-suppressed, to prevent rejection of the graft by the innate and adaptive immune system. Acute rejection has been largely avoided through improved methods of organ procurement, sur...
Mesenchymal stromal cells (MSC) have emerged as promising cell therapies for multiple conditions based on demonstrations of their potent immunomodulatory and regenerative capacities in models of inflammatory disease. Understanding the effects of MSC on T cells has dominated the majority of work carried out in this field to date, however, recently a...
Bone-marrow derived mesenchymal stromal cells (MSCs) have potent immunomodulatory and tissue reparative properties, which may be beneficial in the treatment of inflammatory diseases such as COPD. This study examined the mechanisms by which human MSCs protect against elastase induced emphysema. Using a novel human relevant pre-clinical model of emph...
Purpose of review:
Mesenchymal stromal cells (MSCs) are adult stromal cells with therapeutic potential in allogeneic islet transplantation for type 1 diabetes patients. The process of islet isolation alone has been shown to negatively impact islet survival and function in vivo. In addition, insults mediated by the instant blood-mediated inflammato...
Significance:
The mechanisms used by mesenchymal stromal cells (MSCs) in mediating protective effects in chronic models of lung disease are not understood and remain to be elucidated. These findings from in vitro studies highlight an important role for the MSC-derived soluble factors hepatocyte growth factor (HGF) and prostaglandin E2 in promoting...
Burkholderia cepacia complex (Bcc) causes chronic opportunistic lung infections in people with cystic fibrosis (CF) resulting in a gradual lung
function decline and, ultimately, patient death. Bcc is a complex of eighteen species and is rarely eradicated once a patient
is colonised, therefore vaccination may represent a better therapeutic option. W...
T-cell depletion therapy is used to prevent acute allograft rejection, treat autoimmunity and 'create space' for bone marrow or hematopoietic cell transplantation. The evolved response to T-cell loss is a transient increase in IL-7 that drives compensatory homeostatic proliferation (HP) of mature T cells. Paradoxically, the exaggerated form of this...
The immune suppressive and anti-inflammatory capabilities of bone marrow derived mesenchymal stromal cells represents an innovative new tool in regenerative medicine and immune regulation. The potent immune suppressive ability of MSC over T cells, dendritic cells and natural killer cells has been extensively characterised, however the effect of MSC...
Mesenchymal stromal cells (MSC) have well defined immunomodulatory properties including the suppression of lymphocyte proliferation and inhibition of dendritic cell (DC) maturation involving both cell contact and soluble factors. These properties have made MSC attractive candidates for cellular therapy. However, the mechanism underlying these chara...
Stem cell-based therapies are promising candidates for immunotherapy in transplantation with the potential both to repair the transplant after injury and to modulate the immune response to allogeneic tissue. Hematopoietic stem cells (HSCs) have long been known to modulate the immune response to alloantigens and are currently being used in a number...
Treating muscle disorders poses several challenges to the rapidly evolving field of regenerative medicine. Considerable progress has been made in isolating, characterizing, and expanding myogenic stem cells and, although we are now envisaging strategies to generate very large numbers of transplantable cells (e.g., by differentiating induced pluripo...
Mesenchymal stromal (stem) cells (MSCs) continue to be a strong area of focus for academic- and industry-based researchers who share the goal of expanding their therapeutic use for diverse inflammatory and immune-mediated diseases. Recently, there has been an accelerated rate of scientific publication, clinical trial activity and commercialisation...
Type 1 diabetes mellitus is a complex autoimmune disease process encompassing a number of stages, the most significant of which is the loss of immunological tolerance and the initiation of immune dysfunction resulting in the selective destruction of pancreatic β cells. Although exogenous insulin therapy has proven efficacious, it does not address t...
Umbilical cord tissue represents a unique source of cells with potential for cell therapy applications for multiple diseases. Human umbilical tissue-derived cells (hUTC) are a developmentally early stage, homogenous population of cells that are HLA-ABC dim, HLA-DR negative, and lack expression of co-stimulatory molecules in the unactivated state. T...
Acute graft-versus-host disease (aGVHD) is a life-threatening complication following allogeneic haematopoietic stem cell transplantation (HSCT), occurring in up to 30-50% of patients who receive human leucocyte antigen (HLA)-matched sibling transplants. Current therapies for steroid refractory aGVHD are limited, with the prognosis of patients subop...
Mesenchymal stromal cells (MSCs) have recently emerged as promising candidates for cell-based immunotherapy in solid organ transplantation (SOT). In addition to immune modulation, MSCs possess proreparative properties and preclinical studies indicate that MSCs have the capacity to prolong graft survival and in some cases induce tolerance. Currently...
Mesenchymal stromal cells (MSCs) participate in repair of damaged tissues, possess the potential to serve as a
useful tool in the drug discovery field and exert immunosuppressive effects as demonstrated by their ability to modulate
the immune response. Herein, the roles played by MSC differentiation and/or production of trophic factors involved in...
Human mesoangioblasts are currently in a phase I/II clinical trial for the treatment of patients with Duchenne muscular dystrophy. However, limitations associated with the finite life span of these cells combined with the significant numbers of mesoangioblasts required to treat all of the skeletal muscles in these patients restricts their therapeut...
Acute graft-versus-host disease (aGVHD) is a life-threatening complication following allogeneic haematopoietic stem cell transplantation (HSCT), occurring in up to 30–50% of patients who receive human leucocyte antigen (HLA)-matched sibling transplants. Current therapies for steroid refractory aGVHD are limited, with the prognosis of patients subop...
Multipotent mesenchymal stromal cells (MSCs) have generated considerable interest in the fields of regenerative medicine, cell therapy and immune modulation. Over the past 5 years, the initial observations that MSCs could enhance regeneration and modulate immune responses have been significantly advanced and we now have a clearer picture of the eff...
Human mesoangioblasts are vessel-associated stem cells that are currently in phase I/II clinical trials for the treatment of patients with Duchenne muscular dystrophy. To date, little is known about the effect of mesoangioblasts on human immune cells and vice versa. We hypothesized that mesoangioblasts could modulate the function of immune cells in...
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...
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 u...
Purpose of review:
This review focuses on the immunogenicity of embryonic stem cell (ESC)-derived progenitors and the impact of the immune response on applications of cell replacement therapy (CRT). Possible strategies to induce immunological tolerance to ESC-derived progenitor cells will also be discussed.
Recent findings:
Evidence for the diff...
Mesenchymal stromal/stem cells (MSCs) possess immunomodulatory and reparative properties. Through specific interactions with immune cells that participate in both innate and adaptive responses, MSCs exposed to an inflammatory microenvironment can downregulate many immune effector functions. Clinical trials focusing on MSCs to treat graft-versus-hos...
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 stra...
Bordetella pertussis is the cause of whooping cough and responsible for 300,000 infant deaths per annum. Current vaccines require 6 months to confer optimal immunity on 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, intranasal, single-dose vaccine fo...
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 invol...
While investigating the differentiation potential of bone marrow-derived cells, we previously demonstrated upregulated expression of the lung-related surfactant protein B (SP-B) gene in hematopoietic progenitor cells (HPCs) when they were cocultured with macerated lung tissue. During coculture, HPCs differentiated toward a dendritic-like myeloid ce...
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 an...
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 inflammato...
Lipopolysaccharide (LPS) is a potent endotoxin, which produces "sickness behaviours" including loss of weight, loss of interest in food and decreased exploration. LPS has also been shown in some studies to cause deficits in various learning and memory abilities, while in others these LPS-induced learning impairments have been attributed to performa...
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 pat...
Herein we review recent data that support host tolerance of allogeneic adult mesenchymal stem cells (MSC). Evidence is emerging that donor MSC deploy a very powerful array of mechanisms that allow escape from host allogeneic responses. These mechanisms include limited expression of alloantigen by the stem cell and cell contact-dependent and -indepe...
Lipopolysaccharide (LPS) is a potent endotoxin, which produces "sickness behaviours" including loss of weight, loss of interest in food and decreased exploration. LPS has also been shown in some studies to cause deficits in various learning and memory abilities, while in others these LPS-induced learning impairments have been attributed to performa...
